PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer's disease

Brain. 2017 Dec 1;140(12):3233-3251. doi: 10.1093/brain/awx258.


Mitochondrial dysfunction and synaptic damage are early pathological features of the Alzheimer's disease-affected brain. Memory impairment in Alzheimer's disease is a manifestation of brain pathologies such as accumulation of amyloid-β peptide and mitochondrial damage. The underlying pathogenic mechanisms and effective disease-modifying therapies for Alzheimer's disease remain elusive. Here, we demonstrate for the first time that decreased PTEN-induced putative kinase 1 (PINK1) expression is associated with Alzheimer's disease pathology. Restoring neuronal PINK1 function strikingly reduces amyloid-β levels, amyloid-associated pathology, oxidative stress, as well as mitochondrial and synaptic dysfunction. In contrast, PINK1-deficient mAPP mice augmented cerebral amyloid-β accumulation, mitochondrial abnormalities, impairments in learning and memory, as well as synaptic plasticity at an earlier age than mAPP mice. Notably, gene therapy-mediated PINK1 overexpression promotes the clearance of damaged mitochondria by augmenting autophagy signalling via activation of autophagy receptors (OPTN and NDP52), thereby alleviating amyloid-β-induced loss of synapses and cognitive decline in Alzheimer's disease mice. Loss of PINK1 activity or blockade of PINK1-mediated signalling (OPTN or NDP52) fails to reverse amyloid-β-induced detrimental effects. Our findings highlight a novel mechanism by which PINK1-dependent signalling promotes the rescue of amyloid pathology and amyloid-β-mediated mitochondrial and synaptic dysfunctions in a manner requiring activation of autophagy receptor OPTN or NDP52. Thus, activation of PINK1 may represent a new therapeutic avenue for combating Alzheimer's disease.

Keywords: Aβ; PINK1; autophagy; mitochondrial dysfunction; synaptic injury.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Autophagy
  • Brain / metabolism
  • Cell Cycle Proteins
  • Eye Proteins / metabolism
  • Female
  • Genetic Therapy
  • Hippocampus / metabolism*
  • Humans
  • Male
  • Membrane Transport Proteins
  • Mice, Transgenic
  • Middle Aged
  • Mitochondria / metabolism*
  • Nerve Tissue Proteins / metabolism
  • Oxidative Stress
  • Protein Kinases / metabolism*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Signal Transduction


  • APP protein, human
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Cell Cycle Proteins
  • Eye Proteins
  • Membrane Transport Proteins
  • NDP52 protein, mouse
  • Nerve Tissue Proteins
  • Optn protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Protein Kinases
  • PTEN-induced putative kinase