Neuronal receptors as targets for the action of amyloid-beta protein (Aβ) in the brain

Abstract

Accumulation of neurotoxic soluble amyloid-beta protein (Aβ) oligomers in the brains of patients with Alzheimer disease (AD) and their role in AD pathogenesis have emerged as topics of considerable interest in recent years. Soluble Aβ oligomers impair synaptic and neuronal function, leading to neurodegeneration that is clinically manifested by memory and cognitive dysfunction. The precise mechanisms whereby Aβ oligomers cause neurotoxicity remain unknown. Emerging insights into the mechanistic link between neuronal receptors and soluble Aβ oligomers highlight the potential role of these receptors in Aβ-mediated neurotoxicity in AD. The current review focuses on studies describing interactions between soluble Aβ oligomers and neuronal receptors, and their role in AD pathogenesis. Furthermore, these studies provide insight into potential therapies for AD using compounds directed at putative target receptors for the action of Aβ in the central nervous system. We focus on interactions of Aβ with subtypes of acetylcholine and glutamatergic receptors. Additionally, neuronal receptors such as insulin, amylin and receptor for advanced glycation end products could be potential targets for soluble Aβ-oligomer-mediated neurotoxicity. Aβ interactions with other receptors such as the p75 neurotrophin receptors, which are highly expressed on cholinergic basal forebrain neurons lost in AD, are also highlighted.

The P’s and Q’s of cellular PrP-Aβ interactions

“…20 The list of former partners on both sides of the family has created concern for the longevity of the new union, and certainly hydrophobic aspects of PrP and the multiplicity of physiochemical forms of Aβ might go some way to explaining the situation. In one view, PrP C has an intrinsic range to its binding partners, as it has been proposed to dock different types of amyloid assembly.…”

Impact of Sustained Exposure to β-Amyloid on Calcium Homeostasis and Neuronal Integrity in Model Nerve Cell System Expressing α4β2 Nicotinic Acetylcholine Receptors

“…Among an array of different targets at synapses to which A␤ might bind and exert downstream effects, those of notable significance are neuronal nicotinic acetylcholine receptors (nAChRs) and metabotropic glutamate receptors (9). The nAChRs play important modulatory roles in neuronal development and synaptic plasticity, participating in cognitive functions such as learning, memory, and attention (10).…”

Is Preservation of Cholinergic Activation a Mechanism Underlying Cognitive Reserve?

“…Glutamatergic activation in the hippocampus is modulated by several neuronal networks, including adrenergic and cholinergic neurons [5]. In the AD brain, glutamatergic neuronal activity may be impaired and incompletely suppressed by Aβ oligomers as glutamatergic neurons are in an unsaturated condition [6].Interestingly, enriched environments have been found to prevent the impairment of hippocampal long term potentiation (LTP), the classical electrophysiological model of memory [7]. This process is thought to occur via β2-adrenergic signals, when LTP is incompletely suppressed by synthetic Aβ oligomers [7].…”

“…Glutamatergic activation in the hippocampus is modulated by several neuronal networks, including adrenergic and cholinergic neurons [5]. In the AD brain, glutamatergic neuronal activity may be impaired and incompletely suppressed by Aβ oligomers as glutamatergic neurons are in an unsaturated condition [6].…”