Hyperphosphorylated Human Tau Accumulates at the Synapse, Localizing on Synaptic Mitochondrial Outer Membranes and Disrupting Respiration in a Mouse Model of Tauopathy

Abstract

Neurogenerative disorders, such as Alzheimer’s disease (AD), represent a growing public health challenge in aging societies. Tauopathies, a subset of neurodegenerative disorders that includes AD, are characterized by accumulation of fibrillar and hyperphosphorylated forms of microtubule-associated protein tau with coincident mitochondrial abnormalities and neuronal dysfunction. Although, in vitro, tau impairs axonal transport altering mitochondrial distribution, clear in vivo mechanisms associating tau and mitochondrial dysfunction remain obscure. Herein, we investigated the effects of human tau on brain mitochondria in vivo using transgenic htau mice at ages preceding and coinciding with onset of tauopathy. Subcellular proteomics combined with bioenergetic assessment revealed pathologic forms of tau preferentially associate with synaptic over non-synaptic mitochondria coinciding with changes in bioenergetics, reminiscent of an aged synaptic mitochondrial phenotype in wild-type mice. While mitochondrial content was unaltered, mitochondrial maximal respiration was impaired in synaptosomes from htau mice. Further, mitochondria-associated tau was determined to be outer membrane-associated using the trypsin protection assay and carbonate extraction. These findings reveal non-mutant human tau accumulation at the synapse has deleterious effects on mitochondria, which likely contributes to synaptic dysfunction observed in the context of tauopathy.

A novel human tau knock-in mouse model reveals interaction of Abeta and human tau under progressing cerebral amyloidosis in 5xFAD mice

“…Mitochondria dysfunction is a prominent early feature in the pathogenesis of AD, which has been linked to tau phosphorylation and aggregation in AD patients and multiple animal models [ 52 ]. Interestingly, Trease et al examined synaptic and non-synaptic brain mitochondria of 5- and 8-month-old htau mice, which express wild-type human tau in all 6 isoforms in the absence of murine tau [ 53 ]. Using subcellular proteomics, bioenergetics assessment, and metabolic pathway analysis, the authors revealed alterations in multiple pathways with oxidative phosphorylation yielding the strongest negative activation score for synaptic mitochondria of 8-month-old mice.…”

“…Pathologic forms of tau were found to associate preferentially with synaptic mitochondria, and the maximal respiration of htau synaptosomes was impaired. Thus, apparently, the accumulation of non-mutant human tau at the synapse may compromise proper mitochondrial operation with detrimental consequences for synaptic functioning [ 53 ]. We also observed a decreased expression of genes implicated in extracellular matrix and immune functions in our 5xFADxhtau-KI model at an older age.…”

Subcellular proteomics insights into Alzheimer's disease development

“…Some omics studies have provided explanations for the concept that Aβ accumulation is a major cause of mitochondrial dysfunction and consequently triggers the AD phenotype [67,72,73]. As research progressed, the effect of tau on mitochondrial function has been gradually confirmed [74] as well as the production and growth of Aβ aggregation and tau hyperphosphorylation [77]. This is a terrible "vicious circle" that will eventually lead to an irreversible deterioration of AD.…”

Site-specific phosphorylation of tau impacts mitochondrial biology and response to stressors

“…Accumulation of pathogenic tau is highly associated with neuronal damage and cognitive defects observed in AD (Xia et al, 2021;Trease et al, 2022).…”

“…Indeed, specific soluble and oligomeric species of tau that are abnormally phosphorylated at AD associated sites have been identified as pathogenic forms (Zheng et al, 2020; Xia et al, 2021). Accumulation of pathogenic tau is highly associated with neuronal damage and cognitive defects observed in AD (Xia et al, 2021; Trease et al, 2022).…”