Selective Reduction of Quisqdate (AMPA) Receptors in Alzheirner Cerebellum D. Dewar, PhD, D. T. Chalmers, PhD, A. Shand, BSc, D. I. Graham, MD, and J. McCulloch, PhD Multiple sites involved in glutamatergic neurotransmission were examined in the cerebellar cortex of 6 patients with Alzheimer’s disease and 6 age-matched control patients by using quantitative ligand-binding autoradiography. Quisqualate (AMPA) receptor binding was markedly reduced in the molecular layer of the cerebellum from patients with Alzheimer’s disease (167 ? 13 pmoleslgm) compared with control patients (280 ? 13 pmoles/gm). In adjacent sections from the same patients and controls, there was preservation of kainate and N-methyl-Baspartate receptor binding in the cerebellum from patients with Alzheimer’s disease compared with control patients. Neuropathological examination of the cerebelIar cortex revealed the presence of plaques and preservation of Purkinje cells in the patients with Alzheimer’s disease. Dewar D, Chalmers DT, Shand A, Graham DI, McCulloch J. Selective reduction of quisqualate (AMPA) receptors in Alzheimer cerebellum. Ann Neurol 1990;28:805-810

Abnormlties of glutamatergic neurotransmission in both cortical and archicortical brain regions have been extensively documented in Alzheimer’s disease { 1-61. We have previously reported differential alterations in glutamate receptor subtypes in frontal cortex in Alzheimer’s disease {7]. We found a pronounced increase in kainate receptor subtype binding, localized specifically to deep cortical layers (IV-Vl), which was positively correlated with the local number of neuritic plaques. Classical plaques comprising an amyloid core surrounded by a halo of degenerating neurites and prohferating glia are rarely observed in the cerebellum in Alzheimer’s disease. There are reports of a distinct type of cerebellar plaque, however, which appears to be morphologically distinct from the classic type of plaque observed in cortical regions [S-151. In the present study, we have investigated glutamate receptor subtypes in the cerebellum of subjects with Alzheimer‘s disease by using quantitative ligandbinding autoradiography to determine the status of glutamatergic systems in a brain region that is largely unaffected by the type of structural abnormalities commonly observed in the cerebral cortex.

Materials and Methods Fresh brains were obtained postmortem from 6 control patients who had no known history of neurological or psychiat-

From the Wellcome Neuroscience Group, Wellcorne Surgical Institute and Hugh Fraser Neuroscience Laboratories, University of Glasgow, UK. Received Apr 17, 1990, and in revised form Jun 25. Accepted for publication Jun 25, 1990.

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*

ric disorders ( 2 males, 4 females; age, 84 2 years {mean SEM)) and from 6 patients who had a clinical diagnosis of Alzheimer’s disease (2 males, 4 females; age, 89 f 2 years [mean 5 SEMI). One-centimeter-thick slices of cerebellar cortex, including the dentate nucleus, were dissected out, frozen in isopentane ( - 40”C), and stored at - 80°C. The delay from time of death until freezing of brain tissue ranged from 11 to 23 hours for brains from control patients and from 3 to 15 hours for brains from patients with Alzheimer’s disease. After dissection, the remainder of the cerebellum and a designated number of other regions from the rest of the brain were fmed in 10% formalin for neuropathological examination. All brains had confirmation of control or Alzheimer status according to the number of neuritic plaques in cerebral cortex as described by Khachaturian Cl6). For receptor autoradiography, blocks of cerebellar cortex were cut into nominal 20-pm-thick cryostat sections and mounted onto glass slides. Serial sections were used for the determination of 3H-kainatebinding, 3H-amino-3-hydroxy5-methylisoxazole-4-propionic acid (3H-AMPA) binding, and NMDA-sensitive 3H-glutamatebinding in brains of both patients with Alzheimer’s disease and control patients, according to previously described protocols 171. For each ligand, sections of brain from control patients and patients with Alzhemer’s disease were incubated and washed simultaneously. All sections were preincubated for 1 hour at 4°C followed by 15 minutes at 30°C in the following buffers: 50 mM Trdacetate pH 7.2 for 3H-glutamate binding and 3H-AMPA binding, and 50 mM Tdcitrate pH 7.0 for ?Hkainate binding. Incubations were at 4°C with 150 nM 3H-

