PINK1 Alleviates Cognitive Impairments via Attenuating Pathological Tau Aggregation in a Mouse Model of Tauopathy.

Xing Jun Jiang,Gong Ping Liu,Lu Lu Li,Jia Hui Zhu,Yan Min Chang,Gang Li,Yan Qing Wu,Rong Ma

doi:10.3389/fcell.2021.736267

Abstract

As a primary cause of dementia and death in older people, Alzheimer’s disease (AD) has become a common problem and challenge worldwide. Abnormal accumulation of tau proteins in the brain is a hallmark pathology of AD and is closely related to the clinical progression and severity of cognitive deficits. Here, we found that overexpression of phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) effectively promoted the degradation of tau, thereby rescuing neuron loss, synaptic damage, and cognitive impairments in a mouse model of tauopathy with AAV-full-length human Tau (hTau) injected into the hippocampal CA1 area (hTau mice). Overexpression of PINK1 activated autophagy, and chloroquine but not MG132 reversed the PINK1-induced decrease in human Tau levels and cognitive improvement in hTau mice. Furthermore, PINK1 also ameliorated mitochondrial dysfunction induced by hTau. Taken together, our data revealed that PINK1 overexpression promoted degradation of abnormal accumulated tau via the autophagy–lysosome pathway, indicating that PINK1 may be a potential target for AD treatment.

Highlights

Tauopathies are a group of human neurological disorders, which are pathologically characterized by abnormal accumulation of tau filaments in the brain
We observed an obvious accumulation of tau proteins, neuron loss, synapse injury, mitochondrial function disorders, and cognitive impairments in human Tau (hTau) mice
We found that overexpression of PINK1 effectively reduced neuropathological accumulation of tau proteins, ameliorated mitochondrial function, attenuated damage to neurons and synapses, and rescued cognitive decline in hTau mice

Summary

Introduction

Tauopathies are a group of human neurological disorders, which are pathologically characterized by abnormal accumulation of tau filaments in the brain. The main hallmarks of AD pathology are intracellular deposition of tau neurofibrillary tangles and extracellular amyloid-β (Aβ) plaques. Despite being initially considered as a pathological change driven by the toxic effects of amyloid peptide, our understanding of the role that tau plays in AD has been continuously evolving (Götz et al, 2019). Growing evidence indicates that tau pathology can exert synergistic effects with amyloid peptide and that it correlates more closely to the progression and cognitive impairment of AD than Aβ plaques (Bejanin et al, 2017; Guo et al, 2020). Given the failure of various clinical Aβ-directed therapies, more efforts have been focused on exploring tau-targeted therapies worldwide in recent years (Congdon and Sigurdsson, 2018)

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