Behavioral deficit, oxidative stress, and mitochondrial dysfunction precede tau pathology in P301S transgenic mice

Abstract

Abnormal tau accumulation can lead to the development of neurodegenerative diseases. P301S mice overexpress the human tau mutated gene, resulting in tau hyperphosphorylation and tangle formation. Mice also develop synaptic deficits and microglial activation prior to any neurodegeneration and tangles. Oxidative stress can also affect tauopathy. We studied the role of oxidative stress in relationship to behavioral abnormalities and disease progression in P301S mice at 2, 7, and 10 mo of age. At 7 mo of age, P301S mice had behavioral abnormalities, such as hyperactivity and disinhibition. At the same age, we observed increased carbonyls in P301S mitochondria (∼215 and 55% increase, males/females), and deregulation in the activity and content of mitochondrial enzymes involved in reactive oxygen species formation and energy metabolism, such as citrate synthase (∼19 and ∼5% decrease, males/females), MnSOD (∼16% decrease, males only), cytochrome C (∼19% decrease, females only), and cytochrome C oxidase (∼20% increase, females only). These changes in mitochondria proteome appeared before tau hyperphosphorylation and tangle formation, which were observed at 10 mo and were associated with GSK3β activation. At that age, mitochondria proteome deregulation became more apparent in male P301S mitochondria. The data strongly suggest that oxidative stress and mitochondrial abnormalities appear prior to tau pathology.

LX2343 alleviates cognitive impairments in AD model rats by inhibiting oxidative stress-induced neuronal apoptosis and tauopathy

“…OS is a pivotal cellular response to the damage caused by tau toxicity, and the vicious interaction between these two causative events promotes AD progression [38] . Studies have identified OS as an early marker of tauopathy since OS and mitochondrial dysfunction are detected prior to tau hyperphosphorylation and NFT accumulation in tau P301S transgenic mice, which show tau hyperphosphorylation and tangle formation in 3 months [39] . On the one hand, OS amplifies tauinduced neurotoxicity by induction of apoptosis and dysregulation of cell energy metabolism and promotes tau hyperphosphorylation and aggregation [38] .…”

Oxidative stress in Alzheimer’s disease

“…The functional analysis of proteomics finds mitochondrial dysfunction together with reduced NADH-ubiquinone oxidoreductase activity impairs mitochondrial oxidative phosphorylation and ATP synthesis [84][85][86] . Accordingly, coenzyme Q10 (CoQ10), an antioxidant and key component of the electron transport chain, signifi cantly enhances complex I activity and reduces lipid peroxidation, and consequently, signifi cantly improves survival and the behavioral defi cits in P301S mice [87] .…”

Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer’s Disease: Understanding the Therapeutics Strategies

“…Several lines of evidence support that NO impairs mitochondrial/cellular respiration and other functions by inhibiting the activities of several key enzymes, particularly cytochrome c oxidase, and thereby causing ATP depletion [46]. In cultured neuroblastoma cells, overexpression of tau results in mitochondria with decreased ATP levels and increased susceptibility to oxidative stress [47]. Furthermore, the activity and composition of mitochondrial enzymes are disrupted in the mouse model of tauopathy [48].…”