close

Вход

Забыли?

вход по аккаунту

?

Cytoskeletal protein abnormalities in neurodegenerative diseases.

код для вставкиСкачать
NEUROLOGICAL PROGRESS
Cytoskeletal Protein Abnormahties
in Neurodegenerative Diseases
James E. Goldman, MD, PhD,"t and Shu-Hui Yen, PhDX
~
~~~~~
The nervous system is a rich source of filamentous proteins that assume critical roles in determining and maintaining
neuronal form and function. Neurons contain three major classes of these cytoskeletal organelles: microtubules,
intermediate filaments, and microfilaments. They also contain a variety of proteins that organize them and serve to
connect them with each other. Such major neurodegenerative diseases as Alzheimer's disease, Parkinson's disease, and
amyotrophic lateral sclerosis, as well as a variety of toxic neuropathies, are characterized pathologically by intraneuronal filamentous inclusions. Recent studies using biochemical and immunocytochemical techniques have established that these abnormalities represent disorganized states of the neuronal cytoskeleton and have determined some of
the specific molecular constituents of these inclusions. This knowledge has led to new ways of thinking about their
origins.
Goldman JE, Yen S-H: Cytoskeletal protein abnormalities in neurodegenerative diseases.
Ann Neurol 19209-223, 1986
Neurodegenerative diseases comprise a large number
of disorders characterized by loss of neurons in various
areas of the central nervous system. Besides neuronal
death, these diseases are characterized pathologically
by the formation of abnormal inclusions within nerve
cells. A number of such abnormalities, such as the
neurofibrillary tangles of Alzheimer's disease and the
Lewy bodies of Parkinson's disease, were first noted
many decades ago and still represent neuropathological
hallmarks of these disorders. While neurologists and
neuropathologists have observed these lesions for
many years and have long recognized their diagnostic
value, only recently has anything been learned about
the specific molecular composition of these structures.
Many of the most common inclusions turn out to be
closely related to the major filamentous proteins of
neurons, either representing profoundly abnormal arrangements of normal cytoskeletal structures or representing altered filamentous organelles.
Since the original histological descriptions of the
various inclusions, there have been two major phases
in our understanding of their composition. The first
occurred in the 1960s, when brain biopsies and autopsy material were examined under the electron microscope. A number of important studies revealed, for
the first time, d e n t details of structural organization
and determined the filamentous nature of many of the
abnormalities. Research and review articles at the time
naturally stressed the ultrastructural qualities of these
abnormalities, but were able to offer only conjecture
as to their composition 1117, 1397. The second phase
has taken place within the last several years, during
which time some of the molecular constituents of
these inclusions have been determined. These insights
have been made possible by our far more sophisticated
knowledge about the normal cytoskeletal elements of
neurons and by the availability of new approaches and
reagents, especially polyclonal and monoclonal antibodies to a host of cytoskeletal proteins that are being
used with great success as specific molecular probes.
Furthermore, it has been possible to begin to place
these abnormalities into a framework of neuronal cell
biology and to begin to think about how they form.
In this review, we will trace the evolution of our
knowledge of these abnormalities, summarize current
information about their composition, and provide
our perspectives on future research and on how
our knowledge may be used to illuminate abnormal
neuronal metabolism in neurodegenerative states.
From the Departments of *Pathology (Neuropathology) and
tNeuroscience, Albert Einstein College of Medicine, Bronx, N Y
10461.
Received July 10,1985, and in revised form Aug 15. Accepted for
publication Aug 16, 1985.
Address reprint requests to Drs Goldman or Yen.
Normal Cytoskeletal Elements of Neurons
Neurons, like most other cells, contain three major
polymeric protein systems that have important roles in
determining and maintaining cell shape, allowing cell
motility, and moving molecules and organelles about
within the cytoplasm. In discussing these cytoskeletal
systems and their disorders, we must consider the
three components of each system: microtubules, intermediate filaments, and microfilaments, as well as the
interconnections that link these systems together.
209
M icrotubules
Microtubules are hollow, cylindrical structures, 24 nm
in diameter. They are long, unbranched organelles
found in abundance in both axons and dendrites,
where they are oriented along the long axis of the
process, They are composed of two closely related
globular proteins, alpha and beta tubulin, with molecular weights of 54 kDa and 56 kDa. Tubulins exist in
both polymerized (microtubular) and unpolymerized
forms. The equilibrium between forms can be altered
in vitro by a number of agents, including calcium,
which depolymerizes microtubules; temperature; tubulin concentration; and drugs such as colchicine,
which depolymerizes microtubules, and taxol, which
stabilizes microtubules 1114, 115). These drugs can
also affect states of tubulin polymerization in vivo.
Microtubules interact with other organelles by way
of thin side arms. These side arms are composed of a
variety of proteins that have been termed microtubuleassociated proteins (MAPs) because they co-purify with
microtubules during several types of isolation procedures [11, 22, 1471. The major MAPs are highmolecular-weight proteins (MAPl, 350 kDa; MAP2,
270 kDa); each of these has been further divided into
subgroups on the basis of molecular weights and antigenic reactivities 1147). A group of smaller MAPs, the
tau proteins, have molecular weights in the range of 5 5
to 65 kDa 1221. MAPs also interact in vitro with
neurofilaments 179, 1101 and with actin filaments 152,
86, 113, 123). The high-molecular-weight MAPs are
phosphoproteins, substrates for a cyclic-adenosine
monophosphate (CAMP)-dependent protein kinase activity that is present in microtubule and MAP preparations from brain 1130, 141). Both CAMP-dependent
and CAMP-independent phosphorylation 1141) and
calciumlcalmodulin-dependent phosphorylation 1120)
may occur in vitro. The idea that phosphorylation may
regulate the interaction of MAPs (and therefore microtubules) with other organelles is an attractive one,
and is given some plausibility by the fact that MAP2
interactions with actin in vitro are sensitive to states of
phosphorylation 186, 1231. Studies with antibodies to
specific MAP species have indicated that neurons distribute MAPs differentially within cytoplasmic compartments. For example, MAPla, one of the very highmolecular weight proteins, and MAP2 are found
primarily in dendrites and neuronal cell bodies,
whereas MAPlb, distinguished from MAPla by
molecular weight and by immunological means, can be
detected in both axons and dendrites [9, 17, 26, 82).
Intermediate Filaments
Neurofilaments (NFs) are part of a class of
intermediate-filament (IF) proteins, all forming polymers about 10 nm in diameter 1751. Like microtubules, NFs are unbranched structures traveling
210 Annals of Neurology
Vol 19 No 3 March 1986
down the long axis of axons. NFs are predominantly
axonal organelles, although they also reside in proximal dendrites of large neurons. The density of NFs is
approximately constant over a wide range of axon diameters [38]; small axons, such as parallel fibers of the
cerebellar cortex, apparently do not contain NFs. This
observation as well as studies of regenerating axons
suggest that NFs may have a major role in determining
axonal volume 162). IF proteins show cell-type
specificity: keratin-type IFs ate found in epithelial cells;
desmin in muscle; neurofilaments in neurons; glial
fibrillary acidic protein in astrocytes, ependyma, and
some Schwann cells; and vimentin in cells of mesenchymal origin as well as immature cells of many different lineages 175). All of these IF proteins are structurally related, containing a high concentration of acidic
amino acids, and substantial alpha-helical domains separated by sequences that are less highly organized {40].
Amino acid sequences have shown a high degree of
homology among the different IF proteins, particularly
within the helical-rich portion. Carboxy-terminal ends
of the proteins vary more considerably.
Neurofilaments differ from other IFs in that they are
composed of three different proteins, with molecular
weights of approximately 70 kDa, 160 kDa, and 200
kDa 140, 41, 1161, each of which is a separate transcript. The three proteins are related, particularly the
amino-terminal portions, which contain the alpha helical domains [40,41]. The long carboxy-terminal parts
of the larger proteins do not contain alpha-helical domains, and thus appear to be different from the aminoterminal end. It is not surprising, therefore, that there
are anti-NF antibodies, both polyclonal and monoclonal, that bind to one, two, or all three NF proteins.
The various cross-reactivities of different antibodies
have been a source of confusion, and emphasize the
critical point that antibody reactivities need to be
defined as fully as possible before interpreting the results of immunocytochemical studies. There is evidence that the 70 kDa NF protein and the corresponding amino-termini of the others can form the
core of the filament, and that the long carboxy-termini
of the large NF proteins project from the filaments
I1527.
Microtubule-associated proteins bind to IFs, including NFs, in vivo and in vitro 110, 79, 957. Their interactions must be kept in mind when one considers
several pathological states in which NFs appear to be
disconnected from microtubule systems (as will be discussed later).
Unlike tubulin and actin, which exist in polymerized
and nonpolymerized forms, IFs exist largely or entirely
in polymerized form. They can be solubilized, but solubilization requires ionic detergents such as sodium
dodecyl sulfate (SDS) or other chaotropic agents.
IF proteins are phosphoproteins. The 150 kDa and
200 kDa N F components are much more highly phosphorylated than either the 70 kDa NF or the other
classes of IF proteins C68, 69, 1351. The majority of
phosphorylation sites appear to reside on NF domains
away from the alpha-helical core region. Thus, phosphorylation sites reside on parts of the N F molecules
that project from the N F core. It is likely that states of
phosphorylation may affect the interaction of NFs with
other cytoskeletal organelles. States of phosphorylation may also regulate the association of NF proteins
with each other 1162). Enzyme systems that phosphorylate and dephosphorylate NF proteins have not
been well defined. Protein kinase activity has been
isolated, along with partially purified NF proteins
11091 and partially purified microtubules and MAPS,
although what enzymatic mechanism catalyzes phosphorylation in vivo is not known exactly.
