GLO1/Aβ-mediated mitochondrial and synaptic injury in Alzheimer's disease

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Summary Mitochondrial dysfunction and synaptic damage are early pathological features of Alzheimer’s disease (AD)- affected brain1-5 and aging brains. Memory impairment in AD is a manifestation of brain pathologies such as accumulation of amyloid-β peptide (Aβ) and mitochondrial damage. The underlying pathogenic mechanisms and effective disease modifying therapies for AD remain elusive. Age is a strong risk factor for the onset and progression of AD, particularly late-onset AD. Age-related metabolic changes increase generation and deposition of toxic metabolites such as glucose-derived methylglyoxal (MG) and advanced glycation endproducts (AGEs) Glyoxalase 1 (GLO1) is a key/initial enzyme responsible for eliminating and detoxifying MG to prevent the formation of AGEs. So far, little is known about the role of GLO1 on Aβ-induced mitochondrial and amyloid pathology, neuroinflammation, synaptic and cognitive dysfunction in AD and AD- linked mouse models in AD- and Aβ-affected brain. . It is unclear whether neuronal GLO1 is mechanistic linker between mitochondrial dysfunction and neuroinflammaton and synaptic injury and if gain of neuronal GLO1 could alleviate amyloid We hypothesize that in AD superimposed Aβ, excessive accumulation of MG/AGEs and impaired GLO1 function serve to accelerate and exaggerate amyloid pathology, leading to mitochondrial and synaptic stress, thus, clearance of Aβ and AGEs by gain of GLO1 may be of importance in preventing pathology and synaptic and cognitive dysfunction and slow down disease progression in AD. as causative endogenous danger signals amyloid and mitochondrial pathology. Utilizing novel gain-of-function neuronal GLO1 mice in AD mouse model and multi-color two-photon in vivo imaging to simultaneously visualize excitatory and inhibitory synapses in the same neurons, we will explore new mechanism underlying GLO1-dependent Aβ metabolism and mitochondrial alterations and address whether GLO1 signaling is protective or destructive to neurons in amyloid pathology to fully establish the benefits/pitfalls of enhancing GLO1 as a therapeutic strategy in AD.