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Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain.

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Decreased Pyruvate
Dehydrogenase Complex Activity
in Huntington and Alzheimer Brain
Sandro Sorbi, MD,* Edward D. Bird, MD,+ and John P. Blass, MD, PhD‘
The activity of the pyruvate dehydrogenase complex (PDHC) was reduced in affected areas of brain from patients with
Huntington disease (caudate, putamen) and Alzheimer disease (frontal cortex) where choline acetyltransferase (CAT)
activity was low. PDHC was also deficient in an area (Huntington hippocampus) where CAT was not significantly
reduced. The activity of fumarase, an inner mitochondria1 marker, was normal in all areas examined. The activities of
PDHC and CAT correlated well in caudate, putamen, and amygdala but not in hippocampus or frontal cortex. Both
total activity and activation of PDHC were below normal in fibroblasts from 4 patients with C-21 trisomy Down
syndrome, who are at very high risk to develop Alzheimer disease. However, no abnormality of PDHC was detected in
Huntington or Alzheimer fibroblasts. Deficiency of PDHC may play a role in the pathophysiology of Huntington and
Alzheimer diseases, although it does not appear to be a primary defect. Loss of tissue oxidative capacity may relate to the
reduction in cerebral metabolic rate and blood flow which are characteristic of many dementing illnesses.
Sorbi S, Bird ED, Blass JP Decreased pyruvate dehydrogenase complex activity in Huntington and
Alzheimer brain. Ann Neurol 13:72-78, 1983
Huntington disease is a dominantly inherited disorder
in which specific portions of the nervous system, notably the small Golgi type interneurons of the caudate
and putamen, degenerate [ l If. The onset is typically in
middle age. Alzheimer disease is a degenerative disorder which in some families appears to be inherited as a
dominant trait. The incidence increases with age, but
cases beginning in middle age are well recognized (including Alzheimer’s original patient). Recent studies
[ S 11 indicate that one patient with Alzheimer disease
had marked degeneration of the nucleus basalis of
Meynert, a putative cholinergic structure located near
the pallidum and continuous, in humans, with the
diagonal band and the septa1 nuclei. The neurofibrillary
degeneration that characteristically occurs in Alzheimer disease can also be found, if looked for, in
many Huntington disease brains 121). Both Huntington disease and Alzheimer disease can usefully be
thought of as late-life system degenerations.
Numerous studies have indicated deficits in enzymes
of neurotransmitter metabolism in both these disorders, notably of choline acetyltransferase (CAT) C2, 3,
5 , 8, 9, 11, 12, 15, 27, 30, 4 2 , 431, the synthetic enzyme which is a marker of cholinergic neurons [lS].
Other changes in Huritington disease include loss of
glutamic acid decarboxylase in caudate and putamen
but not cerebral cortex [S}, of muscarinic cholinergic
[IS] and kainic acid receptors [24] but not of yaminobutyric acid (GABA) receptors in caudate [lS],
and possible abnormalities of aminergic systems 1271
despite normal levels of norepinephrine, dopamine,
and tyrosine hydroxylase in basal ganglia IS]. In Alzheimer disease, the importance of alterations in catecholamines has been controversial [I, 7, 91. A decrease
in immunoreactive somatostatin in affected areas of
Alzheimer brain has recently been reported {13].
These changes in neurotransmitter enzymes and other
markers presumably indicate more or less selective vulnerability of particular populations of neurons in these
disorders; they ho not of themselves tell why the cells
die. Isolated studies have reported deficient activities
of enzymes of carbohydrate energy metabolism in Alzheimer disease: phosphofructokinase by Bowen et a1
[ 9 ) and the pyruvate dehydrogenase complex (PDHC)
by Perry et a1 1311. Bird et a1 [41 have reported phosphofructokinase to be deficient in Huntington disease
also. In this study, we confirm the existence of the
PDHC deficit in brain of Alzheimer patients at au-
From the “Alrschul Laboratory for Dementia Research, Division of
Chronic and Degenerative Disease, Department of Neurology, Cornell University Medical College, at the Burke Rehabilitation Center,
White Plains, N Y 10605, and t Harvdrd Univcrsity, Ralph Lmvell
Laboratory, Mailman Research Center, McLean Hospital, Belmont,
MA 02178.
Received Otr 15, 1981, and in revised form Jan 8 and Apr 13, 1982.
