Tau association with synaptic mitochondria coincides with energetic dysfunction and excitatory synapse loss in the P301S tauopathy mouse model

• Published in: Neurobiology of aging 2025-03, Vol.147, p.163-175
• Main Authors: Daniel Estrella, L., Trease, Andrew J., Sheldon, Lexi, Roland, Nashanthea J., Fox, Howard S., Stauch, Kelly L.
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; FTDP-17; Mitochondrial DNA; P301S mice; PS19 mice; Synapse loss; Synaptic mitochondria; Synaptic mitochondrial dysfunction; Tau pathology
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2024.12.006

Neurodegenerative Tauopathies are a part of several neurological disorders and aging-related diseases including, but not limited to, Alzheimer’s Disease, Frontotemporal Dementia with Parkinsonism, and Chronic Traumatic Encephalopathy. The major hallmarks present in these conditions include Tau pathology (composed of hyperphosphorylated Tau tangles) and synaptic loss. in vivo studies linking Tau pathology and mitochondrial alterations at the synapse, an avenue that could lead to synaptic loss, remain predominantly scarce. For this reason, using 3-month-old wild-type and human mutant Tau P301S transgenic mice, we investigated the association of Tau with mitochondria, synaptosome bioenergetics, and characterized excitatory synaptic loss across hippocampal regions (Dentate Gyrus, perisomatic CA3, and perisomatic CA1) and in the parietal cortex. We found a significant loss of excitatory synapses in the parietal cortex and hippocampal Dentate Gyrus (DG) of Tau P301S mice. Furthermore, we found that Tau (total and disease-relevant phosphorylated Tau) associates with both the non-synaptic and synaptic mitochondria of Tau P301S mice and this coincided with synaptic mitochondrial dysfunction. The findings presented here suggest that Tau associates with mitochondria at the synapse, leading to synaptic mitochondrial dysfunction, and likely contributing to synaptic loss. •Tau P301S mice have synapse loss in the Dentate Gyrus and parietal cortex.•Synaptic mitochondria from Tau P301S mice have altered bioenergetics.•Tau P301S mice have increased numbers of synaptic mitochondrial DNA copies.•Tau associates with synaptic and non-synaptic mitochondria in Tau P301S mice.