Alterations of muscarinic acetylcholine receptor subtypes in diffuse Lewy body disease: relation to Alzheimer's disease

摘要

OBJECTIVES—Dementiaassociated with Lewy bodies in cortical and subcortical areas isclassified as dementia of the non-Alzheimer type and termed diffuseLewy body disease (DLBD). The generic term "dementia with Lewy bodies(DLB)" was proposed in the international workshop on Lewy bodydementia to include the similar disorders presenting Lewy bodies. InDLB, a lower level of choline acetyltransferase (ChAT) activity in theneocortex was found compared with that in Alzheimer's disease. Thepurpose of the present study was to determine the total amount ofmuscarinic acetylcholine receptors (mAChRs) and relative proportion ofeach subtype (m1-m4) of mAChRs in the frontal and temporal cortex ofseven DLBD and 11 Alzheimer's disease necropsied brains.
METHODS—A[3H]quinuclidinyl benzilate (QNB) binding assay and animmunoprecipitation assay using subtype-specific antibodies wereperformed. Each antibody was raised against fusion proteins containingpeptides corresponding to the third intracellular (i3) loops of therespective mAChR subtype.
RESULTS—The totalamounts of mAChRs were significantly lower in the preparations oftemporal cortices from DLBD and Alzheimer's disease than in those fromdead controls (seven cases). In both diseases, the proportion of the m3receptor in the frontal cortex was significantly increased and that ofthe m4 receptor in the temporal cortex was significantly decreasedcompared with the control specimens. The proportions of the m1 and m2subtypes were significantly different in the temporal cortex. Theproportion of the m1 receptor was significantly greater in the DLBDbrains, whereas that of the m2 receptor was significantly greater inthe Alzheimer's disease brains than in the controls.
CONCLUSIONS—The m1receptor is the major subtype in the cerebral cortex, and m2 is knownto be present at presynaptic terminals. The higher proportions of m1 inDLBD and m2 in Alzheimer's disease suggest that the manner of degeneration in the cholinergic system is different between the diseases. It is hypothesised that a severe depletion ofpresynaptic cholinergic projective neurons causes the upregulation ofm1 receptor in the temporal cortex in DLBD.