Accepted for publication Apr 10, 1782.
requests tO Dr Sorbi, Dementia Research s~.,,,,..,
The Burke Rehabilitation Center, ,85 Mamaroneck
Plains, NY 10605,
72 0364-5 134/8W010072-0731.50 0 1982 by the American Neurologicsl Association
topsy, using an improved assay procedure, and demonstrate for the first time a deficit in PDHC activity in
Huntington disease brain, including a n area (hippocampus) where CAT activity was normal and histopathological change is known to be minimal.
Materials and Methods
Preparation of Tissue Specimens
Postmortem specimens of caudate, putamen, amygdala, hippocampus, and cerebral and cerebellar cortices were stored at
the Brain Tissue Bank of McLean Hospital, Belmont, MA.
Brains from 2 of the patients with Alzheimer disease were
autopsied at New York Hospital, immediately frozen, and
stored at the Burke Rehabilitation Center. Brains were
studied from 16 patients with Huntington disease, 5 with
Alzheimer disease, and 40 aged-matched controls without
clinical and pathological evidence of neurological disease. All
brains were processed in the same manner, exactly as described by Bird and Iversen [5]. All samples were coded, and
the code was broken after the study was completed. Human
fibroblasts were from the Human Genetic Mutant Cell Repository, Copewood, NJ: controls, G M 1960, G M 2185,
G M 2037, and G M 0288; Huntington proband G M 1169
and Huntington at risk G M 2077; Alzheimer G M 0364; and
C-21 trisomy Down syndrome, G M 2504, G M 2767, G M
2067, and G M 2511.
All brain assays were performed on freshly homogenized
tissue samples. These were weighed and homogenized in 5%
(wlv) 5 mM ethylenediaminetetraacetic acid (EDTAksodium
(pH 7.4). Aliquots of the same homogenate were used for
CAT, PDHC, and fumarase estimations. Fibroblasts were
harvested as described in detail elsewhere 1441. To activate
(dephosphorylate) PDHC, fibroblasts were incubated at 37°C
for different times in phosphate-buffered saline containing 5
mM dichloroacetate, p H 7.4 140, 441. Addition of Y3 vol of
an ice-cold mixture containing 40% ethanol, 25 mM sodium
fluoride, 25 mM EDTA, and 4 mM dithiothreitol (pH 7.8)
stopped the activation 140, 441. Then 1.2 vol of 50 mM
potassium phosphate buffer ( p H 7.8), 1 mM EDTA, 1 mM
mercaptoethanol, and 0.5% (w/v) Triton X-100 were added,
and the cells were disrupted by treatment for 45 seconds at
high speed with a Brinkman polytron {44}.
Choline Acetyltransferase
CAT activity was assayed using the radiochemical method of
Fonnum 1191. An aliquot of the original homogenate was
activated with 0.5% (viv) Triton X-100 to ensure total release of the enzyme activity [16]. Two microliters of this
activated homogenate was incubated in homemade microtubes (20 x 4 mm) for 30 minutes at 37°C with 5 pl of the
following reaction mixture (final concentration): 0.2 mM
[1-'4C)acetylcoenzyme A (acetyl-CoA) (New England Nuclear, 57.7 mCi/mmol), 300 rnM sodium chloride, 41 mM
sodium phosphate buffer ( p H 7.4), 11.4 mM choline
chloride, 18 mM sodium salt EDTA (pH 7.4), and 0.12 mM
physostigmine. The labeled acetyl-CoA was diluted with the
unlabeled compound (Boehringer Mannheim) to a final
specific activity of 17.3 mCi/mmol.
Pyruuate Dehydrogenase Complex
Pyruvate dehydrogenase complex was assayed in both brain
homogenates and cultured fibroblasts by a spectrophotometric coupled enzyme assay using pigeon liver arylamine
acetyltransferase as described in detail elsewhere [22, 441.
