The Association of Tau With Mitochondrial Dysfunction in Alzheimer's Disease.

Ying Cheng,Feng Bai

doi:10.3389/fnins.2018.00163

Abstract

Increasing evidence suggests that abnormally hyperphosphorylated tau plays a vital role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial dysfunction also has a recognized role in the pathophysiology of AD. In recent years, mitochondrial dysfunction has been strongly associated with tau pathology in AD. Overexpression of hyperphosphorylated and aggregated tau appears to damage the axonal transport, leading to abnormal mitochondrial distribution. In addition, pathological tau impairs mitochondrial dynamics by regulating mitochondrial fission/fusion proteins, and further causes mitochondrial dysfunction and neuronal damage. Moreover, mitochondrial dysfunction is also involved in promoting tau pathology in AD. In this article, we evaluate the relationship between phosphorylated tau and mitochondrial dysfunction in AD.

Highlights

To determine the physiopathologic mechanism of Alzheimer’s disease (AD) for effective prevention and treatment, several modeling hypotheses have emerged, the exact cause of AD is still unclear. Hardy and Higgins (1992) first formulated the amyloid hypothesis in 1992, which was widely accepted at the time but is much questioned (Hardy and Selkoe, 2002)
Evidence from these studies suggests that pathological forms of tau play a significant role in the impairment of mitochondrial fission/fusion dynamics in AD, mainly through a molecular mechanism of increasing mitochondrial fission protein such as Drp1 and decreasing fusion protein including optic atrophy protein 1 (OPA-1), mitofusin 1 (Mfn1)/2
In another triple transgenic AD mice (3xTg-AD) with transgenes APPswe, PS1M146V, and TauP301L, mitochondrial impairment was early evidenced by impaired mitochondrial respiration, and decreased pyruvate dehydrogenase (PDH), as well as increased oxidative stress (Yao et al, 2009)

Summary

INTRODUCTION

To determine the physiopathologic mechanism of AD for effective prevention and treatment, several modeling hypotheses have emerged, the exact cause of AD is still unclear. Hardy and Higgins (1992) first formulated the amyloid hypothesis in 1992, which was widely accepted at the time but is much questioned (Hardy and Selkoe, 2002). No new drug based on the amyloid hypothesis has been approved over the past decade Another phase III clinical trial of Alzheimer’s drug targeting Aβ was shuttered because the drug has no chance of benefiting AD patients. Given the failures of the clinical trials based on the amyloid hypothesis, the tau hypothesis, an alternative pathway, is attracting increasing attention. It is well-known that NFTs, which are composed primarily of hyperphosphorylated tau protein (Grundke-Iqbal et al, 1986; Nukina and Ihara, 1986), have been proposed as the second pathological hallmark of AD. The link between phosphorylated tau and mitochondrial dysfunction in AD is evaluated

TAU PROTEIN

TAU IMPAIRS MITOCHONDRIAL TRANSPORT

TAU IMPAIRS MITOCHONDRIAL DYNAMICS

TAU PATHOLOGY AND MITOCHONDRIAL DYSFUNCTION IN AD

Findings

DISCUSSION