Oral Presentation HUPO 2019 - 18th Human Proteome Organization World Congress

Proteomic and bioenergetic analyses demonstrate synaptic mitochondrial alterations due to age-related pathologic tau accumulation (#181)

Andrew J Trease 1 , Joseph W George 1 , Katy Emanuel 1 , Howard S Fox 1 , Kelly L Stauch 1
  1. University of Nebraska Medical Center, Omaha, NE, United States

Alzheimer’s disease (AD), the most common form of dementia, is histopathologically characterized by the accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs, consisting of hyperphosphorylated and aggregated tau) in the brain, which are accompanied by a dramatic synaptic and neuronal loss. Despite evidence that NFT stage is a better correlate with dementia than plaques, the molecular mechanism(s) responsible for tau-induced central nervous system side effects are elusive, although growing evidence points to disturbances in mitochondrial and synaptic function; processes also affected by normal aging. Here, using SWATH-based proteomics and crosslinking mass spectrometry combined with bioenergetics analyses, we establish a role for pathologic tau in synaptic mitochondrial dysfunction. We discover that in mice expressing human tau, but not mouse tau, AD-relevant pathologic forms of tau associate with synaptic mitochondria and induce a compromised energy status at the synapse as these animals age. This work highlights the relationship between tau pathology and impaired mitochondrial function at the synapse, providing a framework for future studies that will lead to improvements in the treatment of neurodegenerative deficits in AD. The mechanism we describe also has implications beyond AD, as tau pathology is observed in a wide range of disease paradigms.