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

Deposition of amyloid‐β peptide (Aβ), a pathological hallmark of Alzheimer's disease (AD), locates upstream of the AD cascade. Aβ is constantly anabolized and catabolized in the brain, and the steady‐state Aβ 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 Aβ 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 Aβ levels in the brain is necessary. There are many strategies to address this, such as β‐, γ‐secretase inhibitors or Aβ vaccination. Recently, we demonstrated that neprilysin is the most potent Aβ‐degrading enzyme in vivo and hypothesized that neprilysin deficiency would influence the steady‐state Aβ levels in the brain by alternating the Aβ 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 Aβ levels. In this review, we describe several therapeutic strategies for manipulating the Aβ level and our current understanding of Aβ metabolism, focusing on the Aβ‐degrading enzyme, neprilysin. Drug Dev. Res. 56:171–183, 2002.