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.
Highlights
Altered synaptic bioenergetics and mitochondrial homeostasis are common features of several neurodegenerative disorders, including Alzheimer’s Disease (AD)
PS396/pS404 phosphorylation is associated with the formation of paired helical fragment (PHF) tau, and are the sites recognized by the PHF1 antibody (Otvos et al, 1994)
These abnormalities exist in the absence of changes to synaptosomal mitochondrial content and consistent with this basal mitochondrial respiration and adenosine triphosphate (ATP) generation remained unaltered in htau mice
Summary
Altered synaptic bioenergetics and mitochondrial homeostasis are common features of several neurodegenerative disorders, including Alzheimer’s Disease (AD) (reviewed in Lin and Beal, 2006; Parihar and Brewer, 2007; Pathak et al, 2013; Norat et al, 2020). Synaptic Tau Alters Bioenergetics understood, a combination of these is likely (reviewed in Lin and Beal, 2006; Parihar and Brewer, 2007; Pathak et al, 2013; Norat et al, 2020). NFTs, of which the majority of tau is aberrantly phosphorylated and misfolded, lead to synaptic alterations and correlate with neuronal loss and cognitive deficits in AD patients more readily than does amyloid burden (Lewis et al, 2000; Jose Metcalfe et al, 2010; Nelson et al, 2012; Thompson and Vinters, 2012). The mechanism by which tau overexpression alters synaptic function remains poorly understood; mutant and hyperphosphorylated forms of tau have been shown to impact the regulators of mitochondrial function and homeostasis, altering molecular transport, mitochondrial maintenance (i.e., fission/fusion), and bioenergetic functions, implicating a mitochondrial contribution to the observed synapse deficits (Vossel et al, 2010; Kopeikina et al, 2011; Llorens-Martín et al, 2011; Shahpasand et al, 2012)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
