Oral Presentation 9th General Meeting of the International Proteolysis Society 2015

Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease (#51)

Taisuke Tomita 1
  1. Laboratory of Neuropathology and Neuroscience at Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo, TOKYO, Japan

Amyloid-β peptide (Aβ) and tau are major components of senile plaques and neurofibrillary tangles, respectively, deposited in the brains of Alzheimer disease (AD) patients. Aβ is derived from amyloid-β precursor protein that is sequentially cleaved by two aspartate proteases, β- and γ-secretases. Secreted Aβ is then catabolized by several proteases. Several lines of evidence suggest that accumulation of Aβ by increased production or decreased degradation induces the tau-mediated neuronal toxicity and symptomatic manifestations of AD. Thus, this dynamics of cerebral Aβ, called as “Aβ economy”, is the mechanistic basis of AD pathogenesis. γ-Secretase is an atypical intramembrane protease that cleaves transmembrane domain of the substrate. Partial loss of γ-secretase activity leads to the increased generation of toxic Aβ isoforms, indicating that activation of γ-secretase based on its structure-and-function relationship would provide a beneficial effect for AD. In addition, we recently identified that kallikrein-related peptidase 7 (KLK7) is a physiological Aβ-degrading enzyme secreted from astrocyte. Loss of KLK7 activity augments the Aβ deposition in model animals, suggesting a possibility that activation of KLK7 is a novel approach for prevention or treatment for AD. I will discuss with these proteases regarding aberrant Aβ economy in AD brains and development of effective treatment.