The reaction mixture contained, in a final volume of 1 ml, 48
mM tris buffer ( p H 7.8), 1 mM magnesium chloride, 4.8 mM
mercaptoethanol, 0.48 mM sodium EDTA ( p H 7.8),0.3 mM
thiamine pyrophosphate hydrochloride, 0.1 mM coenzyme
A, 0.46 mM nicotinamide-adenine dinucleotide, 0.3 mM
dithiothreitol, 0.2% (wlv) Triton X-100, 1 mg of lactate dehydrogenase (0.965 unit), 0.05 mg of plp(aminopheny1)azo1benzenesulfonic acid (AABS; Pfaltz and Bauer, Stamford, CT), 50 ~1 of a pigeon liver preparation containing 4 to
IU of partially purified arylamine acetyltransferase,
an appropriate amount of the tissue to be assayed (0.1 to 0.2
mg of fibroblast protein or 0.05 to 0.1 mg of brain homogenate protein), and either 5 mM pyruvate (in the reaction
cuvette) or an equivalent volume of tris buffer. Before addition to the reaction mixture, brain homogenate was diluted
1:5 in (final concentration) 50 mM sodium phosphate buffer
(pH 7.8), 1 mM sodium EDTA, 1 mM mercaptoethanol, and
0.2% (wlv) Triton X-LOO [22).
Assays were performed at 30°C by double-beam spectrophotometry using a Cary 2 19 spectrophotometer (Varian
Instrument Co., Sunnyvale, CA) following the decrease in
absorbance at 460 nm due to acetylation of AABS. A
baseline was determined with sample and reference cuvettes
both containing the entire reaction mixture except for pyruvate, and was stable. To initiate the reaction, pyruvate was
added to the sample cuvette and an equal volume of tris
buffer ( p H 7.8) to the reference cuvette. The difference in
molar extinction of AABS (8.75 x lo3 cm-'j and acetylAABS (1.64 x lo3 cm- ') was used to calculate the enzyme
activity in nanomoles per minute per milligram of protein.
All samples were assayed at least in triplicate. Previous studies by rwogroups 122,311 have shown that P D H C is stable in
postmortem brain.
Fumarase activity was measured by a modification of the
spectrophotometric method of Racker [35]. Aliquots of
homogenate diluted to 1% (w/v) were activated with 1%
(wiv) Triton X-100. An aliquot of this dilute homogenate
was added directly to a cuvette containing 3 ml of 33 mM
sodium L-malate and 50 mM potassium phosphate buffer
(pH 7.4). The change in optical absorption was followed at
250 nm at a constant temperature of 25°C.
Proteins were determined in each dilution of the original
homogenate and in the fibroblast preparations by the method
of Lowry et a1 [251.
Activities of PDHC were low in affected areas of
Huntington and Alzheimer brain, where CAT activity
was also low (Table 1). The activity of PDHC was
decreased by 34% in Huntington hippocampus where
CAT was not significantly reduced and the histological
Sorbi et al: Brain PDHC in Dementia
Table 1. Enzyme ActivitieJ in Braina
Huntington disease
Frontal cortex (10)
Caudate ( 7 )
Putamen (6)
Amygdala ( 7 )
Hippocampus ( 1 2 )
Alzheimer disease
Frontal cortex ( 5 )
Frontal cortex ( 12)
Caudate ( 8 )
Putamen (18)
Amygdala (18)
Hippocampus ( 12)
3.0 t 0.4
5.3 ?
8.9 ? 2.1'
3.0 ? 0.4
2.7 ? O.Gd
t 0.004
t 0.150b
t 0.450'
3.3 t 0.4
13.3 t 0.8
17.9 % 1.4
3.8 0.5
4.0 t 0.4
t 0.004
t 0.090
"Activities are expressed as nanomoles per minute per milligram of protein, mean
Significance (by t test): ' p < 0.001; ' p < 0.005; ' p < 0.05.
180 -+ 4
200 t 6
207 t 1 1
187 ? 7
189 5 4
r 0.020
181 ? 4
201 t 6
194 t 5
177 ? 4
r 0.180
t 0.060
t 0.013
SEM. Number of patients is given in parentheses.
PDHC = pyruvate dehydrogenase complex; CAT = choline acetyltransferase.
=Huntington (n=55)
=Alzheirner (n=3)
Fig I. Pymvate dehydrogenase complex (PDHC) and choline
acetyltransferase (CAT)in Huntington and control hippocarnpus. Valuesfor CAT and PDHC, measured as described i n the
text, are in nmollminlmg brain protein. (e = controls; 0 =
Huntington disease.)
appearance was normal, although there was an overlap
with control values. In 4 of the 12 Huntington disease
samples, the value for PDHC was less than the lowest
control levels even though CAT activities were comparable to those in controls (Fig 1). The decrease was
significant (p < 0.05) by t test although not by the
Mann-Whitney U test 147). The activity of fumarase
was normal in all areas examined, although this enzyme, like PDHC, is a constituent of the inner mitochondrial membrane [17]. Activities for human brain
PDHC by the technique described here are two to five
times those reported by Perry et al C31). Possible technical reasons for the higher activity using this assay are
discussed elsewhere 122).
