Pink1, amyloid pathology, and mitochondrial quality control in Alzheimer's Disease

University Of Kansas Lawrence, Lawrence KS

Investigators

Linked publications, trials & patents

Abstract

Mitochondrial and synaptic dysfunction is early pathological features of the Alzheimer?s disease (AD)-affected brain. Perturbed bioenergetics function, respiration failure, aberrant mitochondrial dynamics, and increased levels of reactive oxygen species (ROS) are observed in brains and peripheral tissues including platelets of subjects with AD. Amyloid-? peptide (A?) has deleterious effects on mitochondrial and synaptic function. The underlying mechanisms and strategies to repair such injury remain unclear. PTEN-induced putative kinase 1 (PINK1) is important for the maintenance of mitochondrial integrity and quality control by conferring resistance to oxidative stress and toxic insults, modulating proper mitochondrial dynamics, and by eliminating and removing damaged mitochondria via mitophagy. So far, the role of PINK1 in amyloid pathology and A?- induced mitochondrial and synaptic defects is unexplored. We hypothesize that impairment of PINK1 function contributes to chronic A? accumulation relevant to the development of amyloid pathology in AD and to mitochondrial and synaptic degeneration. The goal of this proposal is to gain new insights into the role of PINK1 in AD pathogenesis, focusing on A? accumulation/clearance, amyloid pathology, mitochondrial quality control (function, dynamics, mitochondrial clearance), and synaptic function, utilizing gene delivery of PINK1 technology, novel genetically manipulated transgenic PINK1/AD mouse models and neuronal culture with altered PINK1 levels in neurons, and human neuronal cells containing mitochondria derived from AD and normal aged-matched subjects. The outcomes of the project could present PINK1 as a potential new therapeutic target for limiting amyloid pathology and maintaining mitochondrial integrity thereby halting AD progression.