Address correspondence to Dr Dewar, Wellcorne Surgical Institute and Hugh Fraser Neuroscience Labs, Garscube Estate, Bearsden Road, Glasgow, Gbl lQH, Scotland, UK

Copyright 0 1990 by the American Neurological Association 805

0

Control Alzheimer

* p < 0.001

Molecular Layer

Granular Layer

Fig 2. 3H-Amino-3-hydroxy-5-methylisoxazole-4-propionicacid (jH-AMPA) (A).binding i n cerebellar sections from brains of control patients and patients with Alzheimds disease derived from computer-assisted densitometrzc analysts of autoradiograms. Data are mean SEM, n = 6, for each group. Lpvel of sign$cance was determined by unpaired, two-tailed Student's t test.

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+

Fig 1 . Representative autoradiograms showing the total binding of H-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (jH-AMPA) (A),NMDA-sensitive 'H-glutamctte (B), and 3H-kainate (C) t o consecutive cerebellar sections from a brain fmm a control patient ildt) and a brain from a patient with Alzheime#s disease (right). The molecular (M) and granular (G) layers of the cerebellar cortex are indicated by arrows. Note the pronounced reduction in 'H-AMPA binding (A)in the section from a patient with Alzheimwk disease compared with the section from the control patient, which is confined to the molecular layer. In the same brains, the levels of both NMDA-sensitive 3H-glutamate (B) and 'H-kainate (C) binding are similar in sectionsfrom the control patient and the patient with Alzheimer's disease.

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806 Annals of Neurology

glutamate ( 5 fl quisqualic acid and 100 )LM4-acetamido4'-isothio-cyanatostilbene-2,2'-disulfonic acid, a chloride channel blocker) for 10 minutes, 130 nM 'H-AMPA (+ 100 mM potassium thiocyanate) for 30 minutes, and 50 nM 3Hkainate for 30 minutes. For saturation experiments using 3H-AMPA, sections from all brain, of control patients and patients with Alzheimer's disease were incubated with increasing concentrations of llgand over the range of 25 to 800 nM. After incubation, all sections received 4 x 5-second washes in buffer (4°C) and one rinse in distilled water (4"C), then were dried rapidly in a stream of cold air with the addition of 1 ml 2.5% gluteraldehyde in acetone solution. Sections were then placed in roentgenographic cassettes with 3H-microscales (Amersham International, Aylesbury, England) and apposed to 3H-Hyperfilm (Amersham) for 4 to 6 weeks. The resulting receptor autoradiograms were analyzed by using a Quantimet 970 (Cambridge Instruments, Cambridge, England) image-analysis system. Mean optical density for each lamina was calculated from six individual readings averaged over three sections. Binding to discrete cerebellar laminae was determined by comparison of autoradiograms with adjacent cresyl violet-stained sections. Optical density values were converted to picomoles per gram of tissue with reference to the recalibrated 3H-microscales and the specific activities of the ligands. In brains of both control patients and patients with Alzheimer's disease, the levels of specific binding for 3H-kainate, 3H-AMPA, and NMDA-displaceable 3H-glutamate were 60%, 70%, and 55%, respectively. Neuropathological examination was performed on sections cut from the fixed tissue blocks, which were no more than 0.5 cm medial to those used for receptor autoradiography. To determine the presence of plaques, 28-pm-thick frozen cerebellar sections from both control patients and

Vol 28 No 6 December 1990

GRANULAR LAYER

MOLECULAR LAYER

0.1

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100 200 AMPA Bound (pmol/g tissue)

300

A Fig 3. Saturation analysis of3H-arnino-3-hydroxy-5-methylisoxazole-4-propionicacid (-IH-AMPA) binding to cerebellar sections. The graphs illustrate linear regression linesfrom one typical brain from a conrrol patient (0) and one typical brain fyom a patient wirh Alzheimerj- disease (A).The B,, and &values represent the mean ? SEM, n = 6: for both groups. The mean Em, value for ’H-AMPA binding in the moleczlkzr layer (A) was signifcantlj reduced in the gmup of patients wirh Alzheimer‘s disease compared with conid patients. (B) Granular layer. “p < 0.05, Student’s t test.

