ABCA7 Loss of Function in Aging and Alzheimer’s Disease

2022, 2023

Alzheimer’s disease (AD) is the most common cause of memory loss or dementia in the older population, characterized by brain deposition of toxic molecules, amyloid beta and tau. While diverse genetic and environmental factors contribute to neuronal damages in the disease, accumulating evidence has indicated that lipid metabolism and microglia-related inflammation play a critical role in the pathogenic mechanisms. Thus, a better understanding of lipid homeostasis in microglia is necessary to explore the complex pathogenesis of age-related cognitive decline and AD. Recently, we revealed that deficiency of ATP-binding cassette transporter A7 (ABCA7), which is coded by one of the strongest AD risk genes, causes abnormal phenotypes in microglia as well as altered mitochondria properties. We also found that an AD risk ABCA7-A696S mutation suppresses microglial activation and exacerbates neuronal damage in amyloid model mice. Since ABCA7 is abundantly expressed in microglia in the brain, our overall goal is to explore the potential impacts of ABCA7 loss of function in microglia on lipid metabolism, mitochondrial functions, and AD-related phenotypes using newly generated ABCA7 risk gene knock-in mice and microglia-specific ABCA7 knock-out mice with or without the background of amyloid pathology. We also aim to identify novel cell-specific pathways through nontargeted approaches. Therefore, our study will give us unique opportunities to determine the roles of microglial ABCA7 in both physiological and pathological conditions, and to identify novel targets to develop effective therapeutic interventions for age-related cognitive decline and AD.

 


Funding to Date

$402,500

Focus

Studies of Novel AD Genes, Translational

Researchers

Takahisa Kanekiyo, M.D., Ph.D.