The distribution of phosphorylated and nonphosphorylated NF proteins appears to differ within a
neuron, as assessed using anti-NF monoclonal antibodies that react with phosphorylated versus nonphosphorylated epitopes C1361. Nonphosphorylated
sequences are detected in neuronal cell bodies and
proximal axons, while phosphorylated sequences are
found in axons and preterminal processes. These immunocytochemical studies do not exclude some phosphorylated sites on somal NFs, since these may be
phosphorylated epitopes that are not recognized by
the antiphosphorylated NF antibodies. What properties phosphorylation confers upon NFs remains an important question.
M icrojdaments
Microfilaments, 5 nm in diameter, are the smallest of
the major cytoskeletal filaments and are composed of
actin polymers. The central nervous system is a rich
source of proteins such as actin and myosin that have
been known for years to be the major components of
muscle contractile systems. Actin is widely distributed
within the neuron, with particular concentration of
microfilaments just beneath the plasma membrane, at
postsynaptic densities, and within dendritic spines 117,
20, 31,47, 771. Much of the actin in the brain exists in
nonfilamentous form (G, or globular actin, as opposed
to F, or filamentous actin) C131, but what determines
the equilibrium between G and F actin in neurons is
not known. In both central nervous system and noncentral nervms system cells, there are a variety of actin-binding proteins, some of which serve to polymerize actin, others to cap an end of the filament and
retard either polymerization or depolymerization, and
others to bind G actin and prevent its polymerization
18, l50}. These proteins probably have major roles in
determining polymerization states. In addition to actin,
other contractile system proteins found in the central
nervous system include myosin, tropomyosin [14, 321,
and spectrin-like molecules {4, 761. Conditions that
alter states of actin polymerization or alter the interaction of actin with binding proteins could in turn change
neuronal shape considerably, or cause the formation of
abnormal filamentous aggregates (see below).
Axonal Transport of Cytoskeletal Systems
Since a neuron’s cell body is the primary site of protein
synthesis, special mechanisms have evolved to carry
molecules into axons and dendrites. Membranous organelles are transported at fast rates, on the order of
400 mm per day in poikilotherms. Cytoskeletal proteins, in contrast, move slowly along axons. Metabolic
labeling experiments, using radioactive amino acids,
have delineated two major components to slow transport, which can be distinguished not only by their differences in rates but also by differences in the specific
molecules moving at those rates 16, 63, 1531. The
faster of the two components moves at 2 to 5 mm per
day, although rates vary somewhat among particular
nerves and species. This system includes actin, myosin,
and a variety of other proteins such as clathrin and
calmodulin 16, 12}. The slower component moves at
0.25 to 2 mm per day. This component includes all
three NF proteins. Most tubulin appears also to move
with NFs at the slower rate, but some tubulin is more
widely distributed in its transport profile. The fact that
a number of proteins in each of the slow transport
systems are transported together has been taken as
evidence for the presence of functional connections
among the individual components 161. The idea that
proteins within transport systems are linked is illustrated by the fact that such linkages can be disrupted.
Several neurotoxins, such as aluminum and p-p’iminodipropionitrile (IDPN) (as will be discussed
later) dissociate the transport of NFs from that of
tubulin.
Cytoskeletal proteins themselves are critically involved in the process of axonal transport. For example,
agents that depolymerize or disrupt microtubules or
actin filaments inhibit fast transport C45, 1213. Thus,
aberrations in cytoskeletal organization may have profound secondary consequences upon the distribution
of macromolecules throughout a neuron’s axonal and
dendritic arborization.
Neurofibrillary Tangles
Neurofibrillary tangles (NFTs), first described by Alzheimer in 1906, are argyrophilic intraneuronal inclusions found in a number of central nervous system
diseases. The most common and best studied NFTs
are composed largely of paired helical filaments (PHFs;
Fig 1A). PHFs are structurally unlike any of the normal cytoskeletal elements, being composed of pairs of
10-nm filaments that cross each other at an 80-nm
Neurological Progress: Goldman and Yen: Neuronal Cytoskeletal Abnormalities 2 11
8
Fig I. (A) Electron micrograph of paired helicalfilaments, showing the periodic crossover points (arrowheads). ( x 240,000 befire 20% reduction.)(B) Immunocytochemical staining of Alzheime#s disease hippocampus with a monoclonal antibody to
Alzheimer neurofi brillaty tangle, using a peroxidase-antiperoxidase method. In this field, neurojibrilka y tangles (arrowhead)
and thin processes react with the antibody. ( x 280 befire 20%
reduction.)
interval. The maximum width of the PHF is 20 nm,
and the minimum width is 10 nm [158]. PHFs isolated from brain tissue obtained from subjects with
Alzheimer’s disease have been shown by negative
staining with phosphotungstic acid to contain four
protofilaments of 3 to 5 nm {l55). However, morphological studies of extremely thin sections of brain
from patients with Alzheimer’s disease, showed that
PHFs may contain eight protofilaments { 159). Despite
these detailed structural studies, the molecular composition of PHFs has still not been determined (to be
discussed).
Such NETS are one of the major pathological hallmarks of Alzheimer’s disease, where they are found in
pyramidal neurons of the cerebral cortex and hippocampus and in various brainstem nuclei C24, 611.
They are not specific for Alzheimer’s disease, however, and can be found in cortical and subcortical
neurons of adults with Down’s syndrome [l61], in
brainstem nuclei of patients with postencephalitic parkinsonism 1661, in Parkinson-dementia complex of
Guam 1591, in dementia pugilistica, in neurons of rare
cases of subacute sclerosing panencephalitis and
juvenile neurovisceral lipid storage disease (1601, and
212 Annals of Neurology
VoI 19 No 3 March 1986
in small numbers of hippocampal neurons of normal
elderly people. The concentration of NFTs and
neuritic plaques in Alzheimer’s disease correlates with
the degree of cognitive impairment 17, 151). This type
of NFT exhibits green birefringence when stained with
Congo red, and green fluorescence when stained with
thioflavine S {122, 140). These are nonspecific stains,
which also bind to amyloid, and which may reflect a
prominent P-pleated sheet arrangement in NFTs. Xray diffraction analysis has indicated that PHFs are organized in a @-sheetconformation {71]. Normal NFs
do not bind these dyes. It is important to note that the
term nezlrofibrillay tangle refers to a structure seen at
the light-microscopical level and does not imply a
specific ultrastructural composition. For example,
while most NFI‘s in Alzheimer’s disease are composed
of PHFs, in some tangles straight filaments with a diameter of 15 nm are found occasionally, along with
PHFs E93, 1291.
Biochemical and immunological methods have been
used to examine the molecular structure of NFTs.
However, a major experimental problem in the biochemical analysis of NFTs isolated from brains of patients with Alzheimer’s disease (Alzheimer neurofibrillary tangles, ANTs) has been that the ANTS are
resistant to reagents known to dissolve NFs or other
normal cytoskeletal components, and are insensitive
to various proteolytic enzymes 1125, 126, 168). For
example, the ultrastructure of PHFs treated with
2% SDS is similar to that of control samples. The
insolubility can be used to advantage. A subcellular
fraction greatly enriched in PHFs can be prepared by
removing most of the contaminants with SDS. However, because of their insolubility, the resulting PHFs
cannot be analyzed readily by conventional gel electrophoresis. There is disagreement about whether
small amounts of polypeptides with molecular weights
between 45 and 72 kDa can be released from PHF
fractions after repeated sonication and extraction 1651.
Structural studies of these peptides may give important
clues to the composition of PHFs.
Recently, much work has gone into immunological
analyses, using polyclonal and monoclonal antibodies
raised against a variety of normal cytoskeletal proteins
and against enriched PHF preparations {l, 3, 39, 53,
74, 88, 98, 149, 164, 165, 1661. While most antibodies to normal proteins do not react with ANTs,
some antibodies to N F proteins, MAPS, and vimentin
do. The ANTs do not react with the antiactin or antitubulin antibodies that have been tested to date. In
some studies, not all ANTs in a given tissue section
react with these antibodies, while in others, certain
anti-NF antibodies bind to most tangles. In contrast,
essentially all ANTs react with several of the antibodies raised specifically against ANTs (to be discussed). It is conceivable that phosphorylation or other
‘
biochemical modification, such as covalent crosslinking of proteins or partial proteolysis 187, 1161, may
lead to an alteration or masking of some of the antigenic determinants to NFs and MAPs and the generation of new determinants in ANT. Covalent crosslinking between NFs and cross-linking of NFs to other
intermediate filaments have been demonstrated in
vitro 11241. The resulting structures differ from ANTs
biochemically as well as morphologically, however, although their immunological properties have not been
examined.
The antigenic determinants shared by ANTs and
NFs appear to be expressed mostly on the two highmolecular-weight N F proteins (160 kDa and 200 kDa)
11, 3, 1691. We and others 1137) have found that the
antigenic determinants are phosphorylated, and we
find such determinants located at the carboxy-terminal
part of the NF molecules. Since these anti-NF antibodies rarely bind to NFs in normal neuronal cell
bodies (as mentioned earlier), with the inference that
NFs in the neuronal cell body are less phosphorylated
than those in the axon, it is plausible that tangle accumulation may be the result of a disruption of axonal
transport or an alteration in protein kinase or phosphatase activity in the diseased neurons.
