Proteolytic degradation of amyloid β-protein

Abstract

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

Figure 1.

Aβ degradation is a potent determinant of brain Aβ levels and amyloid pathology. (A) Effects of genetic deletion of NEP on Aβ levels in the interstitial fluid (ISF) of the J9 line of APP transgenic mice monitored by in vivo microdialysis before and after blockade of Aβ production with the γ-secretase inhibitor, LY411575. Note that steady-state levels of Aβ are approximately doubled in J9 mice lacking NEP (JN^−/−). (Panel A is adapted from Farris et al. 2007; reprinted, with permission, from the authors.) (B) The half-life of ISF Aβ determined from the data in (A). Note that deletion of NEP results in a statistically significant (P < 0.01) 23% increase in the half-life of ISF Aβ, from 1.7 to 2.1 hours. (C) Transgenic overexpression of NEP by eightfold results in the complete prevention of amyloid plaque formation in the J20 line of APP transgenic mice up to 14 months of age. (Panel B is adapted from Leissring et al. 2003; reprinted, with permission, from the author.)

Figure 2.

The balance analogy illustrates the relationship between AβDPs and net Aβ levels. By analogy with a balance, net Aβ concentrations (represented by the position of the pointer on the scale) are determined by the rate of Aβ production (represented by a single weight on one arm) relative to the overall rate of Aβ clearance (represented by a collection of counterweights on the other). Aβ clearance is performed by a collection of AβDPs (dark gray counterweights) working jointly with each other and with other eliminative processes (light gray counterweights). See text for additional details.

Figure 3.

AβDPs regulate and help define distinct pools of Aβ. Aβ can be conceptualized as existing in distinct pools localized to different subcellular compartments (rounded rectangles). Each pool is characterized by different “sources” of Aβ (e.g., secretases, secretion) and different combinations of AβDPs. Because AβDPs vary considerably in terms of their subcellular localization, pH optima and other properties, Aβ within different subcellular compartments is regulated by diverse combinations of AβDPs.