Based on all 130 brain samples assayed, a close cor-
74 Annals of Neurology Vol 13 No 1 January 1983
(nmol/min/mg protein)
Fig 2. Relation between pyruvate dehydrogenase complex
(PDHC) and choline acetyltransferase (CAT)in human brain.
PDHC and CAT activities were measured as described in the
text for samples from a total of 59 subjects. The cowelation was
> 0.9 (p < 0.001;PDHC = 6.55 CAT -+ 2.21).
relation was found between the activities of PDHC and
CAT in the regions studied (Fig 2 ) . However, examination of the data indicated that the correlation broke
down partially in two regions (Figs 1, 3). In hippocampus and frontal cortex (Brodmann area lo), PDHC was
9% and 18%, respectively, of the value for putamen,
while CAT activity was, respectively, 6% and 3% of
that for putamen. Note that the regression line in Figure 2 does not intercept zero. The average value for
PDHC for all control samples studied was 8.46 nmol/
mg proteidmin. This is only slightly higher than the
value for pyruvate Aux in human brain calculated from
Fig 3. Pyruvate debydrogenase complex ( P D H C ) and choline
acetyltransferase (CAT) in normal brain. PDHC and CAT,
measured as described in the text, are expressed as percent of putamen. At least 8 subjects were studied for each region. Ewor bars
indicate SEM.
Table 2. PDHC in Hzcntington Disease, Alzheimer Disease,
and Down Syndrome Fibroblasts"
Controls ( 4 )
Huntington (2)
the cerebral metabolic rate for oxygen or glucose,
which is 5 to 6 nmoYmg proteidmin {411. This observation agrees with previous studies which indicate little
excess of PDHC activity in brain {b]. For control
values, the intercept of PDHC activity where CAT
activity equals zero is 2.2 1 nmoYmg proteidmin, close
to the values reported by Perry et al [31] and Prick et
al 1331 for various brain regions. The close correlation
between CAT and PDHC should not be construed to
mean that PDHC activities above this value occur only
in cholinergic structures. Both frontal cortex and cerebellar cortex contain PDHC despite low or absent
CAT (see Fig 3).
No abnormality in activity or activation of PDHC
was detected in cultured skin fibroblasts from the
Huntington and Alzheimer patients, but both activity
and activation were significantly reduced in cells from
patients with C-2 1 trisomy Down syndrome (Table 2).
Alzheimer ( 1 )
D o w n (4)
2.68 +. 0.07
2.69 -C 0.01
1.59 +- 0.04b
44% +. 3
479% +. 2
24% -t- 4b
"Pyruvate dehydrogenase complex (PDHC) activity is expressed as
nanomoles per minute per milligram of protein, mean 5 SEM.
Numbers in parentheses are the number of individual cell lines
studied. Each cell line was studied in at least three different experiments, at least in triplicate in each experiment. PDHC was assayed
before (original) and after (activated) dephosphorylation by incubation at 37°C for 15 minutes with dichloroacetate. Activation is (activated - original)/activated, in percent.
bSignificance (by t test): p < 0.005.
The latter are at high risk to develop Alzheimer disease
Four pieces of information suggested the value of
studying PDHC in Huntington and Alzheimer diseases. There is a cholinergic deficit in these disorders,
Sorbi et al: Brain PDHC in Dementia
and a close correlation exists between pyruvate oxidation and acetylcholine metabolism in health and disease
{b, 20, 36, 37,481. Alzheimer disease and Huntington
disease are primarily neuronal disorders, and recent
data from three laboratories indicate that PDHC has a
major role in neuronal plasticity [lo, 26, 28, 291. Alzheimer and Huntington diseases have characteristics of
system degenerations, and abnormalities of PDHC
have been reported in other system degenerations I6,
461; indeed, there is increasing evidence that derangements of carbohydrate and energy metabolism may be
part of a number of system degenerations. Finally,
Perry et al 1301 described a decrease in PDHC activity
in Alzheimer cortex (which they considered secondary
to the cholinergic degeneration).
The connection between pyruvate oxidation and
acetylcholine synthesis has been discussed in detail [GI.