Monoclonal antibodies specific to ANTs and polyclonal antibodies to an ANT-enriched preparation
have recently been produced [l5, 53, 149, 1641. They
recognize tangles in cell bodies, stain neurites in
neuritic plaques, and bind to numerous fine neuronal
processes in brains from patients with Alzheimer’s disease in areas where abundant tangles are located (Fig
1B). These antibodies show very little reaction with
normal central nervous system tissues that are devoid
of ANTs. The binding sites in cell bodies, detected by
immunoelectronmicroscopy, are located on PHFs 115,
281. The binding sites in fine processes have not been
examined, however. Since a comparable distribution of
PHFs in fine processes has not been reported in previous morphological studies, it is possible that the antigenic determinants in the processes are on structures
that are not yet fully formed PHFs, and that the antiANT antibodies identify early changes in cytoskeletal
systems.
Anti-ANT antibodies have been used to identify
polypeptides in normal brain and in brains from patients with Alzheimer’s disease that might share amino
acid sequences with PHFs. Brain homogenates or
preparations containing a mixture of brain proteins
such as NFs, dial filament proteins, tubulin, and actin
have been separated on polyacrylamide gels by electrophoresis, transferred to nitrocellulose paper, and
then incubated with antibodies. Using this immunoblotting technique, one polyclonal and four monoclonal anti-ANT antibodies were shown to recognize
antigenic determinants unique to ANTs 1105, 149,
1641. In our studies, four additional anti-ANT monoclonal antibodies reacted with polypeptides with
molecular weights of 58 to 70 kDa that are present in
both diseased and normal brains and are soluble in a
buffer containing 50 mM Tris. A polyclonal anti-ANT
antiserum recognized SDS-soluble polypeptides with
molecular weights of 45 to 70 kDa in brains from
patients with Alzheimer’s disease. These polypeptides
are minor components of both normal and diseased
brain homogenates.
The results of biochemical and immunological studies indicate that ANTs are composed of many components, some of which share amino acid sequences with
NFs, MAP2, vimentin, polypeptides of molecular
weights 42 to 70 kDa, and perhaps other unidentified
brain proteins, but some of which are unique. The
determinants shared with normal proteins may well
mean that ANTs are initially formed from NFs and
MAPs and thus retain some of the normal amino acid
sequences. The unique antigenic determinants could
be generated either by posttranslational modification
of normal proteins such as NFs and MAPs or by synthesis of new proteins in brain from Alzheimer’s disease patients. Comparative studies of proteins synthesized in vitro by messenger ribonucleic acid from
normal and diseased brain have not detected new proteins 1112). Nevertheless, the question of how ANTs
are generated still remains a central, unresolved problem.
NFTs composed of PHFs found in diseases other
than Alzheimer’s are also recognized by anti-NF and
anti-ANT antibodies C28, 39, 1061, suggesting that the
PHFs of many diseases are similar, or identical, to
those of Alzheimer’s disease. Further analysis with
biochemical methods is necessary to arrive at firmer
conclusions.
NFTs containing bundles of 15-nm straight filaments are found in the basal ganglia, brainstem, and
deep cerebellar nuclei of patients with progressive supranuclear palsy 11341. PHFs with a periodicity longer
than the classic PHF of Alzheimer’s disease coexist
with the straight filaments in some tangles 11633. The
possibility that NFTs with different morphological
characteristics may be derived from common components has been tested by immunocytochemical staining
with antibodies that bind ANT 128, 167). These studies showed that NFTs from progressive supranuclear
palsy and Alzheimer’s disease do indeed share amino
acid sequences. Furthermore, immunoelectron microscopy revealed that the binding sites for anti-ANT antibodies are located on the 15-nm straight filaments.
Our current view is that PHFs and the straight
filaments are morphological variants constructed from
the same or related polypeptides.
PHFs with a periodicity shorter than that of classic
PHFs have been found in an aged monkey [l56], a
Neurological Progress: Goldman and Yen: Neuronal Cytoskeletal Abnormalities 2 13
Wistar-Kyoto rat 1721, wobbler mice 11561, a whip
spider 1331, and several aged Louvain Wistar rats
11481. The relationship between human and nonhuman PHFs is unknown. Because ultrastructurally distinct NFTs may share antigenic determinants, it is possible that PHFs found in non-human tissues represent
yet another morphological variant of human PHFs.
,
Pick Bodies
Pick bodies are round, cytoplasmic inclusions characteristic of Pick‘s disease 116, 100, 1541. The lesions
appear most abundantly in the cerebral cortex but are
also found in basal ganglia and other subcortical structures. They contain aggregates of straight filaments of
various diameters ranging from 10 to 20 nm 11071. In
some cases, the filaments are admixed with granular
material; in others, PHFs with a periodicity longer than
that of classic PHFs are found in the same inclusion
with straight filaments. Immunocytochemical studies
have revealed the presence of N F antigens in Pick
bodies 128, 39,84, 104). Those Pick bodies containing
filaments coated with granular material appear less
reactive with anti-NF antibodies and with silver stain
than those containing PHFs 1841. Whether the antibody binding site or sites were inaccessible to the antibody because of the coating is unknown. Crossreactivity of Pick bodies with a commercially available
antitubulin antiserum has also been observed @4}.
However, this antiserum, in addition to tubulin, reacts
with MAPS and many other polypeptides on immunoblots Of a crude microtubule fraction (19” and
Our
observations). Further studies with
antibodies to pure antigens are necessary in order
to establish the nature of the antigen detected by
the “antitubulin antiserum.” Antigenic determinants
unique to ANTS have recently been found in some
Pick bodies as well 128, 1061. It is possible that these
inclusions belong to the type that contains paired helical filaments.
Lewy Bodies
Lewy bodies are round cytoplasmic inclusions characteristic of idiopathic Parkinson’s disease. Lewy bodies
are most prominent in the substantia nigra, but are also
often found in a number of other brainstem nuclei,
especially in aminergic systems, and in the substantia
innominata, where Lewy first described them 127, 34,
80, 81, 91). Like many of the other inclusions discussed in this report, Lewy bodies can be found in
small numbers in the central nervous system of people
who are apparently normal neurologically. Similar inclusions can be found in the Guamanian and familial
forms of amyotrophic lateral sclerosis 135, 60, 138).
Ultrastructural studies in the 1960s and 1970s revealed that Lewy bodies are composed of masses of
filaments 129, 36, 1081. The filaments, which are
214
Annals of Neurology
Vol 19 No 3
March 1986
A
Fig 2. (A) Immunocytochemicalreaction of a Lewy body in the
substantia nigra with an antineurofilament antibody. Staining
of axons in the surrounding neuropil is also present. ( x 520.)
(B) Immunocytochemicalreaction of a neocortical Lpwy body with
the same antineurofilament antibody, ( x 520,)
straight and unbranched, measure about 8 nm, a size
that places them within the category of IFs. At the
periphery of the inclusion, the filaments are arranged
radially; in the central zone, the filaments appear more
randomly organized and are admixed with dense
granular and membranous material.
Immunocytochemical studies have shown the presence of N F antigens in Lewy bodies 128, 37, 491 (Fig
2A). In our studies, four different polyclonal antisera
to NFs and two monoclonal antibodies, which recognize the 160 kDa and 200 kDa proteins, bound to
Lewy bodies. An antibody to actin and several antibodies that bind to NFTs did not react. Thus Lewy
bodies share some antigenic determinants with normal
NFs, and, given their appearance, are likely to be composed of NFs. Although Lewy bodies and NJTs can
form in the same neuron [59, 1441, it is likely that the
mechanisms that generate the two abnormalities are
different.
Why Lewy bodies form in the neuronal perikaryon
is not known. A reasonable assumption is that the ex-
port of NFs is interfered with, although the fact that
Lewy bodies do not resemble the NF accumulations in
toxic neuropathies suggests that whatever mechanisms
interfere with the axonal transport of NFs in those
disorders do not apply in Parkinson’s disease.
Intraneuronal inclusions similar to Lewy bodies have
been noted in large numbers in the neocortex and
diencephalon of a few individuals. The clinical histories
of patients with this diffuse type of Lewy body formation characteristically include parkinsonian signs and
symptoms and usually, but not always, dementia 173,
921. The distribution of inclusions differs from patient
to patient, but involves the cerebral cortex, hippocampus, basal ganglia, diencephalon, and brainstem, including the substantia nigra. Although senile plaques
and NFTs can be observed in these brains, they are not
always present, or are present in small numbers. Cortical Lewy bodies react with the same anti-NF antisera
that recognize the nigral inclusions 1491 (Fig 2B). It is
possible that the cortical Lewy bodies are formed by
mechanisms similar to those responsible for the generation of Lewy bodies in the brainstem.
Neurofilament Accumulations
Apparently normal NFs accumulate in neuronal
perikarya and processes in a variety of conditions.
These include amyotrophic lateral sclerosis 118, 581,
animal models of motor neuron disease 1231, and giant
axonal neuropathy 11031. They also include both human and animal neuropathies induced by toxic agents
(as will be discussed). These accumulations are composed of large bundles or swirls of filaments, some
oriented longitudinally along axons (Fig 3A); others
are organized in oblique, interwoven skeins. The
filaments themselves appear ultrastructurally to be normal NFs. Thus, these accumulations are unlike the
tangles made up of PHFs or 15-nm straight filaments,
and are unlike Lewy or Pick bodies. Filament aggregates in amyotrophic lateral sclerosis react with antiNF antibodies (Fig 3B), but not with anti-ANT antibodies 1281. The cause of these abnormalities in motor
neuron disease is not known, although studies of experimental models have shed some light on what may
be common mechanisms.