patients with Alzheimer’s disease were stained with King’s amyloid silver stain. Additional cerebellar sections from patients with Alzheimer’s disease were stained with Congo red, thioflavine T, and antisera to paired helical filaments (ICN Immunobiologicals, High Wycombe, England). Purkinje cell numbers were determined in 10-pm-thick paraffin waxembedded sections stained with cresyl violet. The total number of Purkinje cells lying within the entire Purkinje cell line of a section was determined by using the nucleolus as the cell marker [17]. The length of the cell line was determined by tracing the outline of the line on a photograph of the section by using an image analyzer (Quantimet 520, Cambridge Instruments). The results were then expressed as the number of Purkinje cells per millimeter of cell line. All neuropathological examinations were performed independently by an investigator who had no prior knowledge of the ligandbinding studies or the identity of the sections. The brains of patients with Alzheimer’s disease used in the present study had abundant plaques in the cerebral cortex. For example, in frontal cortex, the mean ? SEM number of plaques was 35 -C 6imm’ in cortical layers 1-111 and 2 1 t 4imm2 in layers IV-VI. Brains of control patients had no

greater than 2 plaques/mm2 in cerebral cortex. Additionally, the brains of patients with Alzheimer’s disease exhibited pronounced reductions in choline acetyltransferase (ChAT) activity in cerebral cortex compared with control patients. For example, in frontal cortex, the mean 2 SEM levels of ChAT activity were 5.3 & 0.8 nmolimg proteinihr for control patients and 2.0 -t 0.3 nmol/mg protein/hr for patients with Alzheimer’s disease. Statistical differences between control patients and patients with Alzheimer’s disease were determined by using an and Kd values from unpaired, two-tailed Student’s t test. B, 3H-AMPA-saturation experiments (25-800 nM) were derived by linear regression analysis.

Results Binding to glutamate receptor subtypes exhibited a differential laminar distribution in cerebellar cortex of control patients. 3H-AMPA binding to quisqualate receptors was greater in the molecular layer than in the granule cell layer, whereas the opposite was true for 3H-kainate and NMDA-sensitive 3H-glutamate binding. In the brains of patients with Alzheimer’s disease, there was a pronounced reduction of 3H-AMPA binding in the molecular layer of cerebellar cortex compared with control patients; whereas, in the granule cell layer, there was no difference between the two groups of patients (Figs lA, 2). Scatchard analysis of 3H-AMPA binding over the range of 25 t o 800 nM in sections from all patients in both the control group and the group of patients with Alzheimer’s disease revealed a significant reduction in the B, value in the

Dewar et al: Alzheimer Cerebellum 807

significant loss of these cells in the brains of the patients with Alzheimer’s disease compared with control patients. This suggests that the reduction in 3H-AMPA binding in the cerebella of the patients with Alzheimer’s disease is unlikely to be due simply to a loss of these neurones. In adjacent sections from the same brains, there was no difference between cerebella of control patients and patients with Alzheimer’s disease in the levels of 3H-kainate binding (molecular layer, control patients 30.8 r 2.8, patients with Alzheimer’s disease 32.0 t 1.1 pmol/gm; granular layer, control patients, 40.1 +2.8, patients with Alzheimer’s disease, 39.4 +- 0.9 Pmol/gm [mean SEMI), or NMDA-sensitive 3H-glutamate binding (molecular layer, control patients, 19.3 _t 1.6, patients with Alzheimer’s disease, 15.7 +- 2.6 pmol/gm; granular layer, control patients, 25.6 ? 1.5, patients with Alzheimer’s disease, 24.7 t_ 2.9 pmol/gm [mean k SEMI). Examination of cerebellar sections stained with Kmg’s amyloid, adjacent to those used for autoradiography, revealed 4 of the 6 patients with Alzheimer’s disease to have plaques in the cerebellar cortex (Fig 4). These lesions, although relatively few in number compared with cerebral cortex, were present predominantly in the molecular layer of the cerebellar cortex and had a diffuse appearance that was quite distinct from that of the classical neuritic plaque of the cerebral cortex. Cerebellar plaques had a characteristically elongated appearance with a perivascular orientation that was somewhat accentuated beneath the pia. These plaques were comprised of degenerating neurites and did not stain with Congo red or thioflavin T. They were also not stained by the antisera to paired helical filaments. The contrasting appearance between cerebella plaques and those observed characteristically in the cerebral cortex is illustrated in Figure 4. Cerebellar plaques were not present in sections from brains of control patients, and neurofibrillary tangles were not observed in cerebellar sections from brains of either control patients or patients with Alzheimer’s disease.

