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Butyrylcholinesterase reactivity differentiates the amyloid plaques of aging from those of dementia.

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Butyrylcholinesterase Reactivity
Dfierentiates the Amyloid Plaques of Aging
from Those of Dementia
M.-Marsel Mesulam, MD,” and Changiz Geula, PhD?
~
In a sample of consecutively received, 4 demented and 4 age-matched nondemented brains, the total cortical area
covered by plaque-like AP amyloid and butyrylcholinesterase deposits was measured at two regions of the temporal
cortex with the help of computed densitometry. Demented as well as age-matched nondemented brains contained AP
and butyrylcholinesterase-positiveplaques. The total cortical area covered by the AP precipitates was higher in
demented individuals but there was overlap with the values seen in the specimens from nondemented individuals.
The proportional plaque area displaying butyrylcholinesterase reactivity was very significantly and fivefold to sixfold
higher in the demented than in the nondemented group and there was no overlap between the two populations.
Diffuse AP deposits in nondemented elderly brains may represent a benign or preclinical stage of plaque deposition
with relatively little pathological effect on brain tissue and mental function. Our results suggest that the progressively
more extensive butyrylcholinesterase reactivity of plaques may participate in their transformation from a relatively
benign form to pathogenic structures associated with neuritic degeneration and dementia.
Mesulam M-M, Geula C. Butyrylcholinesterase reactivity differentiates the amyloid plaques
of aging from those of dementia. Ann Neurol 1994;36:722-727
The brains of patients with Alzheimer’s disease (AD)
display numerous pathological changes. Only the extracellular accumulation of AP amyloid in the form of
plaques is specific to A D and differentiates this condition from other dementing diseases. The AP peptide
is a 4-kd fragment of a membrane-spanning, naturally
occurring amyloid precursor protein (APP). Increased
production, point mutations, deviant sequestration,
and abnormal processing of APP have been invoked
as causative mechanisms for plaque formation and A D
11-41.
Although amyloid deposits constitute necessary elements in the pathogenesis of AD, numerous observations indicate that they are not by themselves sufficient
for triggering the neural degeneration and dementia
characteristic of this disease. The deposition of amyloid
does not initially cause pathological changes in tissue
I51 and may need to go on for years before the emergence of clinically recognizable dementia 161. There is
also very little correlation between dementia severity
and plaque formation 17,81, and many nondemented
elderly individuals have plaque densities in the range
seen in AD [7- 131.
One possibility is that amyloid plaques undergo a
From the “Center for Behavioral and Cognitive Neurology and the
Alzheimer Program, Departments of Neurology and Psychiatry,
Northwestern University M e d i d School, Chicam IL and tlaboratory for Neurodegenerative and Aging Research, Department of
Medicine, New England Deaconess Hospital and Harvard Medical
School, Boston, MA.
722
lengthy process of transformation at the site of deposition before they become pathogenic. Neuropathological observations suggest that the deposition of the AP
peptide initially leads to the formation of a diffuse
plaque which may eventually become transformed into
a compact and fibrillar plaque associated with neuritic
degeneration [ 14- 161. The processes that underlie this
putative transformation remain mysterious.
W e previously showed the presence of butyrylcholinesterase (BChE, EC. 3.1.1.8) activity in senile
plaques [17]. We now report that BChE reactivity covers a greater portion of the plaque area in AD than in
age-matched control brains, suggesting that the accumulation of BChE may be one factor that participates
in the “ripening” and eventual pathogenicity of AP deposits in AD.
Materials and Methods
This study is based on 8 brains obtained at autopsy. The
interval between death and fixation varied from 3.5 to 12.0
hours. The brains were sectioned into 1.5- to 2.0-cm coronal
slabs and fixed by immersion for 24 to 32 hours at 4°C in
45f paraformaldehyde buffered at pH 7.4with phosphate.
The slabs were then rinsed and stored in gradually increasing
Received Dec 10, 1993, and in revised form Mar 3 and Apr 14,
1994. Accepted for publication Apr 21, 1994.
Dr Mesulm, Center for Behavioral and
Address correspondence
Cognitive Neurology, Northwestern University Medical School, 320
E, Superior St, Room 1-450, Chicago, IL 6061
Copyright 0 1994 by the American Neurological Association
concentrations ( 1 0 - 4 0 s ) of buffered sucrose. Cutting was
done with a freezing microtome at a thickness of 40 pm.
