The Role of Amyloid Precursor Protein in the Mitochondria

Abstract

The amyloid precursor protein (APP) is widely recognized for its central role in the generation of amyloid-β (Aβ) peptides and the pathogenesis of Alzheimer’s disease (AD). However, its normal physiological function, particularly in the mitochondria, remains incompletely understood. This study addresses this gap by investigating a novel protein-protein interaction of APP with the mitochondrial phosphatase phosphoglycerate mutase family member 5 (PGAM5) and proposes a role of this interaction on the mitochondrial respiration.PGAM5 is a mitochondrial membrane protein and acts as a serine-threonine phosphatase towards various protein substrates. Through its substrates and binding partners, PGAM5 regulates mitochondrial mobility, mitophagy, redox homeostasis, respiration, and cell death. In this work, I demonstrate a direct, domain-specific interaction of PGAM5 with APP. My data provides evidence for an endogenous interaction between these proteins in the mouse brain. I show that both APP and PGAM5 localize and likely interact at the mitochondria-ER contact sites (MERCS). Using qPCR on isolated mitochondrial samples from mouse brains, I show that this domain-specific interaction can lead to modulation of a well-established Nrf2-dependent stress response pathway in the mitochondria by APP. Moreover, functional experiments using APP KO mouse model reveal that the absence of APP leads to significant impairments in mitochondrial function. Specifically, mitochondria isolated from APP deficient brains exhibit reduced substrate-specific respiration and compromised activity of the electron transport chain (ETC). These findings indicate that APP is necessary for maintaining efficient oxidative phosphorylation and ATP production in the brain mitochondria. Mitochondrial dysfunction is often observed in AD, but the molecular pathways are poorly defined. This study demonstrates a significant reduction in PGAM5 proteolytic cleavage in AD mice. The observed decrease in PGAM5 cleavage in AD mice suggests impaired PARL activity and consequent deficits in mitophagy. In summary, I present APP as a regulator of mitochondrial respiration while PGAM5 as a key player for impaired mitophagy seen in AD. Moreover, the novel APP-PGAM5 interaction described in this study provides a new mechanistic insight into how APP may influence mitochondrial physiology beyond its established role in amyloidogenic processing. By adding mitochondrial respiration to the repertoire of physiological functions of APP and proposing a role of PGAM5 in AD, the findings suggest a new direction for understanding and treating Alzheimer’s disease.