Giant axonal neuropathy is characterized pathologically by the accumulation of masses of IFs in many
cell types, including neurons 12, 1031. Both the central
nervous system and peripheral nervous system contain
swollen axons filled with NFs. The possibility that this
disease represents a disorder in cytoskeletal system interactions has been raised by the observation that giant
axonal neuropathy fibroblasts in vitro contain juxtanuclear coils of IFs 1971. Similar, if not identical, coils
can be induced in many cultured cells by colchicine, a
drug that depolymerizes microtubules 1101. The loss
of the microtubule system thus has important conse-
A
B
Fig 3. (A) Parallelaways of neurofilamentscourse along an axonal spheroid from the spinal anterior horn of a patient with
familial amyotrophic (atera1sclerosis (ALS).{ x 8,000.) (Reprinted from Hirano et al:J Neuropathol Exp Neurol43:471,
1984.) (B) lmmunocytochemical reaction of axonal spheroids in
familial ALS with an antineurofilamentantibody. The section
was counterstained with hematoxylin. ( x 360.)
quences for the organization of IF systems. Furthermore, IF coils induced by colchicine contain MAP2
antigens 1101, suggesting that some of the MAPS serve
to link microtubules with IFs, and will bind to and
distribute with IFs if the microtubule system is impaired.
Masses of 10-nm filaments accumulate in neuropathies resulting from exposure to neurotoxic hexacarbons 183, 111, 131, 1321, carbon disulfide 196,
1281, and acrylamide 178, 1021, and in experimental
disorders induced by aluminum 1145, 1571, IDPN
[2l, 511, or maytansine 1421. The site of accumulation
within neurons differs depending on the chemical, the
dose, and the route of administration. While administration of IDPN or aluminum salts results in proximal
axonal enlargement, other chemicals produce changes
in the distal segment of the axons. The cause of NF
accumulations appears to be related to alterations in
axonal transport and to the dissociation of NFs from
other cytoskeletal proteins, resulting in a physical sep-
Neurological Progress: Goldman and Yen: Neuronal Cytoskeletal Abnormalities 2 15
aration of NFs from other elements. Thus, IDPN and
aluminum impair axonal transport of NFs { 5 , 51, 1701,
but do not affect fast transport or the movement of
tubulin and actin. Ultrastructural studies of IDPNinduced disease have shown a lateral segregation of
organelles within axons, with NFs accumulating in a
subcortical ring surrounding a central channel of microtubules, mitochondria, and smooth endoplasmic reticulum. A similar cytoskeletal segregation can be produced in the peripheral nervous system by hexacarbon
1501.
The 10-nm filaments found in neurotoxin-induced
lesions bind NF antibodies {25, 43, 1271, but do not
bind monoclonal anti-ANT antibodies 1281. Furthermore, bundles of filaments isolated from anterior horn
cells of aluminum-treated animals contain proteins
with molecular weights identical to those of normal
NF proteins E1271. It is thus likely that the filamentous
accumulations are made up of NFs. Whether these
NFs have been somehow altered is not known. Aluminum-induced NF accumulations bind monoclonal antibodies that react with phosphorylated epitopes on NFs
[28, 1467. This was an unexpected finding as antibodies that recognize phosphorylated NFs ordinarily
do not bind well to neuronal cell bodies or proximal
axons 11361.
The biochemical basis of the segregation of cytoskeletal elements is uncertain. Direct intermolecular
crosslinking of NFs, or alteration of the physiochemical properties of NF proteins leading to strong NFNF interactions, has been suggested. Toxic agents may
also disrupt normal interactions between NFs and
other cytoskeletal systems, in some way removing NFs
from transport mechanisms. In view of the fact that
NFs and MAPS are highly phosphorylated proteins,
and given the interactions between different cytoskeletal systems described earlier, it is conceivable that
neurotoxic agents may produce cytoskeletal deformation by means of their direct or indirect interference
with protein phosphorylation. Thus, a comparison of
protein phosphorylation under both normal and
neurotoxic or other neuropathological conditions may
reveal some clues concerning the biochemical mechanisms underlying neurofibrillary abnormalities. A recent study of IDPN neuropathy 1951 showed that a
MAP2 antigenic determinant was found with the NFs
at the axonal periphery but not with the microtubules
located at the center of the axons. This observation is
reminiscent of the MAP localization to IF coils after
colchicine treatment 1101 and further indicates an abnormal cytoskeletal segregation.
Contractile Protein Abnormalities
Rod-shaped, eosinophilic inclusions, or Hirano bodies,
represent a cytoskeletal abnormality that is composed
at least in part of actin filaments {46]. These inclusions
216 Annals of Neurology Vol 19 No 3 March 1986
were first described in the brains of patients with
amyotrophic lateral sclerosidParkinson’s disease complex on Guam [551, but have been described in Alzheimer’s and Pick‘s disease, amyotrophic lateral
sclerosis, and kuru, as well as in the brains of
neurologically normal individuals 130, 44, 903. Their
numbers increase with the age of the patient, and they
are particularly prevalent in Alzheimer’s disease 1443.
In the human central nervous system, Hirano bodies
generally show a more restricted distribution than do
NFTs. Most are found in Sommer’s sector of the hippocampus, in the underlying stratum lacunosum, and
in the subiculum. They have also been described in
cortex, cerebellum, and anterior horns. In the hippocampus, Hirano bodies lie primarily in dendrites.
Unlike NFT’s, Hirano bodies are not restricted to
neurons but can be found in glial cells in both the
central and peripheral nervous system {19, 56, 67,
1331.
Hirano bodies are composed of a latticework of thin
filaments {57, 118, 1191 (Fig 4). The basic units are
sheets of parallel filaments that cross each other at
oblique angles. The filaments of two adjacent sheets
appear to touch at about 25-nm intervals. Depending
upon the angle of viewing, the inclusions can appear as
cross-hatched lattices, rows of parallel filaments, or
beads on a string. These various appearances can be
observed in the same area of the inclusion if the specimen is tilted in the electron microscope 199, 1431. The
filaments themselves have been reported as measuring
6 to 10 nm. However, thin profiles, the size of
microfilaments, have been noted at the ends of Hirano
bodies and in contiguity with the inclusions 11191.
Application of immunocytochemistry with a variety
of cytoskeletal protein antibodies has revealed the
presence of actin, but not myosin, neurofilament proteins, or tubulin {461. None of the anti-NFT antibodies we have used has reacted with Hirano bodies.
The contention that they are composed of ribosomes
lying on membranes 1891 seems not to have merit in
view of recent immunocytochemical and ultrastructural studies.
There is a murine mutant, brindled (Mob‘), characterized by a deficiency in copper metabolism (641, in
which Hirano bodies are formed during neuronal degeneration {851. Mob‘ Hirano bodies, which are found
in dendrites of Purkinje cells and in neocorrical and
hippocampal neurons, appear structurally identical to
those in human brain. They also react with an antiactin
antiserum at both the light and electronmicroscopic
level 1991. We have observed Hirano body formation
in its early stages, a process characterized by one or
two strands of the lattice surrounded by randomly
oriented thin filaments in a granular matrix within the
dendritic cytoplasm. In some neurons, particularly cortical cells, skeins of filaments are formed without the
Fig 4. Electronmicrograph of an Hirano body in brindled mouse
central nervous system. Two views are present in this micrograph: parallel sheets of filaments (center)and cross-hatched latticework (ends).( x 40,000.)
fully formed latticework. Besides the formation of
Hirano bodies, other important structural changes occur in the dendrites. Microtubules disappear, membrane systems become disorganized, and the dendrites
change shape dramatically. Our current point of view is
that Hirano bodies form in at least two stages. The first
involves rearrangement of the normal F-actin within
the neuron, andor a shift in the G to F actin equilibrium, which promotes polymerization. The second
stage involves the further organization of filaments into
regular latticeworks. Furthermore, whatever alters actin organization also depolymerizes microtubules. The
marked changes in dendritic shape may well be secondary to changes in cytoskeletal protein organization.
Several other neuronal inclusions that to date have
been less carefully scrutinized than those described
above have recently been discovered to contain cytoskeletal elements. Filamentous inclusions of a paracrystalline nature in caudate and nigral neurons contain
actin 1481. The presence of these bodies is of no
known pathological significance 170). Intranuclear
masses of 10-nm filaments are the characteristic cellular change of a rare neurodegenerative disorder [54].
Biochemical and immunocytochemical evidence indicates that these so-called intranuclear hyaline bodies
are NFs {941. How NFs accumulate in nuclei remains
a mystery. Granulovacuolar degeneration is an abnormality present in hippocampal neurons of patients with
Alzheimer’s disease [142]. A recent immunocytochemical study has reported binding of an antitubulin
antibody to granulovacuolar change [1011. This observation is the first to note the presence of tubulin antigen, or antigens, in an abnormal inclusion.
Future Research
Major advances in our understanding of cellular
neuropathology have occurred in the last few years.
Progress has been the result of the rapidly expanding
knowledge of neuronal cytoskeletal proteins and of
recent technical progress, notably the use of specific
polyclonal and monoclonal antibodies as probes for
specific molecular structures. Immunological methods
will continue to be used. For example, the generation
of monoclonal antibodies to specific domains of cytoskeletal proteins will allow a more detailed evaluation
of which specific antigens are present in abnormal inclusions. Care must be taken to define antigenic reactivities and cross-reactivities in interpreting purely
immunocytochemical results. New knowledge of cytoskeletal protein interactions and how posttranslational modifications, such as phosphorylation or proteolysis, may alter such interactions will be important.
