Diminished parkin solubility and co-localization with intraneuronal amyloid-β are associated with autophagic defects in Alzheimer's disease.

Alzheimer's disease (AD) is an aging disorder characterized by amyloid-β (Aβ) accumulation in extracellular plaques and formation of intracellular tangles containing hyperphosphorylated tau (p-Tau). Autophagic defects, leading to accumulation of autophagosomes, are recognized in AD. Parkin is an E3 ubiquitin ligase involved in degradation of proteins via autophagy and the proteasome. We investigated the role of parkin in postmortem brain tissues from 21 AD patients and 15 control subjects. We detected decreased parkin solubility in AD cortex and parkin co-localization with intraneuronal Aβ(1-42) in the hippocampus and cortex of AD patients. Parkin accumulation with intraneuronal Aβ and p-Tau was detected in autophagosomes in AD brains. To determine the role of parkin in Aβ clearance, we generated gene transfer animals expressing lentiviral Aβ(1-42)with and without parkin and examined autophagic mechanisms. Lentiviral expression of Aβ(1-42) led to p-Tau accumulation and induced autophagic defects, leading to accumulation of autophagic vacuoles. However, co-expression of wild type parkin facilitated autophagic clearance and promoted deposition of Aβ(1-42) and p-Tau into the lysosome. Taken together, these data suggest that Aβ(1-42) alters normal autophagy and parkin enhances autophagic clearance. In conclusion, decreased parkin solubility may lead to co-localization with intraneuronal Aβ(1-42) and compromise the cell autophagic clearance ability. Parkin may clear autophagic defects via autophagosome degradation.