Converging evidence suggests that the accumulation of cerebral amyloid beta-protein (Abeta) in Alzheimer's disease (AD) reflects an imbalance between the production and degradation of this self-aggregating peptide. Upregulation of proteases that degrade Abeta thus represents a novel therapeutic approach to lowering steady-state Abeta levels, but the consequences of sustained upregulation in vivo have not been studied. Here we show that transgenic overexpression of insulin-degrading enzyme (IDE) or neprilysin (NEP) in neurons significantly reduces brain Abeta levels, retards or completely prevents amyloid plaque formation and its associated cytopathology, and rescues the premature lethality present in amyloid precursor protein (APP) transgenic mice. Our findings demonstrate that chronic upregulation of Abeta-degrading proteases represents an efficacious therapeutic approach to combating Alzheimer-type pathology in vivo.

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Progranulin (PGRN) is involved in wound repair

The amyloid b-protein (Ab) is subject to proteolytic degradation by a diverse array of peptidases and proteinases, known collectively as Ab-degrading proteases (AbDPs). A growing number of AbDPs have been identified, which, under physiological and/or pathophysiological conditions, contribute significantly to the determination of endogenous cerebral Ab levels. Despite more than a decade of investigation, the complete set of AbDPs remains to be established, and our understanding of even well-established AbDPs is incomplete. Nevertheless, the study of known AbDPs has contributed importantly to our understanding of the molecular pathogenesis of Alzheimer disease (AD) and has inspired the development of several novel therapeutic approaches to the regulation of cerebral Ab levels. In this article, we discuss the general features of Ab degradation and introduce the best-characterized AbDPs, focusing on their diverse properties and the numerous conceptual insights that have emerged from the study of each.