Matching sections were stained for Thioflavin-S histofluorescence, BChE histochemistry [17), and AP immunocytochemistry with the avidin-biotin-peroxidase complex (ABC)
method [l8], using a polyclonal antibody generously donated
by Dennis Selkoe. In selected sections, the tissue was processed first for BChE histochemistry and then for Thioflavin-S histofluorescence in order to obtain the concurrent
demonstration of both reaction products [19J
For the BChE reaction, specificity was demonstrated by
showing that the reaction product (with butyrylthiocholine as
the substrate) was inhibited by l o - * M iso-OMPA (a specific
BChE inhibitor) but not by BW284C51 (a specific acetylcholinesterase [AChE) inhibitor). Immunohistochemical specificity was demonstrated by showing that the reaction product
could not be obtained when the antibody was substituted by
an irrelevant IgG.
Four of the specimens (Cases 1-4) were designated as
non-AD controls based on the absence of pre-agonal neurological disease, historical and/or neuropsychological evidence
showing the absence of dementia, Thioflavin-S staining that
showed an average of less than three neocortical tangles and
neuritic plaques/ 10 microscopic fields at 100 x magnification
(“sparse” by the Consortium to Establish a Registry for Alzheimer’s Disease [CERAD} 1201 criteria) in middle temporal
and inferior parietal cortex, and the absence of neuropathological lesions other than rare microinfarctions. One of the
normal subjects was tested 6 months before death at which
time he had a perfect score on the Mini-Mental State examination [21). The other 3 control subjects were not tested
formally but an examination of extensive medical records,
including hospital admissions within 1 month of death, indicated that there was no abnormality in the neurological examination and no personal o r family history of dementia. The 4
subjects (Cases 5-8) included in the A D group had a clinical
history of progressive dementia and the specimens had a
density and distribution of Thioflavin-S-positive neuritic
plaques and tangles that fulfilled the criteria for A D outlined
by Khachaturian [22). The two groups did not differ with
respect to age (79.2 i 6.8 vs 78.75 2 8.5 years), postmortem interval (7.6 3.5 vs 7.1 -+ 3.3 hours), o r fixation time
(28.5 +- 3 vs 28.8 2 3.4 hours). The causes of death included
cardiac insufficiency, pneumonia, and generalized infection.
The specimens were unselected in the sense that we included
all consecutively received samples that fulfilled the criteria
noted above until we had entered into the study 4 non-AD
and 4 A D brains from subjects above the age of 65. These
brains were collected within a period of 18 months. During
that interval only 1 potentially relevant subject was eliminated because of insufficient information about cognitive
state.
In each specimen, computed semiautomated densitometric
morphometry (Imaging Research) at 60 x magnification was
used to calculate proportional areas of the cerebral cortex
covered by BChE- and AP-positive plaques. Since plaques
display great size variations, the proportional area that they
cover is a more accurate measure of the regional “amyloid
burden” than their numerical density. The measurement of
proportional area also circumvents the considerable difficulties inherent in the counting of confluent plaque clusters and
*
very small fragments of reaction product. The output of the
image analyzer was the percentage of the imaged cortical area
occupied by plaques.
This study focused on the temporal cortex because of its
severe and consistent involvement in AD. Sections processed
for BChE histochemistry alone were used to select two areas,
one in inferotemporal and the other in midtemporal cortex.
Only areas where the overwhelming majority of the darkblue BChE reaction product was confined to structures with
the morphological appearance of plaques were selected. Areas and layers that contained more than four BChE-positive
neuroglia or neurofibrillary tangles per 200 x field were excluded. The morphometric analysis was confined to layers 2
to 4 and to the immediately adjacent parts of layer 5. The
deeper layers were excluded because they contain numerous
BChE-positive tangles and neuroglia in A D {17, 23). The
beginning of layer 2 was identified by the boundary of the
molecular layer, and layer 4 was identified by the presence
of tightly packed granule cells.
During imaging, the intensity of background illumination
was kept constant for all samples. The average density of 10
typical plaques at each analysis site was determined and used
to set the target density for that region. The image analyzer
then automatically set the threshold value and calculated the
proportional area covered by suprathreshold pixels. First, the
proportional area of cortex covered by the BChE reaction
product was calculated within the imaging window. Then
the proportional area covered by A@plaques at exactly the
same sites was determined in identically positioned windows
within adjacent sections that had been processed immunohistochemically.
Since the eight resultant columns of percentages shown in
the Table did not display significant deviations from normalcy, the results were analyzed with a two-factor repeated
measures analysis of variance (ANOVA) followed by Newman-Keul’s test for pairwise comparisons.
Results
Sections stained for the AP peptide showed plaques in
all 8 specimens. Sections stained with Thioflavin-S or
BChE histochemistry showed plaques in all the specimens, a few tangles in t h e entorhinal cortex and adjacent medial temporal areas of the non-AD specimens,
and numerous widespread tangles in t h e AD specimens. I n keeping with our previous observations, t h e
BChE-containing tangles were located predominantly
in deeper cortical layers [23}. There were also numero u s BChE-positive neuroglia, especially in deeper corticd layers { 17).