A close correlation between CAT and PDHC activity
in brain was reported in 1976 {36, 37) and confirmed
by Perry et alE31). Sterri and Fonnum 148) found that
lesions of rat brain which reduce CAT also selectively
decrease PDHC. The data in Figure 2 confirm and
extend these studies in human brain. Extensive experiments indicate that cholinergic systems are exquisitely
sensitive to conditions that impair pyruvate oxidation
in vivo and in vitro, and the resulting deficits in acetylcholine synthesis appear to be physiologically important 1201. Recent studies indicate that PDHC activity
may correlate even more closely with acetylcholine
turnover than does CAT activity 131, 49). The suggestion has been made that provision of acetyl-CoA from
pyruvate oxidation may be a rate-limiting step in acetylcholine synthesis [SO).
Studies of phosphoproteins in synaptic plasticity in
two laboratories have independently demonstrated that
the major protein for which the phosphorylation pitch
changes with training [28,29) or habituation [ 10,261 is
the 41,000 dalton a-peptide of PDHC. The critical
role of this enzyme in both synaptic plasticity and
neuronal energy metabolism makes it reasonable to
expect that it will be involved in the pathophysiology of
diseases which kill neurons.
Abnormalities of PDHC and other enzymes of carbohydrate and energy metabolism have been reported
in a number of system disorders: abnormalities of
PDHC in spinal ataxias {46}, Leigh disease [14, 451,
and Alzheimer disease [31); of glutamate dehydrogenase in cerebellar ataxias 132); of pyruvate carboxylase
in a selective degeneration of the cerebellar vermis
with intermittent ataxia {39}; and of phosphofructokinase in Alzheimer disease I91 and Huntington disease
[A]. In some of these conditions, the enzymatic
deficiencies do not appear to be genetically determined
since they are not expressed in all tissues examined,
and notably not in cultured skin fibroblasts. However,
the possibility of a brain-specific or brain-region-
76 Annals of Neurology Vol 13 No 1 January 1983
specific genetic deficit has not been completely ruled
out c331.
What, then, might the importance of the deficit in
PDHC be? Lassen et al[23] speculated that the reduction in cerebral glucose metabolism and blood flow
common to many dementing diseases results from loss
of brain structures with a high oxidative capacity. The
reduction in activity of PDHC, probably the ratelimiting enzyme for carbohydrate oxidation in brain,
agrees with that proposal. The decrease in PDHC activity might prove to play a role in the pathophysiology
of neuronal damage and death. In 1932, Quastel [343
The mental symptoms accompanying anoxaemia (as, for instance, that following ascents to high altitudes) are well
known. They incude loss of judgment and memory disorientation for time, irritability, and emotional instability. Abnormal mental symptoms accompany or follow carbon monoxide
poisoning, and there seems to be little question that anoxaemia of the brain leads to irrational behavior. Anoxaemia
may not only be created by lack of oxygen, however, but by
conditions being set up which render the oxygen unavailable
for oxidative purposes. Hence disturbances in the nervous
system which result in diminished rates of oxidation will be as
productive of mental disorder as lack of oxygen alone.
PDHC is a critical enzyme for carbohydrate oxidation, present in minimal excess in brain, and closely
involved in synaptic plasticity. It is reasonable to speculate that even mild impairments in this protein could
affect brain function. In Huntington disease the reduced value for PDHC in hippocampus, a histologically normal area with normal CAT, suggests that reductions in PDHC precede loss of CAT and death of
nerve endings in affected areas rather than simply
reflecting such damage, although further studies with
more samples are needed to test this proposal. Similarly, the existence of an abnormality of PDHC activity
and activation in Down syndrome fibroblasts suggests
that PDHC deficiency may have a role in the
pathophysiology of some forms of dementia, since
more than 90% of patients with C-21 trisomy Down
syndrome who live beyond 40 years have Alzheimer
changes and progressive intellectual deterioration [38).
The notion that intrinsic disorders of carbohydrate metabolism are a common mechanism in many system
deteriorations is a relatively simple (and old) idea. It
can now be checked experimentally.
Supported by The Will Rogers Institute, The Winifred Masterson
Burke Relief Foundation, Grant 6-215 from The National Foundation, and Grants NS 15125, NS 16994, NS 31862, and AA 03883
from the National Institutes of Health.
We thank Ms Andrea Baker for skilled technical assistance
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