Role of amyloid β peptides in the regulation of central cholinergic function and its relevance to Alzheimer's disease pathology
✍ Scribed by S. Kar
- Publisher
- John Wiley and Sons
- Year
- 2002
- Tongue
- English
- Weight
- 156 KB
- Volume
- 56
- Category
- Article
- ISSN
- 0272-4391
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✦ Synopsis
Abstract
The neuropathological features associated with Alzheimer's disease (AD) brain include the presence of extracellular neuritic plaques composed of amyloid β protein (Aβ), intracellular neurofibrillary tangles containing hyperphosphorylated tau protein, and the loss of basal forebrain cholinergic neurons that innervate regions such as the hippocampus and the cortex. Studies of the pathological changes that characterize AD and several other lines of evidence indicate that Aβ accumulation in vivo may initiate and/or contribute to the process of neurodegeneration and thereby the development of AD. However, the mechanisms by which Aβ peptide influences/causes degeneration of the basal forebrain cholinergic neurons and/or the cognitive impairment characteristic of AD remain obscure. A number of recent studies indicate that physiological concentrations of soluble Aβ‐related peptides, under acute conditions, can negatively regulate various steps of acetylcholine (ACh) synthesis and release without inducing any apparent toxicity, suggesting a possible neuromodulatory role for the peptide in the regulation of central cholinergic functions. Chronic exposure to μM concentrations of Aβ peptides, on the other hand, evokes toxicity in cholinergic neurons, possibly via hyperphosphorylation of tau protein. Activation of selected cholinergic receptors has been shown to influence the processing of amyloid precursor protein as well as modulation of tau phosphorylation. More recently, a direct interaction between nicotinic ACh receptor and Aβ peptides have been demonstrated using a variety of approaches. This review focuses on the role of Aβ‐related peptides in the regulation of function/survival of central cholinergic neurons and its relevance to the cholinergic deficits observed in AD brains. Drug Dev. Res. 56:248–263, 2002. © 2002 Wiley‐Liss, Inc.