Role of Aβ degrading enzymes in synaptic plasticity and neurogenesis in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a leading cause of dementia in the aging population. This progressive neurodegenerative disorder is characterized neuropathologically by the presence of plaques composed of amyloid-β (Aβ) peptides and neurofibrillary tangles containing phosphorylated τ however, neurodegeneration in AD probably initiates with damage to the synaptic terminal. In addition to the neurodegenerative features of AD, the pathological process in this disorder is accompanied by significant alterations in adult neurogenesis in the hippocampus. Although the precise mechanisms leading to neurodegeneration and neurogenic alterations in AD are not completely understood, several lines of investigation indicate that enzymatic cleavage of Aβ may play an important role in preventing or reversing the neurodegenerative process in AD. Neprilysin (NEP) is one such Aβ-degrading enzyme, and in addition to its Aβ-dependent effects, NEP is capable of promoting neurogenesis and synaptic remodeling. Since this endopeptidase is capable of cleaving a wide range of neuropeptides with neurotrophic activity, its trophic action in the CNS is probably related to enzymatic processing of substrates such as neuropeptide Y (NPY) that results in the generation of neuroactive products. Thus, NEP represents a unique example of a proteolytic enzyme with dual action: degradation (Aβ) and processing (NPY); both actions are neuroprotective. Therefore, understanding the effects of NEP on NPY and other neuropeptides might provide new information about the neuroprotective mechanisms of NEP in the mature CNS and in animal models of AD. © Springer Science + Business Media, LLC 2009.