# Neuronal ABCA7 loss of function and Alzheimer’s disease

> **NIH NIH RF1** · MAYO CLINIC  JACKSONVILLE · 2023 · $2,063,098

## Abstract

PROJECT SUMMARY/ABSTRACT
MAYO CLINIC JACKSONVILLE
Current genetic studies indicate that susceptibility loci in late-onset Alzheimer’s disease (AD) are correlated
with lipid metabolism. While ATP-binding cassette transporter A7 (ABCA7) gene variants are strongly
associated with AD risk, the premature termination codon (PTC) mutations in ABCA7 significantly increases
the risk for both early-onset and late-onset AD. ABCA7 belongs to the ABC transporter family regulating
distribution of lipids and other lipid-related molecules across cellular membranes. Thus, exploring functions of
ABCA7 in lipid metabolism should provide us important clues to determine the central pathogenic pathway for
AD. While ABCA7 expression is the highest in neurons among brain cell types, our preliminary study showed
that ABCA7 deficiency alters the compositions of mitochondria-related lipids and impairs mitochondria function
accompanied with synaptic dysregulation in the cortical organoids and neurons derived from human induced
pluripotent stem cells (iPSCs). In addition, RNA-sequencing analysis also found that pathways related to fatty
acid β-oxidation in mitochondria and cellular membrane homeostasis are predominantly affected by ABCA7
deficiency in mouse brains. As lipids substantially contribute to the regulation of neuronal functions, we
hypothesize that ABCA7 loss of function alters the lipid metabolism among cellular organelles, and disturbs
mitochondria functions in neurons, resulting in neurodegeneration and synaptic dysfunction during aging and
AD. Therefore, this proposal uniquely aims to dissect how ABCA7 deficiency impacts lipid metabolism in
neurons and contributes to AD-related phenotypes including mitochondria dysregulation and synaptic
dysfunction. In Aim 1, we will examine how ABCA7 deficiency influences lipid metabolism, mitochondria
function, and AD-related phenotypes using iPSC-derived neurons and cortical organoids. In Aim 2, we will
dissect roles of neuronal ABCA7 in AD-related phenotypes using neuron specific Abca7 knockout mouse
models with or without amyloid pathology, accompanied with single cell-RNA sequencing. In Aim 3, we will
explore impacts of ABCA7 deficiency on synapses, including mitochondria functions and lipid profiles, by
isolating synaptosomes from conventional Abca7 knockout mice as well as neuron specific Abca7 knockout
mice with or without amyloid pathology. Collectively, these studies should provide us new insights for the
molecular mechanisms in which ABCA7 floss of function causes the pathogenic processes of AD by disturbing
neuronal lipid homeostasis.

## Key facts

- **NIH application ID:** 10629715
- **Project number:** 1RF1AG081203-01
- **Recipient organization:** MAYO CLINIC  JACKSONVILLE
- **Principal Investigator:** Takahisa Kanekiyo
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $2,063,098
- **Award type:** 1
- **Project period:** 2023-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10629715

## Citation

> US National Institutes of Health, RePORTER application 10629715, Neuronal ABCA7 loss of function and Alzheimer’s disease (1RF1AG081203-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10629715. Licensed CC0.

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