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Fig 4. Photomacrographs of sections stained with King’s smyloid from a patient wtth Alzheimer’s disease. (A) A section of cerebellar cortex illustrating the typical dtffzse, elongated appearance of

cerebellar plaques. Contrast this wzth the appearance o j the classical neuriticplaqzre in (B}, which shows a section of cwebral cortex. (Originalmagnification X 127.)

molecular layer of the brains from patients with Alzheimer’s disease compared with control patients (Fig 3A). B, values in the granule cell layer were no different between the two groups of patients, and Kd values were similar in cerebella of both control patients and patients with Alzheimer’s disease, in both the molecular and granular layers (Fig 3B). Thus, the reduction in 3H-AMPA binding in the cerebellar molecular layer of the patients with Alzheimer’s disease most probably reflects a loss of quisqualate (AMPA) receptors rather than an alteration in the ligand-binding properties of these sites. Autoradiographic studies in rodents indicate that the majority of cerebellar quisqualate receptors are localized on the dendrites of Purkinje cells that extend into the molecular layer [la]. Determination of Purkinje cell numbers in cerebellar cortices of both control patients (cells/mm, 2.3 ? 0.2 {mean -+ SEM}) and patients with Alzheimer’s disease (cells/mm, 2.0 +- 0.2 {mean 1 SEM}) in the present study revealed no 808 Annals of Neurology Vol 28

Discussion The cerebellum, until recently, has been regarded as a brain region largely spared by the pathophysiological process of Alzheimer’s disease, particularly in comparison with the pronounced morphologcal changes that take place in the cerebral cortex and hippocampus {19}. There is increasing evidence, however, that the cerebellar cortex undergoes a degree of pathological change in Alzheimer’s disease [S-15}. In view of the prominent role played by glutamate in cerebellar neurotransmission C20-22) and an increasing body of evidence indicating cortical glutamatergic dysfunction in Alzheimer’s disease [1-7], the present study examined multiple glutamate receptor subtypes in brains of

No 6 December 1990

patients with Alzheimer’s disease by using ligandbinding autoradiograp hy . The most striking finding of the present study is the massive and selective reduction in AMPA binding to quisqualate (AMPA) receptors in the molecular layer of the cerebellar cortex of patients with Alzheimer’s disease. In adjacent sections from the same brains of patients with Alzheimer’s disease, there was no alteration in the level of kainate or NMDA-sensitive glutamate binding in the molecular layer. Autoradiographic studies of glutamate-binding sites in the rodent cerebellum indicate that the majority of cerebellar quisqualate receptors are localized on the apical dendrites of Purkinje cells that extend into the molecular layer 1181. In the patients with Alzheimer’s disease in the present study, however, the reduction in the number of AMPA-binding sites was not associated with a significant loss of Purkinje cells. Moreover, there was no significant correlation between levels of AMPA binding and the number of Purkinje cells either in the group of patients with Alzheimer’s disease alone ( r = 0.158) or when data from control patients and patients with Alzheimer’s disease were combined ( v = 0.226). Although determinations of Purkinje cell numbers were made in our study, we did not examine the dendritic arbor of these cells. Atrophic changes in the Purkinje cell tree, which pervades the cerebellar molecular layer, may explain the loss of quisqualate (AMPA) receptors in the brains of patients with Alzheimer’s disease. Kainate receptor binding, however, was unchanged in the molecular layer of the cerebellar cortex of patients with Alzheimer’s disease, and there is electrophysiological evidence indicating the presence of these receptors on Purkinje cells {23]. Moreover, the autoradiographic study of Olson and colleagues 1181 indicates that kainate receptors in the molecular layer are not located on the presynaptic terminals of parallel fiber inputs to Purkinje cells from the granule cells. Thus, it may be that at least a proportion of kainate receptors in the molecular layer are located on Purkinje cell dendrites. If the loss of quisqualate (AMPA) receptors in the molecular layer of the brains from the patients with Alzheimer’s disease was due entirely to dendritic atrophy, we might have anticipated that in the same patients, at least a proportion of the kainate receptor binding would be lost; however, t h s was not the case. The presence of cerebellar plaques in the molecular layer indicated that a degree of structural change had occurred in at least 4 of the 6 patients with Alzheimer’s disease. All patients with Alzheimer’s disease had significantly reduced AMPA binding in the molecular layer regardless of whether cerebellar plaques were observed. It was noted, however, that the 2 subjects who did not have cerebellar plaques had slightly higher levels of AMPA binding than the other patients

