Tau oligomers (oTau) are thought to precede neurofibrillary tangle formation and likely represent one of the toxic species in disease. This study addresses whether mitochondrial reactive oxygen species (ROS) contribute to tau oligomer accumulation. First, we determined whether elevated oxidative stress correlates with aggregation of tau oligomers in the brain and platelets of human Alzheimer’s disease (AD) patient, tauopathy mice, primary cortical neurons from tau mice and human trans-mitochondrial ‘cybrid’ (cytoplasmic hybrid) neuronal cells, whose mitochondria are derived from platelets of patients with sporadic AD- or mild cognitive impairment (MCI)-derived mitochondria. Increased formation of tau oligomers correlates with elevated ROS levels in the hippocampi of AD patients and tauopathy mice, AD- and MCI-derived mitochondria and AD and MCI cybrid cells. Furthermore, scavenging ROS by application of mito-TEMPO/2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride, a mitochondria-targeted antioxidant, not only inhibits the generation of mitochondrial ROS and rescues mitochondrial respiratory function but also robustly suppresses tau oligomer accumulation in MCI and AD cybrids as well as cortical neurons from tau mice. These studies provide substantial evidence that mitochondria-mediated oxidative stress contributes to tau oligomer formation and accumulation.

Mitochondrial dysfunction is an early pathological feature of Alzheimer disease and plays a crucial role in the development and progression of Alzheimer’s disease. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore, leading to mitochondrial dysfunction and cell death. Blocking membrane permeability transition pore opening by inhibiting CypD activity is a promising therapeutic approach for Alzheimer’s disease. However, there is currently no effective CypD inhibitor for Alzheimer’s disease, with previous candidates demonstrating high toxicity, poor ability to cross the blood–brain barrier, compromised biocompatibility and low selectivity. Here, we report a new class of non-toxic and biocompatible CypD inhibitor, ebselen, using a conventional PPIase assay to screen a library of ∼2000 FDA-approved drugs with crystallographic analysis of the CypD-ebselen crystal structure (PDB code: 8EJX). More importantly, we assessed the effects of genetic and pharmacological blockade of CypD on Alzheimer’s disease mitochondrial and glycolytic bioenergetics in Alzheimer’s disease-derived mitochondrial cybrid cells, an ex vivo human sporadic Alzheimer’s disease mitochondrial model, and on synaptic function, inflammatory response and learning and memory in Alzheimer’s disease mouse models. Inhibition of CypD by ebselen protects against sporadic Alzheimer’s disease- and amyloid-β-induced mitochondrial and glycolytic perturbation, synaptic and cognitive dysfunction, together with suppressing neuroinflammation in the brain of Alzheimer’s disease mouse models, which is linked to CypD-related membrane permeability transition pore formation. Thus, CypD inhibitors have the potential to slow the progression of neurodegenerative diseases, including Alzheimer’s disease, by boosting mitochondrial bioenergetics and improving synaptic and cognitive function.

Background: Advanced glycation end products (AGEs) are an important risk factor for the development of cognitive decline in aging and late-onset neurodegenerative diseases including Alzheimer’s disease. However, whether and how dietary AGEs exacerbat

Mitochondrial and synaptic dysfunction are pathological features of brain aging and cognitive decline. Synaptic mitochondria are vital for meeting the high energy demands of synaptic transmission. However, little is known about the link between age-related metabolic changes and the integrity of synaptic mitochondria. To this end, we investigate the mechanisms of advanced glycation endproducts (AGEs)-mediated mitochondrial and synaptic stress and evaluate the strategies to eliminate these toxic metabolites. Using aged brain and novel transgenic mice overexpressing neuronal glyoxalase 1 (GLO1), we comprehensively analyzed alterations in accumulation/buildup of AGEs and related metabolites in synaptic mitochondria and the association of AGE levels with mitochondrial function. We demonstrate for the first time that synaptic mitochondria are an early and major target of AGEs and the related toxic metabolite methylglyoxal (MG), a precursor of AGEs. MG/AGEs-insulted synaptic mitochondria exhibit deterioration of mitochondrial and synaptic function. Such accumulation of MG/AGEs positively correlated with mitochondrial perturbation and oxidative stress in aging brain. Importantly, clearance of AGEs-related metabolites by enhancing neuronal GLO1, a key enzyme for detoxification/of AGEs, reduces synaptic mitochondrial AGEs accumulation and improves mitochondrial and cognitive function in aging and AGE-challenged mice. Furthermore, we evaluated the direct effect of AGEs on synaptic function in hippocampal neurons in live brain slices as an ex-vivo model and in vitro cultured hippocampal neurons by recording long-term potentiation (LTP) and measuring spontaneously occurring miniature excitatory postsynaptic currents (mEPSCs). Neuronal GLO1 rescues deficits in AGEs-induced synaptic plasticity and transmission by fully recovery of decline in LTP or frequency of mEPSC. These studies explore crosstalk between synaptic mitochondrial dysfunction and age-related metabolic changes relevant to brain aging and cognitive decline. Synaptic mitochondria are particularly susceptible to AGEs-induced damage, highlighting the central importance of synaptic mitochondrial dysfunction in synaptic degeneration in age-related cognitive decline. Thus, augmenting GLO1 function to scavenge toxic metabolites represents a therapeutic approach to reduce age-related AGEs accumulation and to improve mitochondrial function and learning and memory.

Background: Mitochondrial dysfunction, bioenergetic deficit, and extensive oxidative stress underlie neuronal perturbation during the early stage of Alzheimer’s disease (AD). Previously, we demonstrated that decreased PTEN-induced putative kinase 1 (PINK1) expression is associated with AD pathology in AD-affected human brains and AD mice. Objective: In the present study, we highlight the essential role of PINK1 in AD-relevant mitochondrial perturbation and neuronal malfunction. Methods: Using trans-mitochondrial “cybrid” (cytoplasmic hybrid) neuronal cells, whose mitochondria are transferred from platelets of patients with sporadic AD, we observed the effect of PINK1 in neuronal-like differentiation and synaptogenesis and mitochondrial functions. Results: In AD cybrid cells, the downregulation of PINK1 is correlated to the alterations in mitochondrial morphology and function and deficit in neuronal-like differentiation. Restoring/increasing PINK1 by lentivirus transduction of PINK1 robustly attenuates mitochondrial defects and rescues neurite-like outgrowth. Importantly, defective PINK1 kinase activity fails to reverse these detrimental effects. Mechanistically, AD cybrid cells reveal a significant decrease in PINK1-dependent phosphorylated mitofusin (Mfn) 2, a key mitochondrial membrane protein that participates in mitochondrial fusion, and an insufficient autophagic activity for the clearance of dysfunctional mitochondria. Overexpression of PINK1, but not mutant PINK1 elevates phosphorylation of Mfn2 and autophagy signaling LC3-II. Accordingly, PINK1-overexpressed AD cybrids exhibit increases in mitochondrial length and density and suppressed reactive oxygen species. These results imply that activation of PINK1 protects against AD-affected mitochondrial dysfunction and impairment in neuronal maturation and differentiation. Conclusion: PINK1-mediated mitophagy is important for maintaining mitochondrial health by clearance of dysfunctional mitochondria and therefore, improves energy homeostasis in AD.