Role of mitochondrial Complex I deficiency in Alzheimer disease and dementia

Summary Alzheimer’s disease (AD) and dementia present enormous social and economic burdens to the United States. In 2019, AD was recognized as the sixth leading cause of death (121,499 cases) in the nation. The number of AD cases within the country is predicted to rise to 13.8 million by the year 2060. Most cases are sporadic in

nature and their molecular causes remain unknown. A clinical report from last year suggests that the Complex I deficiency may cause early onset AD in humans. This report linked a pathogenic mutation in the NDUFA1 gene, which encodes an essential subunit of Complex I. Therefore, we will test the hypothesis that Complex I

deficiency predisposes to AD and dementia by elevating neuroinflammation and proteinopathy. It may also confer sex disparity in the disease susceptibility. To test this hypothesis, we propose studies with two specific aims. Aim 1) will determine the effects of Complex I deficiency on humanized Aβ proteinopathy. Aim 2)

will determine the susceptibility of Complex I-deficient mice to AD and dementia. We will cross the Complex I- deficient Ndufa1S55A mice with ApphAβ mice that express humanized amyloid beta (hAβ) to generate double knock-in mice (Ndufa1S55A-ApphAβ). These mice Ndufa1S55A-ApphAβ will be used to determine predisposition to

AD and dementia in the presence and absence of humanized Aβ. Proteinopathy due to Aβ aggregation is one of the hallmarks of AD. Therefore, in Aim 1, we will develop a real-time quaking induced conversion (RT-QuIC) assay to quantify Aβ proteinopathic seeds present in brain and blood. In Aim 2, we will perform biochemical and

histopathological evaluation to assess the levels of Aβ plaques, neurofibrillary tangles, neuroinflammation, neuronal loss, and synaptic degeneration in mice brains. We will also assess cognitive decline by behavioral assays for spatial learning and memory. We expect to demonstrate that Complex deficiency increases

susceptibility to AD and dementia in the presence of humanized Aβ. The outcome of this project will have a significant impact on our understanding of the risks of AD and dementia, which can help in early diagnosis and prevention.