ABCA7 Loss of Function in Aging and Alzheimer’s Disease

2020

Alzheimer’s disease is the most common cause of memory loss or dementia in the aging 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 microglia plays a critical role in the pathogenic mechanisms. Thus, better understanding of interaction between neurons and microglia in AD 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 one of the AD risk genes, causes abnormal phenotypes in microglia as well as neurons in cell models and mice. Since ABCA7 is abundantly expressed in neurons and microglia in the brain, our overall goals are to explore potential impacts of ABCA7 deletion in those cell types on AD-related phenotypes. To do this, we will use newly generated microglia- or neuron-specific ABCA7 knockout mice with or without the background of amyloid pathology. We also aim to identify novel cell-specific pathways through nontargeted approaches. Furthermore, we will examine ABCA7 function using mono- or co-culture system of neurons and microglia from human-induced pluripotent stem cells, where the ABCA7 gene is deleted by CRISPR/Cas9. Therefore, our study will give us unique opportunities to determine the roles of ABCA7 depending on brain cell types 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

$172,500

Focus

Genes to Therapies™, Translational Research

Researchers

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


Guojun Bu, Ph.D.