Further studies on experimental and hereditary animal
models in which cytoskeletal abnormalities are produced will allow insights into early stages of cytoskeletal disorganization. We also predict that future
biochemical studies will focus on the isolation and di-
Neurological Progress: Goldman and Yen: Neuronal Cytoskeletal Abnormalities 2 17
Cytoskeletal Abnomlities”
Abnormality
Conditions Where Found
Composition (partial)
Neurofibrillary tangles
Alzheimer’s disease
Down’s syndrome
Progressive supranuclear palsy
Postencephalitic Parkinson’s disease
Parkinsoddementia of Guam
Dementia pugilistica
Dystonic lipidoses
Normal aging
Pick‘s disease
PHFs andor straight 10 to 15-nm
filaments; antigens in common with NFs,
MAPS, plus unique antigens
Pick bodies
Lewy bodies
Cortical Lewy bodies
NF accumulations
Intranuclear “hyaline”
inclusions
Hirano bodies
Rod-shaped inclusions in
caudate and substantia nigra
Granulovacuolar change
Parkinson’s disease
Parkinson’s disease with or without
dementia
Amyotrophic lateral sclerosis
Animal models of motor neuron
disease
Toxic neuropathies (e.g., IDPN,
CS2,aluminum, hexacarbons)
lntranuclear hyaline inclusion
d‘isease
Alzheimer’s disease
Amyotrophic lateral sclerosis
Glial cells in axonopathies
Brindled mouse (copper deficiency)
N o known significance
Alzheimer’s disease
Normal aging
10 to 20-nm filaments plus PHFs; react
with NF antibodies
10-nm filaments; react with NF antibodies
10-nm filaments; react with NF antibodies
NFs
NFs
Latticework of thin filaments; react with
actin antibodies
Paracrystalline, thin filaments; react with
actin antibody
Reacts with tubulin antibody
T h e table gives conditions in which the various abnormalities may be found, but is not meant to be fully inclusive. Compositions are summarized
by giving major ultrastructural features and what is known about biochemical properties and antibody reactivities. The full compositions of the
inclusions and mechanisms of genesis are not yet known.
NF = neurofilament; MAP = microtubule-associated protein; PHF = paired helical filament; IDPN = p-p’-iminodipropionitrile;CS2 =
carbon disulfide.
rect characterization of cytoskeletal inclusions and on
in vitro studies with isolated cytoskeletal proteins to
study directly any possible interactions between toxins
and filament systems and to attempt to generate some
of the abnormalities.
Conclusions
Many of the prominent cellular changes in major
neurodegenerative diseases represent alterations in cytoskeletal proteins (Table).
In conditions such as amyotrophic lateral sclerosis,
certain toxic neuropathies, giant axonal neuropathy,
and Parkinson’s disease, NFs accumulate in cell bodies
or along axons. It is likely that NF proteins are synthesized by neurons, but then are not exported from the
perikarya or transported properly along axons. While
there may be many reasons for these abnormalities, we
might consider two general explanations to account for
common features. The first is that NFs are modified so
218 Annals of Neurology
Vol 19 No 3 March 1986
that they can no longer move into or along axons. Such
modification could include direct cross-linking by toxins, phosphorylation, partial proteolysis, or other posttranslational modifications. The second is that NFs are
not themselves altered but that the interconnections
that associate them with other cytoskeletal systems,
particularly microtubules, are interrupted. Some combination of both ideas is also possible.
In some conditions, such as Alzheimer’s disease, abnormal accumulations of contractile proteins (Hirano
bodies) occur. They may arise from local changes in
dendrites that promote microtubule depolymerization
and shifts in the equilibrium between monomeric and
polymeric actin. Such changes in the dendritic cytoskeleton are accompanied by profound changes in
dendritic size and shape.
In Alzheimer’s disease, Pick‘s disease, progressive
supranuclear palsy, Down’s syndrome, and a variety of
other disorders, filaments accumulate in NFTs that
contain amino acid sequences of NFs and MAPS, but
that also have new properties, not present in normal
cytoskeletal systems. These new properties are likely
to be generated by posttranslational modification of
normal structures, but it is not yet clear how this
occurs.
None of these abnormalities is itself the underlying
cause of a given neurological disease, but rather a
reflection of the disease. Nevertheless, cytoskeletal abnormalities are well worth studying because understanding how they form will provide important insights
into how neuronal metabolism changes in these conditions. Furthermore, since cytoskeletal elements are
critically involved in maintaining cell shape and in axonal transport processes, the disorganization of a
neuron’s cytoskeleton will in turn have profound consequences on neuronal function.
Supported in part by United States Public Health Service Grants
NS17125, AG05386, AG01136, AG04145, and TeacherInvestigator Award NS00524 (Dr Goldman).
We thank Drs Asao Hirano and Kmuko Suzuki for electron micrographs and Mrs Marilyn Sass0 for secretarial assistance.
References
1. Anderton BH, Breinhurg D, Downes MJ, et al: Monoclonal
antibodies show that neurofihrillary tangles and neurofilaments
share antigenic determinants. Nature 298:84-86, 1982
2. Ashury AK, Gale MK, Baringer JR, Berg BO: Giant axonal
neuropathy-a unique case with segmental neurofilamentous
masses. Acta Neuropathol (Berl) 20:237-247, 1972
3. Audio-Gambetti L, Gamhetti P, Crane RC: Paired helical
filaments: relatedness to neurofilaments shown by silver staining and reactivity with monoclonal antibodies. In Katzman R
(ed): Biological Aspects of Alzheimer’s Disease. Vol 15, Banbury Report. Cold Spring Harbor, NY: Cold Spring Harbor
Laboratory, 1983, pp 117-124
4. Bennett V, Davis J, Fowler WE: Brain spectrin, a membraneassociated protein related in structure and function to erythrocyte spectrin. Nature 299:126-131, 1982
5. Bizzi A, Crane RC, Autilio-Gamhetti L, Gamhetti P: Aluminum effect on slow axonal transport: a novel impairment of
neurofilament transport. J Neurosci 4:722-731, 1984
6. Black MM, Lasek RJ: Slow components of axonal transport:
two cytoskeletal networks. J Cell Biol 86:616-623, 1980
7. Blessed G, Tomlinson BE, Roth M: The association between
quantitative measures of dementia and of senile change in the
cerebral gray matter of elderly subjects. Br J Psychiatry
114:797-811, 1968
8. Blikstad I, Sundkrist I, Eriksson S: Isolation and characterization of profilactin and profilin from calf thymus and brain. Eur
J Biochem 105:425-433, 1980
9. Bloom GS, Schoenfeld TA, Vallee RB: Widespread distribution of the major polypeptide component of MAP1 (microtuhule-associated protein 1) in the nervous system. J Cell
Biol 98:320-330, 1984
10. Bloom GS, Vallee RB: Association of microtuhule-associated
protein 2 (MAP2) with microtubules and intermediate
filaments in cultured brain cells. J Cell Biol 96:1523-1531,
1983
11. Borisy GG, Marcum JM, Olmsted JB, et d.Purification of
tuhulin and associated high molecular weight proteins from
porcine brain and characterization of microtubule assembly in
v i m . Ann N Y Acad Sci 253:107-132, 1975
12. Brady ST, Lasek RJ: Axonal transport: a cell-biological method
for studying proteins that associate with the cytoskeleton.
Meth Cell Biol 25(Part B):365-398, 1982
13. Bray D, Thomas C: Polymerized actin in fibroblasts and brain.
J Mol Biol 105:527-544, 1976
14. Bretscher A, Weber K: Tropomyosin from bovine brain contains two polypeptide chains of slightly different molecular
weights. FEBS Lett 85:145-148, 1978
15. Brion JP, Couck AM, Dassareiro E, Flament-Durand J:
Neurofibrillary tangles of Alzheimer’s disease: an immunohistochemical study. J Submicrosci Cytol 17:89-96, 1985
16. Brion S, Mikol J, Psimaras A: Recent findings in Pick‘s disease.
Neuropathol 2:42 1-45 2, 1973
17. Caceres A, Payne MR, Binder LI, Steward 0: Immunohistochemical localization of actin and microtubule-associated
protein MAP2 in dendritic spines. Proc Natl Acad Sci USA
80:1738-1742, 1983
18. Carpenter S: Proximal axonal enlargements in motor neuron
disease. Neurology (Minneap) 18:842-85 1, 1968
19. Cavanagh JB, Blakemore WF, Kyu MH: Fihrillary accumulations in oligodendroglial processes of rats subjected to portacaval anastomosis. J Neurol Sci 14:143-152, 1971
20. Chang CM, Goldman RD: The localization of actin-like fibers
in cultured neurohlastoma cells as revealed by heavy meromyosin binding. J Cell Biol 57:867-874, 1973
21. Clark AW, Griffin JW, Price D L The axonal pathology in
chronic IDPN intoxication. J Neuropathol Exp Neurol 39:425 5 , 1980
22. Cleveland DW, Hwo S-Y, l r s c h n e r MW: Purification of tau,
a microtubule-associated protein that induces assembly of microtuhules from purified tubulin. J Mol Biol 116:207-225,
1977
23. Cork LC, Griffin JW, Munnell JF, et ak Hereditary canine
spinal muscular atrophy. J Neuropathol Exp Neurol 38:209221, 1979
24. Curcio CA, Kamper T: Nucleus raphe dorsalis in dementia of
the Alzheimer type: neurofihrillary changes and neuronal
packing density. J Neuropathol Exp Neurol 43:359-368,
1984
25. Dahl D, Nguyen BT, Bignami A: Ultrastructural localization
of neurofilament proteins in aluminum-induced neurofihrillary
tangles and rat cerebellum by immunoperoxidase labelling.
