Abstract
Brain aging is a natural process characterized by cognitive decline and memory loss. This impairment is related to mitochondrial dysfunction and has recently been linked to the accumulation of abnormal proteins in the hippocampus. Age-related mitochondrial dysfunction could be induced by modified forms of tau. Here, we demonstrated that phosphorylated tau at Ser 396/404 sites, epitope known as PHF-1, is increased in the hippocampus of aged mice at the same time that oxidative damage and mitochondrial dysfunction are observed. Most importantly, we showed that tau PHF-1 is located in hippocampal mitochondria and accumulates in the mitochondria of old mice. Finally, since two mitochondrial populations were found in neurons, we evaluated tau PHF-1 levels in both non-synaptic and synaptic mitochondria. Interestingly, our results revealed that tau PHF-1 accumulates primarily in synaptic mitochondria during aging, and immunogold electron microscopy and Proteinase K protection assays demonstrated that tau PHF-1 is located inside mitochondria. These results demonstrated the presence of phosphorylated tau at PHF-1 commonly related to tauopathy, inside the mitochondria from the hippocampus of healthy aged mice for the first time. Thus, this study strongly suggests that synaptic mitochondria could be damaged by tau PHF-1 accumulation inside this organelle, which in turn could result in synaptic mitochondrial dysfunction, contributing to synaptic failure and memory loss at an advanced age.
Highlights
Brain aging is a natural process characterized by cognitive decline and memory loss
These results strongly suggested that age-related synaptic impairment could be due to the accumulation of phosphorylated tau PHF-1 in the synaptic mitochondria and propose a mechanism that explains why synaptic mitochondria are more vulnerable to damage during aging[31]
It is reported that phosphorylated tau alters the mitochondrial dynamics in Alzheimer’s disease (AD), increasing the fission proteins by their interaction with Drp-1, and decreasing the fusion p roteins[37]. These results suggest that tau affect mitochondrial morphology in pathological conditions and a similar effect could be occurring in the aging; whether tau PHF-1 induces structural changes by any of these mechanisms or it is directly responsible for mitochondrial dysfunction at an advanced age needs to be determined
Summary
Brain aging is a natural process characterized by cognitive decline and memory loss. This impairment is related to mitochondrial dysfunction and has recently been linked to the accumulation of abnormal proteins in the hippocampus. We demonstrated that phosphorylated tau at Ser 396/404 sites, epitope known as PHF-1, is increased in the hippocampus of aged mice at the same time that oxidative damage and mitochondrial dysfunction are observed. We reported for the first time that tau PHF-1 accumulation occurs mostly in synaptic mitochondria, which was evidenced by biochemical and immunogold assays in hippocampal samples of 18 month-old WT mice These results strongly suggest that tau PHF-1 is located in the interior of the mitochondria. More importantly, using a proteinase K protection assay, we demonstrated that tau PHF-1 is located within the synaptic mitochondria, with a minor proportion in the mitochondrial matrix These results indicate that during normal aging tau is phosphorylated in PHF-1 sites, a modification that promotes its accumulation within synaptic mitochondria. This provides an alternative explanation for the cognitive impairment related to memory loss that is widely reported in the aged population
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