Pathologically phosphorylated tau at S396/404 (PHF-1) is accumulated inside of hippocampal synaptic mitochondria of aged Wild-type mice

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.

Simple, Single-Shot Phosphoproteomic Analysis of Heat-Stable Tau Identifies Age-Related Changes in pS235- and pS396-Tau Levels in Non-human Primates

“…However, this is the first report, to our knowledge, of age-related changes in phosphorylation at these two sites in vulnerable regions of the primate brain. A recent publication demonstrated an age-related increase in PHF-1 in synaptic mitochondria of wild-type mice, suggesting this may be a common mechanism of age-related neuronal dysfunction ( Torres et al, 2021 ).…”

Transcranial Red LED Therapy: A Promising Non-Invasive Treatment to Prevent Age-Related Hippocampal Memory Impairment

“…Interestingly, all pathological conditions mentioned previously involve, almost in part, dysfunction of hippocampal neurons attributable to mitochondrial defects [64,65]. For example, mitochondrial dysfunction is considered a hallmark of aging and could be considered one of the factors leading to neurodegeneration [4,22,66]. Studies in humans and animal models showed that decreased memory correlates with reduced cerebral energetics metabolism and more specifically to mitochondrial bioenergetics deficits [4,22,66].…”

“…For example, mitochondrial dysfunction is considered a hallmark of aging and could be considered one of the factors leading to neurodegeneration [4,22,66]. Studies in humans and animal models showed that decreased memory correlates with reduced cerebral energetics metabolism and more specifically to mitochondrial bioenergetics deficits [4,22,66]. Therefore, the mitochondrial focus of aging and neurodegenerative diseases is of great interest for the development of a potent and ideally non-invasive anti-aging intervention to improve or attenuate cognitive impairment in the elderly.…”

Symmetric and Asymmetric Synapses Driving Neurodegenerative Disorders

“…The hyperphosphorylation of tau causes most of the pathological synaptic features seen in AD by increasing the mislocalization of tau from the axonal compartment to the somatodendritic compartment, where it aggregates into oligomers [80,111]. Indeed, AD brains show decreased levels of protein phosphatase 2 (PP2A), a phosphatase implicated in the regulation of AMPARs in membrane.…”