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Central cholinergic activity in aluminum-induced neurofibrillary degeneration.

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Central Cholinergic
Activitv in
Bogumil Hetnarski, PhD,
Henryk M. Wisniewski, MD, PhD, Khalid Iqbal, PhD,
John D. Dziedzic, PhD, and Abel Lajtha, PhD
Choline acetyltransferase (CAT) and acetylcholinesterase (AChE) activities were measured in spinal cord
homogenates from rabbits with aluminum-induced
neurofibrillary degeneration and a group of salinetreated, age-matched controls. All aluminum-treated
animals showed neurofibrillary changes in the spinal
cord, but CAT and AChE activities were not significantly different from levels in control animals.
These results are at variance with the greatly reduced
activity of these enzymes observed in Alzheimer disease and senile dementia of the Alzheimer type.
Hetnarski B, Wisniewski HM, Iqbal K, et al:
Central cholinergic activity in aluminuminduced neurofibrillary degeneration.
Ann Neurol 7:489-490, 1980
Recent studies at several laboratories [l, 4,8,9] have
revealed a decrease in the activities of cerebral cholinergic enzymes and an elevated level of brain
aluminum in Alzheimer disease (AD) and senile
dementia of the Alzheimer type (SDAT) [2, 31. Although we were unable to corroborate the high aluminum levels [7], it has been suggested that aluminum, as a neurotoxic agent, might be involved in the
inception and development of the AD and SDAT.
One of the most characteristic features of these disorders is the presence of many intraneuronal
neurofibrillary tangles. The cited studies prompted
us to examine alterations in the activity of cholinergic
enzymes accompanying aluminum-induced neurofibrillary degeneration in rabbits.
Materials and Methods
We used spinal cord to analyze cholinergic activity inasmuch as this region of the central nervous system shows the
From the New York State Institute for Basic Research in Mental
Retardation, Staten Island, NY, and the Center for Neurochemistry, Wards Island, NY.
Received Oct 1, 1979. Accepted for publication Nov 11, 1979.
Address reprint requests to Dr Wisniewski, N.Y.S. Institute for
Basic Research in Mental Retardation, 1050 Forest Hill Rd, Staten
Island, NY 10314.
most consistent neurofibrillary changes in aluminuminduced encephalomyelopathyin rabbits [ 101. For this purpose we used ten 7-week-old rabbits of both sexes, five of
which were injected via the cisterna magna with 0.1 ml of a
1% solution of aluminum chloride in saline; the other 5
animals were injected only with saline and served as controls. After 10 to 1 5 days, when the aluminum-treated animals developed neurological symptoms, the experimental
and control rabbits were decapitated and their spinal cords
were dissected into cervical, thoracic, and lumbosacral regions. A 5 mm section from the cervical region of the spinal
cord was fixed in 10% neutral formalin, embedded in
paraffin, and stained according to the Bodian method. The
remaining tissue was used for assaying the activity of
choline acetyltransferase (CAT) and acetylcholinesterase
(AChE) according to the modified Fonnum radiochemical
method [5].
Results and Discussion
All aluminum-treated animals showed neurofibrillary
changes in the spinal cord, while saline-in jected controls were unaffected. The activities of CAT and
AChE are listed in the Table. It can be seen that the
activity of cholinergic enzymes in spinal cord was
practically the same in control and experimental animals. There was some difference in the CAT activity
in lumbosacral spinal cord between the two groups,
but it was not statistically significant.
T o study whether the effect of neurofibrillary
changes on central cholinergic activity was masked by
the epileptic seizures in aluminum-treated animals,
CAT and AChE activities were determined in a group
of five rabbits 5 days after aluminum treatment. At
this stage, neurofibrillary changes in spinal cord
were present to a moderate degree but the animals
showed no clinical symptoms. We were unable to
detect any significant differences in either CAT or
AChE activities in the lumbar spinal cord between
aluminum-treated and saline-treated animals.
The direct effect of aluminum on CAT was an associated problem in this investigation. T o test the
effect of aluminum on enzyme activity, aluminum
chloride was added to the incubation mixtures of the
thoracic spinal cord homogenate. Aluminum had an
inhibitory influence on CAT, as shown in the Figure.
