Differential Alteration of Various Cholinergic Markers in Cortical and Subcortical Regions of Human Brain in Alzheimer's Disease

Abstract

The main objective of the present study was to determine whether cholinergic markers (choline acetyltransferase activity and nicotinic and muscarinic receptors) are altered in Alzheimer's disease. Choline acetyltransferase activity in Alzheimer's brains was markedly reduced in various cortical areas, in the hippocampus, and in the nucleus basalis of Meynert. The maximal density of nicotinic sites, measured using the novel nicotinic radioligand N-[3H]methylcarbamylcholine, was decreased in cortical areas and hippocampus but not in subcortical regions. M1 muscarinic cholinergic receptor sites were assessed using [3H]pirenzepine as a selective ligand; [3H]pirenzepine binding parameters were not altered in most cortical and subcortical structures, although the density of sites was modestly increased in the hippocampus and striatum. Finally, M2-like muscarinic sites were studied using [3H]-acetylcholine, under muscarinic conditions. In contrast to M1 muscarinic sites, the maximal density of M2-like muscarinic sites was markedly reduced in all cortical areas and hippocampus but was not altered in subcortical structures. These findings reveal an apparently selective alteration in the densities of putative nicotinic and muscarinic M2, but not M1, receptor sites in cortical areas and in the hippocampus in Alzheimer's disease.

Comparison of Noninvasive Quantification Methods of in Vivo Vesicular Acetylcholine Transporter Using [123I]-IBVM SPECT Imaging

“…The reference region was the occipital cortex where choline acetyltransferase levels from postmortem studies (McGeer et al, 1980;Araujo et al, 1988) and [ 123 I]-IBVM specific binding from an in vivo study (Kuhl et al, 1994) were found to be lowest.…”

Roles of Nicotinic Receptors in Acetylcholinesterase Inhibitor-Induced Neuroprotection and Nicotinic Receptor Up-Regulation

“…2,3) Selective depletion of cholinergic neurons in the basalis of Meynert, decreased choline acetyltransferase and acetylcholinesterase activity, or down-regulation of neuronal nicotinic acetylcholine receptors suggest the roles of cholinergic deficits in Alzheimer's disease. [3][4][5][6][7][8][9][10] Donepezil, galantamine and tacrine are acetylcholinesterase inhibitors (AChEI) that have been developed for the treatment of AD under the presumption that increasing cholinergic transmission through inhibition of acetylcholinesterase will enhance cognitive function. 11,12) Donepezil is a potent and reversible acetylcholinesterase inhibitor that shows moderate improvement of cognitive function with minimal side effects 13) (Fig.…”

Aversive stimulus attenuates impairment of acquisition in a delayed match to position T-maze task caused by a selective lesion of septo-hippocampal cholinergic projections

“…Based on experiments utilizing muscarinic antagonists and/or nonselective physical or chemical lesions, cholinergic neurons projecting to the cerebral cortex and hippocampus have been identified as playing an important role in learning, memory, and attentional processes [2,3,15,19]. Moreover, in humans the loss of basal forebrain cholinergic neurons has been associated with Alzheimer's disease [1]. An understanding of the role of the basal forebrain in learning and memory has accelerated since the development of agents such as 192 IgG-saporin (SAP), that selectively lesion p75NTR-containing cholinergic neurons [9,46,48].…”