Develop Neurosci 5:54-63, 1982
26. DeCamilli P, Miller PE, Navone F, et al: Distribution of microtuhule-associated protein 2 in the nervous system of the rat
studied by immunofluorescence. Neurosci 11:819-846, 1984
27. Den Hartog Jager WA, Bethlem J: The distribution of Lewy
bodies in the central and autonomic nervous systems in
idiopathic paralysis agitans. J Neurol Neurosurg Psychiatry
23:283-290, 1980
28. Dickson DW, Kress Y, Crowe A, Yen S-H: Monoclonal antibodies to Alzheimer neurofihrillary tangles (ANT). 2. Demonstration of a common antigenic determinant between ANT
and neurofihrillary degeneration in progressive supranuclear
palsy. Am J Pathol 120:292-303, 1985
29. Duffy PE, Tennyson VM: Phase and electron microscopic observations of Lewy bodies and melanin granules in the suhstantia nigra and locus ceruleus in Parkinson’s disease. J
Neuropathol Exp Neurol 24:398-414, 1965
30. Field EJ, Mathews JD, Raine CS: Electron microscopic ohservations on the cerebellar cortex in kuru. J Neurol Sci 8:209224, 1969
3 1. Fitkova E, Delay RJ: Cytoplasmic actin in neuronal processes
Neurological Progress: Goldman and Yen: Neuronal Cytoskeletal Abnormalities
2 19
as a possible mediator of synaptic plasticity. J Cell Biol
95:345-350, 1982
32. Fine RE, Blitz AL: A chemical comparison of tropomyosins
from muscle and non-muscle tissues. J Mol Biol 95:447-454,
1975
33. Foelix RF, Hanser M: Helically twisted filament in giant
neurons of whip spider. Eur J Cell Biol 19:303-306, 1979
34. Forno LS: Concentric hyaline intraneuronal inclusions of Lewy
tape in the brains of elderly persons (50 incidental cases): relationship to parkinsonism. J Am Geriatr SOC17:557-575, 1969
35. Forno LS, Barbour PJ, Norville RL: Presenile dementia with
Lewy bodies and neurofibrillary tangles. Arch Neurol35:818822, 1978
36. Forno LS, Norville R L Ultrastructure of Lewy bodies in the
stellate ganglion. Acta Neuropathol (Berl) 34:183-197, 1976
37. Forno LS, Strefling AM, Sternberger LA, et al: Immunocytochemical staining of neurofibrillary tangles and the periphery
of Lewy bodies with a monoclonal antibody to neurofiiaments
(abstract). J Neuropathol Exp Neurol 42:342, 1983
38. Friede RL, Samorajski T: Axon caliber related to neurofilaments and microtubules in sciatic nerve fibers of rats and
mice. Anat Rec 167:379-388, 1970
39. Gambetti P, Shecket G, Ghetti B, et al: Neurofibrillary change
in human brain: an immunocytochemical study with neurofilament antiserum. J Neuropathol Exp Neurol 42:69-79,
1983
40. Geisler N , Fischer S, Vandekerckhore J, et al: Proteinchemical characterization of NF-H, the largest mammalian
neurofilament component; intermediate filament-type sequences followed by a unique carboxy-terminal extension.
EMBO J 4:57-63, 1985
41. Geisler N , Plessmann U, Weber K The complete amino acid
sequence of the major mammalian neurofilament protein
(NF-L). FEBS Lett 182:475-478, 1985
42. Ghetti B: Induction of neurofibrillary degeneration following
treatment with maytansine in vim Brain Res 1639-19, 1979
43. Ghetti B, Autilio-Gambetti L, Gambetti P: Immunocytochemical characterization of the neurofibrillary tangles in maytansine
encephalopathy (abstract). J Neuropathol Exp Neurol 40:313,
1981
44. Gibson PH, Tomlinson BE: Numbers of Hirano bodies in the
hippocampus of normal and demented people with Alzheimer’s disease. J Neurol Sci 33:199-206, 1977
45. Goldberg DJ: Microinjection into an identified axon to study
the mechanism of fast axonal transport. Proc Natl Acad Sci
USA 79~4818-4822, 1982
46. Goldman JE: The association of actin with Hirano bodies. J
Neuropathol Exp Neurol 42:146-152, 1983
47. Goldman JE: Immunocytochemical studies of actin localization
in the central nervous system. J Neurosci 3:1952-1962, 1983
48. Goldman JE, Horoupian DS: An immunocytochemical study
of intraneuronal inclusions of the caudate and substantia nigra:
reaction with an anti-actin antiserum. Acta Neuropathol (Berl)
58:300-302, 1982
49. Goldman JE, Yen S-H, Chiu F-C, Peress N: Lewy bodies of
Parkinson’s disease contain neurofilament antigens. Science
22111082-1084, 1983
50. Griffin JW, Fahnestock KE, Price DL, Cork LC: Cytoskeletal
disorganization induced by local application of p-p’iminodipropionirrile and 2,s-hexanedione. Ann Neurol 14:
55-61, 1983
5 1. Griffin JW, Hoffman PN, Price D L Axonal transport in p-p‘iminodipropionitrile neuropathy. In Weiss DG, Gorio A (eds):
Axoplasmic Transport in Physiology and Pathology. Berlin:
Springer-Verlag, 1982, pp 109-1 18
52. Griffith L, Pollard TD: Evidence for actin filament-microtubule
interaction mediated by microtubule-associated proteins. J Cell
Biol 78:958-965, 1978
220 Annals of Neurology Vol 19 No 3 March 1986
53. Grundke-Iqbal I, Jqbal K, Tung Y-C, Wisniewski HM: Alzheimer paired helical filaments: immunochemical identification
of polypeptides. Acta Neuropathol (Berl) 62:259-267, 1984
54. Haltia M, Somer H , Palo J, Johnson WG: Neuronal intranuclear inclusion disease in identical twins. Ann Neurol 15:316321, 1984
55. Hirano A: Pathology of amyotrophic lateral sclerosis. In Gajdusek DC, Gibbs CJ (eds): Slow, Latent, and Temperate Infections. NINDB Monograph N o 2. Washington, DC: National
Institutes of Health, 1965, pp 3-37
56. Hirano A, Dembitzer HM: Eosinophilic rod-like structures in
myelinated fibers of hamster spinal roots. Neuropathol Appl
Neurobiol 2:225-232, 1976
57. Hirano A, Dembitzer HM, Kurland LT, Zimmerman HM:
The fine structure of some intraganglionic alterations. J
Neuropathol (Berl) 2 8:365 -3 66, 1968
58. Hirano A, Donnenfield H , Sasaki S, Nakano I: Fine structural
observation of neurofilamentous changes in amyou-ophic lateral sclerosis. J Neuropathol Exp Neurol 43:461-470, 1984
59. Hirano A, Malamud N, Elizan TS, Kurland L T Amyotrophic
lateral sclerosis and Parkinsonism-dementia complex on
Guam. Arch Neurol 15:35-51, 1966
60. Hirano A, Nakano I, Kurland LT, et al: Fine structural study
of neurofibrillary changes in a family with amyotrophic lateral
sclerosis. J Neuropathol Exp Neurol 43:47 1-480, 1984
61. Hirano A, Zimmerman HM: Alzheimer’s neurofibrillary
changes: a topographic study. Arch Neurol 7:73-88, 1962
62. Hoffman PN, Griffin JW, Price DL Control of axonal caliber
by neurofilament transport. J Cell Biol 99:705-714, 1984
63. Hoffman PN, Lasek RJ: The slow component of axonal transport: identification of major structural polypeptides of the
axon and their generality among mammalian neurons. J Cell
Biol 66:351-366, 1975
64. Hunt DM: Primary defect in copper transport underlies
mottled mutants in the mouse. Nature 249:852-854, 1974
65. Iqbal K, Zaidi T, Thompson CH, et al: Alzheimer paired helical filaments: bulk isolation, solubility, and protein composition. Acta Neuropathol (Berl) 62:167-177, 1984
66. Ishii T, Nakamura Y Distribution and ultrastructure of Alzheimer’s neurofibrillary tangles in postencephalitis parkinsonism of Economo type. Acta Neuropathol (Berl) 55:59-62,
1981
67. Jacobs JM, Cavanagh JB: Aggregations of filaments in
Schwann cells of spinal roots of the normal rat. J Neurocytol
1:161-167, 1973
68. Jones SM, Williams RC Jr: Phosphate content of mammalian
neurofilaments. J Biol Chem 257:9902-9905, 1982
69. Julien J-P, Mushynski WE: The distribution of phosphorylation sites among identified proteolytic fragments of mammalian neurofilaments. J Biol Chem 258:4019-4025, 1983
70. Kawano N, Horoupian DS: Jntracyroplasmic rod-like inclusions in caudate nucleus. Neuropathol Appl Neurobiol 7 307314, 1981
71. l r s h n e r DA, Abraham C, Selkoe DJ: Structure of Alzheimer
paired helical filaments by x-ray diffraction (abstract). Trans
Am SOCNeurochem 16:142, 1985
72. &ox CA, Yates RD, Chen J-L: Brain aging in normotensive
and hypertensive strains of rats. Acta Neuropathol (Berl)
52:7-15, 1980
73. Kosaka K, Yoshimura M, Iheda K, Budka H : Diffuse type of
Lewy body disease: progressive dementia with abundant cortical Lewy bodies and senile changes of varying degree-a new
disease? Clin Neuropathol 3:185-192, 1984
74. Kosik K, Duffy LK, Dowling MM, et al: Microtubuleassociated protein 2: monoclonal antibodies demonstrate the
selective incorporation of certain epitopes into Alzheimer
neurofibrillary tangles. Proc Natl Acad Sci USA 81:79417945, 1984
75. Lazarides E: Intermediate filaments as mechanical integrators
of cellular space. Nature 283249-256, 1980
76. Lazarides E, Nelson WJ: Erythrocyte form of spectrin in cerebellum: appearance at a specific stage in the terminal differentiation of neurons. Science 222:93 1-933, 1983
77. LeBeaux YJ, Willemot J: An ultrastructural study of the
microfilaments in rat brain by means of E-FTA staining and
heavy meromyosin labeling. 11. The synapses. Cell Tissue Res
160:37-68, 1975
78. LeQueene DM: Acrylamide. In Spencer PS, Schaumburg H H
(eds): Experimental and Clinical Neurotoxicology. Baltimore:
Williams & Wilkins, 1980, pp 309-324
79. Leterrier J-F, Liem RKH,Shelanski ML: Interactions between
neurofilaments and microtubule-associated proteins: a possible
mechanism for intraorganellar briding. J Cell Biol 95932986, 1982
80. Lewy FH. Paralysis agitans. I. Pathologische Anatomie. In
Lewandowsky M (ed): Handbuch der Neurologie. Berlin:
Springer, 1912, pp 920-933
81. Lpkin LE: Cytoplasmic inclusions in ganglion cells associated
with parkinsonian states. Am J Pathol 35:1117-1133, 1959
82. Matus A, Bernhardt R, Hugh-Jones T: High molecular weight
microtubule-associated proteins are preferentially associated
with dendritic microtubules in brain. Proc Natl Acad Sci USA
78:3010-3014, 1981
83. Monaco S, Wongmongkolrit T, Sayre LM, et ak Giant axonopathy in 3-methyl-2,5-hexanedione:
effect on morphology
and slow axonal transport (abstract). J Neuropathol Exp
Neurol 43:304, 1984
84. Munoz-Garcia D, Ludwin S K Classic and generalized variants
of Pick‘s disease: a clinicopathological, ultrastructural, and immunocytochemical comparative study. Ann Neurol 16:467480, 1984
85. Nagara H, Yakajima K, Suzuki K: An ultrastructural study of
the cerebellum of the brindled mouse. Acta Neuropathol
(Berl) 52:41-50, 1980
86. Nishida E, Kuwaki T, Sakai H: Phosphorylation of microtubule-associated proteins (MAPs) and p H of the medium
control interaction between MAPs and actin filaments. J
Biochem (Tokyo) 90:575-578, 1981
87. Nixon RA: Proteolysis of neurofilaments. In Marotta CA (ed):
Neurofilaments. Minneapolis: University of Minnesota Press,
1983, pp 117-154
88. Nukina N , Ihara Y: Immunocytochemical study on senile
plaques in Alzheimer’s disease. Proc Japan Acad 59:284-292,
1983
89. OBrien L, Shelly K, Towfighi J, McPherson A: Crystalline
ribosomes are present in brains from senile humans. Proc Natl
Acad Sci USA 77:2260-2264, 1980
90. Ogata J, Budzilovich GN, Cravioto H: A study of rod-like
structures (Hirano bodies) in 240 normal and pathology brains.