Sections stained for AP immunohistochemistry
or Thioflavin-S histofluorescence displayed detailed
plaque morphology and confirmed the previously published observations that a m u c h higher proportion of
plaques are neuritic in the AD than in t h e non-AD
brain and that a substantial part of t h e AP deposits in
t h e non-AD brain form diffuse rather than compact
plaques C14, 161.
I n brain sections concurrently stained with BChE
histochemistry and Thioflavin-S histofluorescence, vir-
Mesulam and Geula: BChE Reactivity in Amyloid Plaques
723
Proportional Area (%) Covered by AP and Buty rylcholinesterase (BChE) at the lnferotemporal and iM idtemporal Imaging Sitesa
Inferotemporal
Case No.
Sex, Age (yr)
AP
F, 72
M, 75
F, 84
M, 86
12.2
5.5
9.5
11.2
9.6 t 3
Midtemporal
BChE
BChEIAP
AP
9.8
16.4
8.4
8
10.7 s 3.9
10.3
8
6.3
5.3
7.5 +- 2.2
0.9
0.8
59.3
87.6
61
63.3
67.8
23
17.7
23.4
12.5
19.2 t 5.1
14.7
12
15.3
7.1
12.3
BC hE J AP
BChE
Nondemented
1
2
3
4
Mean +- SD
Alzheimer
5
6
7
8
Mean
?
F, 67 (9)
F, 79 (12)
F, 82 (9)
F, 87 (10)
SD
22.1
14.6
17.7
9
15.8 -r- 5.5
1.2
0.9
0.8
0.9
1
* 0.2
13.1
12.8
10.8
5.7
10.6 t 3.4
2
13.3
1.4
0.3
0.8
2
-t
0.4
13.6
3.8
12.7
17
11.8 +- 5.6
3.7
63.9
67.8
65.4
56.8
63.5 t 4.7
~~
~
*The numbers within the parentheses in the second column indicate disease duration in the Alzheimer patients The AP and BChE columns
indicate the proportional areas within the cerebral cortex that were occupied by the relevant reaction product The BChEiAP column indicates
the proportion of the total AP plaque area that is BChE positive
SD
=
standard deviation
tually all (96%) plaque-like BChE deposits were also
stained with Thioflavin-S (Fig l), confirming previous
observations {24, 25J that BChE-positive plaques constitute a subset of amyloid plaques. In sections stained
for BChE enzyme activity, either alone or in combination with Thioflavin-S, the presence of a BChE-positive
plaque could be identified reliably but derails of plaque
morphology were not optimal. Inspection of these sections provided individual examples of BChE-positive
cored, neuritic, and also diffuse plaques but the exact
percentage of BChE plaques that belonged to each of
these three categories could not be determined reliably.
The image analyzer identified plaque-like structures
with clearly delineated boundaries in the AP as well as
the BChE sections (Fig 2). Based on the results described above and on previous observations 1141, we
assumed that AP staining reflected total plaque area
and that plaque-like BChE staining reflected a subset
of this total. The proportional area covered by BChEpositive plaques was therefore divided by the proportional area covered by AP-positive plaques at the same
cortical site in order to calculate the percentage of the
amyloid plaque area that also displayed BChE reactivity
(see Table).
This ratio was 5.8 times higher in AD than in the
nondemented comparison group. The difference was
highly significant (ANOVA p < 0.00002; NewmanKeul's p < 0.001) and there was no overlap between
the two groups. We can therefore conclude that a
greater proportional area of the A@deposits expresses
BChE activity in AD than in nondemented aged brains.
The proportional cortical area covered by AP plaques
was higher in the AD group (17.5 vs 8.69%)bur the
significance level was lower (ANOVA p < 0.02; Newman-Keul's p < 0.025) and there was overlap with the
724 Annals of Neurology
Fig 1 . Concurrent demonstration of butyrylcholinesterase
IBChE) and Thioflavin-S histojuorescence in the mediotemporal
cortex of a patient with Alzheimer's ahease. The tissue was first
stained for BChE histochemistry and then for Thiojavin-S.
The black rim of the plaque represents BChE reaction product.
The bright fluorescent material inside the rim represents neurites
and amyloid ( x 640 before 29% reduction).
values seen in the control group. The proportional area
covered by BChE was also higher in AD (11.4 vs
0.7%). The difference was significant (ANOVA p <
0.0008; Newman-Keul's p < 0.001) and there was no
overlap between the control and AD groups (see Table).
