Role of clearance of toxic metabolites in mitochondrial and tau pathology

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Summary Mitochondrial dysfunction and synaptic damage are early pathological features of the AD-affected brain. The underlying mechanisms and strategies to rescue such injury remain elusive. There is limited mechanistic study investigating the likely interplays between mitochondrial dysfunction and neuroinflammation and their contribution to synaptic damage and tauopathy in AD and related disorder (ADRD). Age-related accumulation of toxic metabolites such as advanced glycation end products (AGEs) and methylglyoxal (MG) perturbs mitochondrial and synaptic dysfunction. Thus, clearance of these toxic metabolites are important for maintaining mitochondrial integrity. Glyoxalase 1 (GLO1) is a key enzyme for scavenging/detoxifying toxic metabolite MG to reduce AGEs formation. So far, the role of GLO1 on tau-mediated mitochondrial stress, tau pathology, neurotoxic oligomer tau metabolism, neuroinflammation, synaptic and cognitive dysfunction in AD and ADRD remains unexplored. It is unclear whether circulating AGEs metabolites correlate to synaptic mitochondrial function and glycation, whether neuronal GLO1 is a mechanistic linker between mitochondrial dysfunction and neuroinflammation and synaptic injury and if gaining of neuronal GLO1 could alleviate tau pathology and synaptic and cognitive dysfunction and slow down disease progression in AD. We hypothesize that sustained accumulation of toxic metabolites (MG/AGEs) serves as causative endogenous danger signals to initiate and accelerate mitochondrial perturbation and tau pathology, leading to neuroinflammation and synaptic failure. Clearance of AGEs metabolites by GLO1 may be important for reducing the pathophysiological modifications associated with age-related carbonyl stress and mitochondrial pathology. This proposal will address the fundamental unexplored questions of whether GLO1 is a key player in tau-induced synaptic injury, tau pathology, and neuroinflammation, whether augmentation of GLO1 proves beneficial for clearance of tau and toxic metabolites, mitochondrial quality, and cognitive function as a therapeutic strategy in AD and ADRD, whether circulating serum and platelet AGEs-related metabolites associate with cerebral mitochondrial dysfunction, and whether these toxic metabolites can serve as risk factors/biomarkers for the onset and/or progression of early AD and age-related cognitive dysfunction.