Human HtrA2 delays the aggregation of the Alzheimer's disease associated amyloid β-(1-42) peptide

Abstract

Human HtrA2 is part of the HtrA family of ATP-independent serine proteases that are conserved in both prokaryotes and eukaryotes and localizes to the inter-membrane space of the mitochondria. Several recent reports have suggested that HtrA2 is important for maintaining proper mitochondrial homeostasis and may play a role in several neurodegenerative disorders. One disorder HtrA2 is implicated in is Alzheimer's disease (AD). AD is characterized by the presence of oligomers and fibrils of the amyloid 13 (AI3) peptide that is generated from cleavage of the amyloid precursor protein (APP) by 13- and y-secretases. HtrA2 degrades APP at the mitochondria, and binds the neurotoxic Al3 (1-42) peptide. In this report, the ability of HtrA2 to prevent the aggregation of a model suqstrate CS and the toxic Al3 (1-42) peptide were investigated. Using CS aggregation assays, HtrA2 was seen to have a moderate ability to delay and prevent the aggregation of CS, and this activity was significantly increased following removal of the PDZ domain. Additionally, using EM and lD-WG NMR analyses HtrA2 was seen to significantly delay the aggregation of the Al3 (1-42) peptide via a dual proteolytic and chaperone-like function. These results show a novel chaperone-like activity for HtrA2 and a model emerges from this work in which HtrA2 monitors the inter-membrane space of the mitochondria using a dual proteolytic and chaperone-like function to turnover stress-damaged proteins. Furthermore HtrA2, along with other quality control factors, may be involved in the metabolism of regular as well as aberrant levels of intramitochondrial Al3 (1-42) peptide, which is known to lead to oxidative stress and mitochondrial dysfunction.