P3‐031: AMYLOID‐BETA DEGRADATION BY HUMAN ASTROCYTES IS IMPAIRED BY APOJ AND APOE

Background: The autophagic ubiquitin adaptor p62 mediates clearance of ubiquitinated cellular components through chaperone-assisted selective autophagy and package of ubiquitinated proteins into inclusion bodies as it self-assembles.As hyperphosphorylated tau in the brains of Alzheimer’s disease and related tauopathies is ubiquitinated, p62 is presumed to be involved in the degradation and sequestration of this pathological form of tau. Here, weprovide the first evidence that p62 acts protectively against neuronal death provoked by abnormal tau accumulation.Methods: In the P301Smutant human tau transgenic mouse (PS19), abundant accumulation of fibrillar tau inclusions resembling neurofibrillary tangles (NFTs) in human tauopathies are concurrent with gradual loss of neurons in the brainstem, while massive neuronal death prior to the formation of NFTs rapidly occurs in the hippocampus. We crossbred p62-knockout mice with PS19 mice to investigate roles of p62 in processing of abnormal tau.Results:Deficiency in p62 alone did not induce overt neuropathologies, but accelerated neuronal loss in the hippocampus of P19 mice. Putatively neurotoxic tau oligomers were markedly increased in p62-deficient PS19 mice as assayed by immunoblotting and immunohistochemistry. Formation of granular inclusions packaging p62 and organelles observed in the PS19 hippocampus was nearly completely abolished by p62 deficiency. Sequestration of phosphorylated tau into neuronal somas was characteristic of the PS19 brainstem, and was in sharp contrast with diffuse somatodendritic and synaptic localization of phospho-tau in the hippocampus. Notably, this compartmentalization of phospho-tau in the brainstem was disrupted in p62-deficient PS19 mice, leading to neurodegeneration accompanied by inflammatory gliosis. Formation of NFT-like inclusions in the PS19 brainstem was partially suppressed by p62 deficiency. Finally, biochemical data indicated that insufficient reserve of authophagic capacity in the PS19 hippocampus may account for profound tau-induced neuronal loss in the hippocampus versus slow progression of neurodegeneration in the brainstem. Conclusions: Our findings have demonstrated that p62 protects neurons against tau-induced neurotoxicities by 1) eliminating phosphorylated tau oligomers primarily through selective autophagy; 2) sequestering abnormal tau species into neuronal somas; and 3) packaging damaged organelles tagged with ubiquitins.