Neuronal mitochondrial transport-linked neuroinflammation and amyloid pathology in Alzheimer's disease

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Summary Mitochondrial dysfunction and synaptic damage are early pathological features of the Alzheimer’s disease (AD)-affected brain. Memory impairment in AD is a manifestation of brain pathologies such as the accumulation of amyloid-β peptide (Aβ) and mitochondrial damage. Synaptic mitochondria are early targets of Aβ and are more vulnerable to Aβ-induced mitochondrial and synaptic dysfunction. Efficient mitochondrial trafficking to synapses, via axonal transport, is essential for the maintenance of proper synaptic mitochondrial density and energy in order to sustain synaptic activity; thus, impaired axonal transport may compromise synaptic transmission. The underlying mechanisms and strategies to rescue such injury remain elusive. Miro1, a mitochondrial Rho-GTPase on the mitochondrial outer membrane, plays a vital role in facilitating mitochondrial axonal transport and sustaining synaptic activity and neuronal survival. Defective Miro1 in Drosophila depletes the supply of mitochondria in synaptic terminals, and enhances neurodegeneration. However, the role of Miro1 on Aβ- and AD-induced mitochondrial trafficking, amyloid pathology, neuroinflammation, and synaptic and cognitive dysfunction in AD and AD- linked mouse models remains unexplored. There is no report showing altered expression of Miro1 in Alzheimer’s brain. It is unclear whether neuronal Miro1 is a mechanistic linker between mitochondrial dysfunction and neuroinflammation and synaptic injury and if gaining of neuronal Miro1 could alleviate amyloid pathology and synaptic and cognitive dysfunction and slow down disease progression in AD. We hypothesize that neuronal Miro1-mediated mitochondrial dysfunction contributes to Aβ accumulation and neuroinflammation, leading to synaptic degeneration and cognitive decline. The goal of this proposal is to gain new insights into the role of Miro1 in AD pathogenesis, focusing on Aβ accumulation/clearance, amyloid pathology, mitochondrial function and mitochondrial trafficking neuroinflammtion, and synaptic function, utilizing novel genetically manipulated transgenic Miro1/AD mouse models and neuronal culture with altered Miro1 levels in neurons, and human neuronal cells containing mitochondria derived from AD and normal aged-matched subjects. The outcomes of the project could present Miro1 as a potential new therapeutic target for limiting amyloid pathology and maintaining mitochondrial and synaptic integrity thereby halting AD progression.