Alzheimer disease (AD) is a debilitating neurodegenerative disorder characterized by extracellular deposition of the amyloid β-protein (Aβ) and intraneuronal accumulation of the microtubule-associated protein, tau. Despite a wealth of experimental and genetic evidence implicating both Aβ and tau in the pathogenesis of AD, the precise molecular links between these two pathological hallmarks have remained surprisingly elusive. Here, we review emerging evidence for a critical nexus among Aβ, tau, and the lysosomal protease cathepsin D (CatD) that we hypothesize may play a pivotal role in the etiology of AD. CatD degrades both Aβ and tau in vitro, but the in vivo relevance of this lysosomal protease to these principally extracellular and cytosolic proteins, respectively, had remained undefined for many decades. Recently, however, our group found that genetic deletion of CatD in mice results in dramatic accumulation of Aβ in lysosomes, revealing that Aβ is normally trafficked to lysosomes in substantial quantities. Moreover, emerging evidence suggests that tau is also trafficked to the lysosome via chaperone-mediated autophagy and other trafficking pathways. Thus, Aβ, tau and CatD are colocalized in the lysosome, an organelle that shows dysfunction early in AD pathogenesis, where they can potentially interact. Notably, we discovered that Aβ42-the Aβ species most strongly linked to AD pathogenesis-is a highly potent, low-nanomolar, competitive inhibitor of CatD. Taking these observations together, we hypothesize that Aβ42 may trigger tauopathy by competitive inhibition of CatD-mediated degradation of tau-pathogenic forms of tau, in particular. Herein, we review the evidence supporting this hypothesis and explore the implications for the molecular pathogenesis of AD. Future research into these novel mechanistic links among Aβ, tau and CatD promises to expand our understanding of the etiology of AD and could potentially lead to novel therapeutic approaches for combatting this devastating disease of brain and mind.
Keywords: Alzheimer disease; Amyloid β-protein; Cathepsin D; Lysosome; Tau.