Acta Neuropathol (Berl) 21:61-67, 1972
91. Ohama E, Ikuta F: Parkinson’s disease: distribution of Lewy
bodies and monoamine neuron systems. Acta Neuropathol
(Berl) 34:311-319, 1976
92. Okazaki H, Lipkin LE, Aronson SM: Diffuse intracytoplasmic
ganglionic inclusions (Lewy type) associated with progressive
dementia and quadriparesis in flexion. J Neuropathol Exp
Neurol 20:237-244, 1961
93. Oyanagi S: Electron microscopic observations on the brains of
patients with senile dementia: conversion of neurofilaments
to twisted tubules and interactions between Alzheimer’s
neurofibrillary tangles and Pick‘s bodies. Adv Neurol Sci Jpn
18177-88, 1974
94. Palo J, Haltia M, Carpenter S, et al: Neurofilament subunitrelated proteins in neuronal intranuclear inclusions. Ann
Neurol 15:322-328, 1984
95. Papasozomenos SCH, Binder LI, Bender PK, Payne MR: Mi-
crotubule-associated protein 2 within axons of spinal motor
neurons: associations with microtubules and neurofilaments in
normal and P-P’-iminodipropionitrile-treated axons. J Cell
Biol 100:74-85, 1985
96. Papolla M, Monoco S, Weiss H , et al: Slow axonal transport in
carbon disulfide giant axonopathy (abstract). J Neuropathol
Exp Neurol43:305, 1984
97. Pena SDJ: Giant axonal neuropathy: intermediate filament
aggregates in cultured skin fibroblasts. Neurology (NY)
3 1 1470-147 3, 1981
98. Perry G, Rizzuto N, Autilio-Gambetti L, Gambetti P: Paired
helical filaments from Alzheimer disease patients contain cytoskeletal components. Proc Natl Acad Sci USA 82:39163920, 1985
99. Peterson C , Suzuki K, Kress Y, Goldman JE: Microfilament
lattices (Hirano bodies) in brindled mice (abstract). J
Neuropathol Exp Neurol 44:326, 1985
100. Pick A: Ueber einen Weiteren Symptomenkomplex im
Rahmen der Dementia, bednight durch umschriebene starkere
Hirnatrophie (gemischte Apraxie). Monatasschr Psychiarr
Neurol 1997-108, 1906
101. Price DL, Struble RG, Altschuler RJ, et al: Aggregation of
tubulin in neurons in Alzheimer’s disease (abstract). J
Neuropathol Exp Neurol44:366, 1985
102. Prineas J: The pathogenesis of dying back polyneuropathies.
11. An ultrastructural study of experimental acrylamide intoxication in the cat. J Neuropathol Exp Neurol28:598-62 1, 1969
103. Prineas JW, Ouvier RA, Wright RG, et al: Giant axonal neuropathy: a generalized disorder of cytoplasmic microfilament
formation. J Neuropathol Exp Neurol 35:458-471, 1976
104. Probst A, Anderton BH, Ulrich J, et al: Picks disease: an
immunocytochemical study of neuronal changes. Monoclonal
antibodies show that Pick bodies share antigenic determinant
with neurofibrillary tangles and neurofilament. Acta Neuropathol (Berl) 60:175-182, 1983
105. Rasool C, Abraham C, Anderton B, et ak Alzheimer’s disease: immunoreactivity of neurofibrillary tangles with antineurofilament and anti-paired helical filament antibodies. Brain
Res 310:249-260, 1984
106. Rasool CS, Selkoe DJ: Recognition of Pick bodies by antibodies to neurofibrillary tangles in Alzheimer’s disease. N Engl
J Med 312:700-705, 1985
107. Rewcastle NB, Ball MJ: Electron microscopy of the inclusion
bodies in Pick‘s disease. Neurology (Minneap) 18:1205-1213,
1968
108. Roy S, Wolman L Ultrastructural observations in parkinsonism. J Pathol 99:39-44, 1969
109. Runge MS, El-Maghrabi MR, Clans T, et al: A MAP2stimulated protein kinase activity associated with neurofilaments. Biochem 20:175-180, 1981
110. Runge MS, Lane TM, Yphantis DA, et al: ATP-induced formation of an associated complex between microtubules and
neurofilaments. ProcNarl Acad Sci USA 78:1431-1435,1981
111. Saida K, Mendell JR, Weiss HS: Peripheral nerve changes
induced by methyl N-butyl ketone and potentiation by methyl
ketone. J Neuropathol Exp Neurol 35:207-225, 1976
112. Sajdel-Sulkowska EM, Coughlin JF, Staton DM, Marotta CA:
In vitro protein synthesis by messenger RNA from Alzheimer’s disease brain. In Katzman R (ed): Biological Aspects of
Alzheimer’s Disease. Vol 15, Banbury Report, Cold Spring
Harbor, NY. Cold Spring Harbor Laboratory, 1983, pp 193200
113. Sattilaro RF, Dentler WL, LeCluyse EL Microtubuleassociated proteins (MAPs) and the organization of actin
filaments in vitro. J Cell Biol 90:467-473, 1981
114. Schiff PB, Horwitz SB: Taxol stabilizes microtubules in mouse
fibroblast cells. Proc Natl Acad Sci USA 77:1561-1565, 1980
115. Schiff PB, Horwitz SB: Taxol assembles tubulin in the absence
Neurological Progress: Goldman and Yen: Neuronal Cytoskeletal Abnormalities
22 1
of exogenous guanosine 5’-triphosphate or microtubuleassociated proteins. Biochem 20:3242-3252, 1981
116. Schlaepfer WW: Nature of mammalian neurofilaments and
their breakdown by calcium. In Zimmerman H M (ed): Progress in Neuropathology. New York, Raven, 1979, pp 101-123
117. Schochet SS Jr: Neuronal inclusions. In Bourne GH (ed): The
Structure and Function of Nervous Tissue. Vol4. New York,
Academic, 1972, pp 129-177
118. Schochet SS Jr, Lampert PW, Lindenberg R Fine structure of
the Pick and Hirano bodies in a case of Picks disease. Acta
Neuropathol (Berl) 11:330-337, 1968
119. Schochet SS Jr, McCormick WF: Ultrastructure of Hirano
bodies. Acta Neuropathol (Berl) 21:50-60, 1972
120. Schulman H: Phosphorylation of microtubule-associated proteins by a Caf +/calmodulin-dependentprotein kinase. J Cell
Biol 99:ll-19, 1984
12 1. SchwartzJH: Axonal transport: components, mechanisms, and
specificity. Annu Rev Neurosci 2:467-504, 1979
122. Schwartz P: Amyloid degeneration and tuberculosis in the
aged. Gerontologia 28:321-362, 1972
123. Selden SC, Pollard TD: Phosphorylation of microtubuleassociated proteins regulates their interaction with actin
filaments. J Biol Chem 258:7064-7071, 1983
124. Selkoe DJ, Abraham CD, Ihara Y: Brain transglutaminase: in
vitro cross-linking of human neurofilament proteins into insoluble polymers. Proc Natl Acad Sci USA 79:6070-6074, 1982
125. Selkoe DJ, Ihara Y, Abraham C, et al: Biochemical and immunocytochemical studies of Alzheimer paired helical
filaments. In Katzman R (ed): Biological Aspects of Alzheimer’s Disease. Vol 15, Banbury Report. Cold Spring Harbor,
NY: Cold Spring Harbor Laboratory, 1983, pp 155-165
126. Selkoe DJ, Ihara Y, Salazar FJ: Alzheimer’s disease: insolubility of partially purified paired helical filaments in sodium
dodecyl sulfate and urea. Science 215:1243-1245, 1982
127. Selkoe DJ, Liem RKH, Yen S-H, Shelanski ML: Biochemical
and immunological characterization of neurofilaments in experimental neurofibrillary degeneration induced by aluminum.
