Targeting intracellular Aβ42 for Alzheimer's disease drug discovery

Michael R. D'Andrea, Daniel H.S. Lee, Hoau Yan Wang, Robert G. Nagele

Research output: Contribution to journalReview article

12 Scopus citations

Abstract

For years, extracellular deposition of the "pathologic" β-amyloid1-42 (Aβ42) in the brain has been considered as the major cause of the appearance of neuritic plaques that are subsequently responsible for neuronal death in Alzheimer's disease (AD). However, recent work has shown that significant amounts of β-amyloid, especially Aβ42, are being sequestered within the perikaryon of affected pyramidal neurons prior to the appearance of plaques. This has led us to challenge the prevailing theory and suggest that at least some of the amyloid plaques, specifically the dense-core plaques in the cerebrum and hippocampus, may derive from the lysis of those neurons that are overburdened with intracellular Aβ42. We discuss the possible role of intracellular Aβ42 accumulation in the development of AD pathology and review an alternate hypothesis, where Aβ42 is first accumulated inside the neurons and later released out to the brain parenchyma via neuronal lysis finally forming a dense-core plaque ("Inside-Out" hypothesis). We describe a mechanism for Aβ42 internalization into neurons that involves the high affinity interaction between Aβ42 and the alpha7 nicotinic acetylcholine receptor (α7nAChR) and the internalization and intracellular accumulation of the Aβ42/α7nAChR complex. This alternative hypothesis can account for many of the well-known features of AD pathology, including specific cholinergic and cholinoceptive neuronal and synaptic loss that affects cognitive and memory functions, the distribution, morphology and composition of dense-core plaques, and their association with inflammation. More importantly, it provides the scientific rationale for targeting the mechanisms that lead to the intraneuronal Aβ42 as a novel strategy for AD drug discovery.

Original languageEnglish (US)
Pages (from-to)194-200
Number of pages7
JournalDrug Development Research
Volume56
Issue number2
DOIs
StatePublished - Jun 2002

All Science Journal Classification (ASJC) codes

  • Drug Discovery

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