in the group with Alzheimer’s disease. Thus, the AMPA receptor change occurred in the absence of cerebellar plaques. Until a structural basis for the alteration in quisqualate (AMPA) receptors can either be definitively established or refuted, alternative explanations for this finding may be proposed in terms of altered synaptic function. It cannot be determined from postmortem studies of this kind whether glutamate neuronal terminals in the cerebellum were functioning normally in vivo, that is, releasing and taking up normal levels of glutamate. Electrophysiological studies in rodents indicate that long-term modification of synaptic efficacy at Purkinje cell synapses results from alterations in presynaptic inputs 1241. Moreover, this phenomenon, known as long-term depression, involves desensitization of quisqualate receptors located on Purkinje cell dendrites [25]. Elucidation of such a phenomenon occurring in patients with Alzheimer’s disease, however, may require in vivo measurements of glutamate release. There are now many reports concerning cerebellar plaques in Alzheimer’s disease 18-15] as well as one report of neurofibrillary tangles in this brain area {26]. In the present study, we noted cerebellar plaques in the patients with Alzheimer’s disease which were situated predominantly in the molecular layer and which were much less profuse than cortical plaques. They had a structural appearance quite distinct from classical plaques, appearing as diffuse elongated structures with no obvious central core. Recently, preamyloid deposits have been described in the cerebellum of brains from patients with Alzheimer’s disease, which are postulated to consist of P-protein precursors and to precede amyloid deposition and neuritic degeneration 1271. The King’s silver stain used in the present study does not allow amyloid and neuritic components of cerebellar plaques to be differentiated, and therefore, the exact composition of these structures remains illdefined at present. They bear a striking resemblance to the diffuse cerebellar plaques described previously 112, 131, however, which stained both with Bielschowsky silver stain and p-protein antibodies. Lesions of this type are also present in cerebral cortex, in addition to classical neuritic plaques, and it has been suggested that they represent an early stage in plaque evolution [28]. In conclusion, we have found a significant reduction in quisqualate (AMPA) receptor binding in the cerebellar cortex in brains of patients with Alzheimer’s disease; whereas, in the same patients, there was preservation of kainate and NMDA receptor binding. It is not clear at present whether this selective alteration in quisqualate (AMPA) receptors is directly related to the pathophysiological process of the disease or if it is a consequence of morphological changes in anatomically related regions. It may be significant, however, that a Dewar et al: Alzheimer Cerebellum 8W

receptor loss of this magnitude occurs in the absence of gross neuronal loss. Thus, alterations in receptor populations may act as an interface between the pathogenic agents of Alzheimer’s disease and the appearance of structural change.

This work was entirely supported by the Wellcome Trust. We are grateful to Drs A. Moffoot and B. Murphy, Gartnavel Royal Hospital, Glasgow, for clinical information on patients, Mrs A. Lynch, Department of Neuropathology, Institute of Neurological Sciences, Glasgow, for neuropathological data, and Ann Marie Colquhoun for excellent secretarial assistance.

References 1 Cowburn R, Hardy J, Roberts P, Briggs R. Presynaptic and postsynaptic glutamatergic function in Alzheimer’s disease. Neurosci Lett 1988;86:109-113 2. Simpson MDC, Royston MC, Deakin JFW, et al. Regional changes in [3H]-D-aspartate and [3H]-TCP binding sites in Alzheimer’s disease brains. Brain Res 1988;462:76-82 3. Hardy J, Cowburn R, Baton A, et al. Region-specific loss of glutamate innervation in Alzheimer’s disease. Neurosci Lett 1987;73:77-80 4. Geddes JW, Chang-Chui H, Cooper SM, et al. Density and distribution of NMDA receptors in the human hippocampus in Alzheimer’s disease. Brain Res 1986;339:156-161 5. Greenamyre JT, Penney JB, DAmato CJ, Young AB. Demenria of the Alzheimer’s type: changes in hippocampal L-[~H)glutamate binding. J Neurochem 1987;48:543-551 Yao D, et al. [’H]TCP binding 6. Monaghan DT, Geddes JW, sites in Alzheimer’s disease. Neurosci Lett 1987;73: 197-200 7. Chalmers DT, Dewar D, Graham DI, et al. Differential alterations of cortical glutamatergic binding sites in senile dementia of the Alzheimer type. Proc Natl Acad Sci USA 1990;87: 1352-1356 8. Ishino H, Higashi S, Chuta M, Ohta H. Juvenile Alzheimer’s disease with myoclonus: amyloid plaques and grumose alteration in the cerebellum. Clin Neuropathol 1984;3:193-198 9. Vakili ST, M d e r J. Juvenile Alzheimer’s disease with cerebellar involvement. Arch Pathol Lab Med 1987;111:480-482 10. Pro JD, Smith CH, Sumi SM. Presenile Alzheimer disease: amyloid plaques in the cerebellum. Neurology 1980;30:82082 5 11. Cole G, Williams P, Alldryck D, Singharo S. Amyloid plaques in the cerebellum in Alzheimer’s disease. Clin Neuropathol 1989;8:188- 191 12. Joachim CL, Morris JH, Selkoe DJ. Diffuse senile plaques occur

