A Tau Fragment Links Depressive-Like Behaviors and Cognitive Declines in Alzheimer’s Disease Mouse Models Through Attenuating Mitochondrial Function

Introduction Alzheimer's disease (AD) is the most prevalent neurodegenerative disease characterized by extracellular senile plaques including amyloid-beta peptides and intracellular neurofibrillary tangles consisting of abnormal Tau. Depression is one of the most common neuropsychiatric symptoms in AD, and clinical evidence demonstrates that depressive symptoms accelerate the cognitive deficit of AD patients. However, the underlying molecular mechanisms of depressive symptoms present in the process of AD remain unclear.Methods Depressive-like behaviors and cognitive decline in hTau mice were induced by chronic restraint stress (CRS). Computational prediction and molecular experiments supported that an asparagine endopeptidase (AEP)-derived Tau fragment, Tau N368 interacts with peroxisome proliferator-activated receptor delta (PPAR-delta). Further behavioral studies investigated the role of Tau N368-PPAR-delta interaction in depressive-like behaviors and cognitive declines of AD models exposed to CRS.Results We found that mitochondrial dysfunction was positively associated with depressive-like behaviors and cognitive deficits in hTau mice. Chronic stress increased Tau N368 and promoted the interaction of Tau N368 with PPAR-delta, repressing PPAR-delta-mediated transactivation in the hippocampus of mice. Then we predicted and identified the binding sites of PPAR-delta. Finally, inhibition of AEP, clearance of Tau N368 and pharmacological activation of PPAR-delta effectively alleviated CRS-induced depressive-like behaviors and cognitive decline in mice.Conclusion These results demonstrate that Tau N368 in the hippocampus impairs mitochondrial function by suppressing PPAR-delta, facilitating the occurrence of depressive-like behaviors and cognitive decline. Therefore, our findings may provide new mechanistic insight in the pathophysiology of depression-like phenotype in mouse models of Alzheimer's disease.