Therapeutic strategies of Alzheimer's disease through manipulation of Aβ metabolism: a focus on Aβ‐degrading peptidase, neprilysin

Abstract

Deposition of amyloid-b peptide (Ab), a pathological hallmark of Alzheimer's disease (AD), locates upstream of the AD cascade. Ab is constantly anabolized and catabolized in the brain, and the steady-state Ab level is physiologically determined by the metabolic balance between the anabolic and catabolic activities. Even subtle alterations in this metabolic balance over a long period of time could turn Ab into a pathogenic agent that influences both the pathological progression and incidence of the disease. Therefore, AD may be a consequence of proteolytic disorder. In order to overcome AD, lowering the Ab levels in the brain is necessary. There are many strategies to address this, such as b-, g-secretase inhibitors or Ab vaccination. Recently, we demonstrated that neprilysin is the most potent Ab-degrading enzyme in vivo and hypothesized that neprilysin deficiency would influence the steady-state Ab levels in the brain by alternating the Ab metabolism. Therefore, to maintain or upregulate neprilysin activity in the brain will be a relevant strategy for prevention and therapy of AD through reduction of the Ab levels. In this review, we describe several therapeutic strategies for manipulating the Ab level and our current understanding of Ab metabolism, focusing on the Ab-degrading enzyme, neprilysin. Drug Dev.

Metallostasis and amyloid β-degrading enzymes

“…172,173 However, the use of metal chelators as possible drugs to reduce the Ab burden can be hindered by the fact that many Ab degrading metalloproteases require zinc for their activity. 174 For this reason, metal protein attenuating compounds (MPACs) like clioquinol (CQ) and derivatives, initially designed to control metal dyshomeostasis, have been recently reviewed for alternative mechanisms related to their potential ability to promote Ab clearance via PI3-K/Akt activation and MMPs up-regulation. It has been demonstrated that CQ modulates secreted levels of Ab in vitro promoting intracellular increase of copper and zinc and acting as an ionophore agent.…”