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commonly in the cerebellum in Alzheimer’s disease. Am J Pathol 1989;135:309-319 13. Suenaga T, Hirano A, Llena JF, et al. Modified Bielschowsky and immunocytochemical studies on cerebellar plaques in Alzheimer’s disease. J Neuropathol Exp Neurol 1990;49:31-40 14. Yamaguchi H, Hivai S, Morimatsu M, et al. Diffuse type of senile plaques in the cerebellum of Alzheimer-type dementia demonstrated by B-protein imrnunostain. Acta Neuropathol 1989;77:320-328 15. Braak H, Braak E, Bohl J, Lang W. Alzheimer’s disease: amyloid in the cerebellum. J Neurol Sci 1989;93:277-287 16. Khachaturian 2s. Diagnosis of Alzheimer’s diseasc. Arch Neurol 1985;42:1097- 1104 17. Hall TC, Miller AKH, Corsellis JAN. Variations in the human Purkinje cell population according to age and sex. Neuropathol Appl Neurobiol 1975 ;1:267-292 18. Olson JMM, Greenamyre JT,Penney JB, Young AB. Autoradiographic localization of cerebellar excitatory amino acid binding sites in the mouse. Neuroscience 1987;22:913-923 19. Tomlinson BE, Corsellis JAN. Ageing and the dementias. In: Adams JH, Corsellis JAN, Duchen LW, eds. Greenfield‘s Neuropathology. London: Edward Arnold, 1984:951-1025 20. Foster GA, Roberts PJ. Neurochemical and pharmacological correlates of inferior olive destruction in the rat: attenuation of the events mediated by an endogenous glutamate-like substance. Neuroscience 1983;8:277-284 2 1. Freeman ME, Lane JD, Smith JE. Turnover rates of amino acid neurotransmitters in regions of the rat cerebellum. J Neurochem 1983;40: 1441-1447 22. Hudson BD, Valcana T, Bean G, Timiras PS. Glutamic acid, a strong candidate as the neurotransmitter of the cerebellar granule cell. Neurochem Res 1976;1:73-81 23. Garthwaite J, Garthwaite G, Hajos F. Amino acid neurotoxicity: relationship to neuronal depolarizdtion in rat cerebellar slices. Neuroscience 1986;18:449-460 24. It0 M, Sakurai M, Tongroach P. Climbing fibre induced depression of both mossy fibre responsiveness and glutamate sensitivity of cerebellar Purkinje cells. J Physiol (Lond) 1982;324:113134 25. Kano M, Kato M. Quisqualate receptors are specifically involved in cerebellar synaptic plasticity. Nature 1987;325:276279 26. Tabaton M, Cammarata S, Manetto V, et al. Tau-reactive neurofibrillary tangles in cerebellar cortex from patients with Alzheimer’s disease. Neurosci Lett 1989;103:259-262 27. Bugiani 0, Giaccone G, Frangione B, et al. Alzheimer patients: preamyloid deposits are more widely distributed than senile plaques throughout the central nervous system. Neurosci Lett 1989;103:263-268 28. Iselu E, Matsushita M, Kosaka K, et al. Distribution and morphology of brain stem plaques in Alzheimer’s disease. Acta Neuropathol 1989;78:13 1-136

Vol 28 No 6 December 1990

Selective reduction of quisqualate (AMPA) receptors in Alzheimer cerebellum.

Multiple sites involved in glutamatergic neurotransmission were examined in the cerebellar cortex of 6 patients with Alzheimer's disease and 6 age-mat...
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