Brain Res 163:235-252, 1979
128. Seppalaionen AM, Haltia M: Carbon disulfide. In Spencer PS,
Schaumburg H H (eds): Experimental and Clinical Neurotoxicology. Baltimore: Williams & Wilkins, 1980, pp 356-373
129. Shibayama H , Kitoh J: Electron microscopic structure of the
Alzheimer’s neurofibrillary changes in a case of atypical senile
dementia. Acta Neuropathol (Berl) 41:229-234, 1978
130. Sloboda RD, Rudolph SA, Rosenbaum JL, Greengard P:
Cyclic AMP-dependent endogenous phosphorylation of a
microtubule-associated protein. Proc Natl Acad Sci USA
72:177-181, 1975
131. Spencer PS, Couri D, Schaumburg HH: N-Hexane and
methyl N-butyl ketone. In Spencer PS, Schaumburg HH
(eds): Experimental and Clinical Neurotoxicology. Baltimore:
Williams & Wilkins, 1980, pp 456-475
132. Spencer PS, Griffin JW: Disruption of axoplasmic transport by
neurotoxic agents: the 2.5-hexanedione model. In Weiss DG,
Goria A (eds): Axoplasmic Transport in Physiology and
Pathology. Berlin: Springer-Verlag, 1982, p p 92-103
133. Spencer PS, Thomas P K Ultrastructural studies of the dyingback process. 11. The sequestration and removal by Schwann
cells and oligodendrocytes of organelles from normal and diseased axons. J Neurocytol 3:763-783, 1974
134. Steele JC, Richardson EP, Olszewski J: Progressive supranuclear palsy: a heterogeneous degeneration involving the brain
stem, basal ganglia and cerebellum with vertical gaze and
pseudobulbar palsy, nuchal dystonia and dementia. Arch
Neurol 10:333-359, 1964
135. Steinert PM, Wantz ML, Idler WW. 0-phosphoserine content
of intermediate filament subunits. Biochem 21:177-183, 1982
222 Annals of Neurology
Vol 19 No 3
March 1986
136. Sternberger LA, Sternberger NH: Monoclonal antibodies distinguish phosphorylated and non-phosphorylated forms of
neurofilaments in situ. Proc Natl Acad Sci USA 80:61266130, 1983
137. Sternberger NH, Sternberger LA, Ulrich J: Aberrant
neurofilament phosphorylarion in Alzheimer disease. Proc
Natl Acad Sci USA 82:4274-4276, 1985
138. Takahashi K, Nakamura H , Okada E: Hereditary amyotrophic
lateral sclerosis: hiscochemical and electron microscopic study
of hyaline inclusions in motor neurons. Arch Neurol 27:292299, 1972
139. Terry RD: Neuronal fibrous proteins in human pathology. J
Neuropathol Exp Neurol 30%-19, 1971
140. Terry RD, Katzman R: Senile dementia of the Alzheimer type:
defining a disease. In Katzman R, Terry RD (eds): The Neurology of Aging. Vol 22, Contemporary Neurology Series.
Philadelphia: Davis, 1983, pp 5 1-84
141. Theurkauf WE, Vallee RB: Extensive CAMP-dependent
and CAMP-independent phosphorylation of microtubuleassociated protein-2. J Biol Chem 258:7883-7886, 1983
142. Tomlinson BE, Kitchner D: GranuIovacuoIar degeneration of
hippocampal pyramidal cells. J Pathol 106:165-185, 1972
143. Tomonaga M: Ultrastructure of Hirano bodies. Acta Neuropathol (Berl) 28:365-366, 1974
144. Tomonaga M: Neurofibrillary tangles and Lewy bodies in the
locus ceruleus neurons of the aged brain. Acta Neuropathol
(Berl) 53:165-168, 1981
145. Troncoso JC, Price DL, Griffin JW, Parhard IM: Neurofibrillary axonal pathology in aluminum intoxication. Ann
Neurol 12:278-283, 1982
146. Troncoso JC, Sternberger LA, Sternberger N H , et al: Immunocytochemical studies of neurofilament antigens in the
neurofibrillary pathology induced by aluminum (abstract). J
Neuropathol Exp Neurol44:376, 1985
147. Vallee RB, Bloom GS: High molecular weight microtubuleassociated proteins (MAPS). Mol Cell Biol 3:21-75, 1984
148. Van den Bosch de Aguilar PH, Goemeare-VannesteJ: Paired
helical filaments in spinal ganglion neurons of elderly rats. Virchows Arch 47:217-222, 1984
149. Wang GP, Grundke-Iqbal I, Kascsak RJ, et al: Alzheimer
neurofibrillary tangles: monoclonal antibodies to inherent antigen(s). Acta Neuropathol (Berl) 62:268-275, 1984
150. Weeds A: Actin-binding proteins-regulators of cell architecture and motility. Nature 296311-816, 1982
15 1. Wilcock GK, Esiri MM, Bowen DM, Smith CCT: Alzheimer’s
disease: correlation of cortical choline acetyltransferase activity
with the severity of dementia and histological abnormalities. J
Neurol Sci 59:407-417, 1982
152. Willard M: Neurofilaments and axonal transport. In Marotta C
(ed): Neurofilaments. Minneapolis: University of Minnesota
Press, 1983, pp 86-116
153. Willard M, Wiseman M, Levine J, Skene P: Axonal transport
of actin in rabbit retinal ganglion cells. J Cell Biol81:581-591,
1979
1J4. Wisniewski HM, Coblentz JM, Terry RD: Pick‘s disease: a
clinical and ultrastructural study. Arch Neurol 26:97-108,
1972
155. Wisniewski HM, Merz DA, Iqbal K: Ultrastructure of paired
helical filaments of Alzheimer’s neurofibrillary tangle. J
Neuropathol Exp Neurol43:643-656, 1984
156. Wisniewski HM, Soifer D: Neurofibrillary pathology: current
status and research perspectives. Mech Aging Dev 9:119-142,
1979
157. Wisniewski HM, Sturman JA, Shek JW: Aluminum chloride
induced neurofibrillary changes in the developing rabbit: a
chronic animal model. Ann Neurol 8:479-490, 1980
158. Wisniewski HM, Terry RD: Neuropathology of the aging
brain. In Terry RD, Gershon S (eds): Neurobiology of Aging.
New York: Raven, 1978, Vol 3, pp 265-280
157. Wisniewski HM, Wen G Y Substructures of paired helical
filaments from Alzheimer’s disease neurofibrillary tangles.
Acta Neuropathol 66:173-176, 1785
160. Wisniewski K, Jervis GA, Moretz RC, Wisniewski HM: Alzheimer neurofibrillary tangles in diseases other than senile and
presenile dementia. Ann Neurol 5:288-294, 1979
161. Wisniewski KG, Wisniewski HM: Age-associated changes and
dementia in Down’s syndrome. In Reisenberg B (ed): Alzheimer’s Disease: The Standard Reference. New York: Free
Press, 1983, pp 317-326
162. Wong J, Hutchinson SB, Liem RKH: Isoelectric variant of the
150,000-dalton neurofilament polypeptide. J Biol Chem
259:10867-10874, 1984
163. Yagishita S, Itoh Y, Amano N, Nakano T, Saitoh A: Ultrastructure of neurofibrillary tangles in progressive supranuclear
palsy. Acta Neuropathol (Berl) 48:27-30, 1777
164. Yen S-H, Crowe A, Dickson DW: Monoclonal antibodies to
Alzheimer neurofibrillary tangles. 1. Identification of polypeptides. Am J Pathol 120:282-291, 1985
165. Yen S-H, Gaskin F, Fu SM: Neurofibrillary tangles in senile
dementia of the Alzheimer type share an antigenic determinant with intermediate filaments of the vimentin class. Am J
Pathol 113:373-381, 1983
166. Yen S-H, Gaskin F, Terry RD: Immunocytochemical studies
of neurofibrillary tangles. Am J Pathol 104:77-89, 1981
167. Yen S-H, Horoupian DS, Terry RD: Immunocytochemical
comparison of neurofibrillary tangles in senile dementia of
Alzheimer type, progressive supranuclear palsy and postencephalitic parkinsonism. Ann Neurol 13:172-1 75, 1983
168. Yen S-H, Kress Y: The effect of chemical reagents or proteases on the ultrastructure of paired helical filaments. In Katzman R (ed): Biological Aspects of Alzheimer’s Disease. Vol
15, Banbury Report, Cold Spring Harbor, NY: Cold Spring
Harbor Laboratory, 1983, pp 155-165
167. Yen S-H, Reding H, Davies P, Ciment G: The composition of
neurofibrillary tangles of senile dementia of the Alzheimer
type: an immunological study. Ann N Y Acad Sci 455:819825, 1985
170. Yokoyama K, Tsukita S, Ishikawa IT, Kurokawa M: Early
changes in the neuronal cytoskeleton caused by p-p’iminodipropionitrile selective impairment of neurofilament
polypeptides. Biomed Res 1:537-547, 1980
Neurological Progress: Goldman and Yen: Neuronal Cytoskeletal Abnormalities
223
Документ
Категория
Без категории
Просмотров
0
Размер файла
2 675 Кб
Теги
neurodegenerative, cytoskeleton, protein, abnormalities, disease
1/--страниц
Пожаловаться на содержимое документа