Discussion
The presence of AP amyloid deposits, especially when
determined by sensitive immunohistochemical procedures, is a common finding in the brains of nondemented elderly individuals C12, 133. There is either a
fundamental difference between the pathogenicity of
Vol 36 No 5 November 1994
Fig 2. Densitometric quantitation of the cortical area covered by
amyloid (A, C) and butyrylcholinesterase (BChE) (B. Di. The
rectangular area outlines the imaging window. The bright objects within the imaging window represent plaques that were detected by the image analyzer. The dark globular material outside
of the imaging window represents digitized plaques that were
not included in the measurements. (A, B) The midtemporal cortex of a 79-year-oldpatient with Alzheimer’s disease (Case 6).
The area covered by BChE represents 67% of the area covered
by AP. (C, D ) The inferotemporal cortex of an 86-year-old nondemented subject. The area covered by BChE represents only 8%
of the area covered by AD. In all frames, the first layer of cortex
is toward the bottom ( X 206 before 14% reduction).
AP deposition in physiological aging and AD or alternatively, nondemented elderly individuals with amyloid plaques in the brain may represent an initial, preclinical stage of the disease process 113, 151. If the
plaque deposits of “normal” aging represent a preclinical stage of AD, our observations indicate that a greater
area of the amyloid plaque contains BChE enzyme activity as the pathological process of AD proceeds from
early to advanced stages. Alternatively, the amyloid deposits of normal aging may be different from those of
AD and may have a special property that restricts their
BChE reactivity and also their ability to trigger neuritic
degeneration.
The cortical area covered by AP deposits was higher
in the AD group but the values overlapped with those
seen in the non-AD group whereas there was no overlap in the proportional plaque area displaying BChE
reactivity. The extent of amyloid deposits that displayed BChE reactivity was therefore a much better
marker than the area covered by amyloid alone for
distinguishing the plaque-related changes of normal
aging from those of AD.
The origin of the plaque-bound BChE is not fully
understood. The normal cerebral cortex contains very
little neuronal, dendritic, or axonal BChE 1241. Plaquebound BChE is therefore unlikely to represent the passive entrapment of premorbid neuronal or neuritic
BChE. Recent observations indicate that neuroglia provide a potential source for the BChE of cortical plaques
C17). It is interesting to note that AD is associated with
a significant increase in the density of BChE-positive
neuroglia {17} and total BChE activity {261in the temporal lobes.
The physiological role served by BChE remains mysterious. Detoxifying, growth-promoting, and morphogenetic functions have been described [27}. The BChE
in plaques and neuroglia is selectively inhibited by indoleamines and carboxypeptidase inhibitor 1281. In
keeping with these inhibitor responses, BChE displays
serotonin-sensitive aryl-acylamidase and perhaps also
metalloprotease activity 1291. BChE thus joins a number of other substances, such as a,-antichymotrypsin
Mesulam and Geula: BChE Reactivity in Amyloid Plaques
725
[30], protease nexin 1 [311, and a,-antitrypsin [32],
that are found in association with the amyloid plaque
deposits and may disrupt the delicate local balance between proteases and their inhibitors.
The excessive deposition of insoluble AP amyloid
in the cerebral cortex is a necessary and specific factor
in the pathogenesis of AD {I, 3}. This conclusion
needs to be reconciled with the inconsistent temporal
and quantitative relationship between AP deposits and
either tissue injury or dementia [b-8, 131. One explanation is that the deposition of AP is a necessary but
not sufficient factor and that additional downstream
events are required for the development of AD. The
characterization of these downstream events is crucial
for understanding how AD evolves and also for finding
ways in which the disease process can be altered.
At least in this sample of consecutively received 4
AD brains and 4 control brains, our findings identify
the increase of BChE reactivity as a potentially significant downstream event in the complex life cycle of AP
plaques. The initially diffuse AP deposits induce little
or no pathological changes in the brain tissue I S ] and
may in fact promote neurite outgrowth {33]. At these
early or benign stages of plaque formation, our observations indicate that BChE reactivity is limited to less
than 20% of the surface area covered by the amyloid
deposit. At later or more pathogenetic stages of plaque
formation, the proportional plaque area displaying
BChE reactivity increases by a factor of 5 to 6 and may
reach values that are as high as 87%. The BChE may
become inserted into the area of AP deposits through
the mediation of neuroglia and may alter the pathogenicity of amyloid plaques. This potential sequence of
events suggests that BChE inhibitors may play an important and hitherto unexpected role in the prevention
of AD. Human BChE displays numerous allelic polymorphic variants 1341 and it would be of considerable
interest to determine if some of these are more closely
associated with AD.
This work was supported in part by N I H grants NS20285,
AG10282, and AGO5134.
We thank Deborah C. Mash, PhD, Director of the University of
Miami Brain Endowment Bank, for providing some of the specimens
used in this study. Leah Christie, Kristin Bouve, and Tamar Hashimi
provided expert secretarial and technical assistance.
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