However, in spite of the very high aluminum concentration (550 pg/gm wet tissue), maximum inhibition was 20%. The aluminum concentration in Alzheimer brain is much lower (about 1 pg/gm wet
tissue; see [3]) while CAT activity is reduced up to
80% [ l , 4, 91, suggesting that aluminum cannot be
blamed for direct inhibition of CAT.
The observation that cholinergic enzyme activity
was unaltered in spinal cord showing neurofibrillary
degeneration is at variance with the greatly reduced
activity of these enzymes observed in A D and SDAT.
McDermott et a1 [6] have reported a deficiency in
0364-5 134/80/050489-02$01.25
1979 by Henryk M. Wisniewski 489
Effect of Aluminum-induced Encephalomyelopathy on Activity of Choline Acetyltransferase and Acetylcholinesterase
Differe n c e (%)
(t test)
1.4 It_ 0.2 (N = 12)
1.2 2 0.1 (N = 12)
1.4 ? 0.1 (N = 1 2 )
0.2 (N = 12)
1.2 f 0.3 (N = 12)
1.8 2 0.2 (N = 1 2 )
< 0.2
542 50 (N = 12)
433 30 (N = 12)
479 -+ 49 (N = 1 2 )
Lum bosacral
7 9 (N
* 47 (N = 12)
443 +. 5 5 (N = 1 2 )
- 5.0
- 15.2
not significant.
r 3
.E 10.
uq AICI, / g W e t Tissue
In vitro effect of aluminum chloride (AlCLj) on activity of
choline acetyltransferase ( C A T ) i n normal rabbit spinal cord.
Aluminum chloride solution was added to the incubation
mixture f o r CAT assay.
central cholinergic activity in scrapie-infected mice.
These animals are known to show no neurofibrillary
changes. It is therefore possible that the deficiency of
cholinergic activity in A D and SDAT may be independent of neurofibrillary degeneration in these patients. Many synapses forming the neuritic (senile)
plaques in A D and SDAT are abnormal, which may
contribute to cholinergic deficiency in these conditions. The lack of change in cholinergic activity in
aluminum-induced encephalomyelopathy described
here may be due to the short clinical course of this
condition in contrast to the chronicity of AD, SDAT,
and scrapie.
490 Annals of N e u r o l o g y Vol 7 No 5 May 1980
Supported in part by Grant NS-14495 from the National Institutes of Health.
1. Bowen MD, Smith CB, White P, et al: Neurotransmitterrelated enzymes and indices of hypoxia in senile dementia and
other abiotrophies. Brain 99:459-496, 1976
2. Crapper DR, Krishnan SS, Dalton AJ: Brain aluminum distribution in Alzheimer's disease and in experimental
neurofibrillary degeneration. Science 180:511-513, 1973
3. Crapper DR, Krishnan SS, Quittkart S: Aluminum,
neurofibrillary degeneration and Alzheimer's disease. Brain
99~67-80, 1976
4. Davies P, Maloney AJE: Selective loss of central cholinergic
neurons in Alzheimer's disease. Lancet 2:1403, 1976
5. Fonnum F Radiochemical assays for choiine acetyltransferase
and acetylcholinesterase, in Marks N , Rodnight R (eds): Research Methods in Neurochemistry. New York, Plenum,
1975, V O ~3, pp 253-215
6. McDermott JR, Fraser H, Dickinson AG: Reduced cholineacetyltransferase activity in scrapie mouse brain. Lancet
11218-219, 1978
7 McDermott JR, Smith AI, Iqbal K, ec al: Aluminum and
Alzheimer's disease. Lancet 2:7 10-71 1, 1977
8. Perry EK, Gibson PH, Blessed G, et al: Neurotransmitter enzyme abnormalities in senile dementia. J Neurol Sci 34:247265, 1977
9. Perry EK, Perry RH, Blessed G, et al: Necropsy evidence of
central cholinergic deficits in senile dementia. Lancet 1:189,
10. Wisniewski H , Narkiewicz 0,Wisniewski K: Topography and
dynamics of neurofibrillary degeneration in aluminum encephalopathy. Acta Neuropathol 9:127-133, 1967
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central, induced, degeneration, activity, aluminum, neurofibrillary, cholinergic
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