Ni Wang, Yining Pan, Skylar C. Starling, Devon H. Haskell, Astrid C. Quintero, Keiji Kawatani, Yasuteru Inoue, Francis Shue, Xiaoye Ma, Tomonori Aikawa, Yuka A. Martens, Aishe Kurti, Tammee M. Parsons, Ralph B. Perkerson, Bhaskar Roy, Ana-Caroline Raulin, Yingxue Ren, Michael DeTure, Dennis W. Dickson, Hanmei Bao, Xianlin Han, Guojun Bu, Takahisa Kanekiyo
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引用次数: 0
Abstract
INTRODUCTION
Loss-of-function variants of the ABCA7 gene are associated with an increased risk of Alzheimer's disease (AD). How neuronal ABCA7 contributes to AD pathogenesis is unknown.
METHODS
Using neuron-specific Abca7 KO mice (nAbca7−/−) with or without 5×FAD amyloid model background and post mortem AD brains, we investigated AD-related phenotypes through comprehensive approaches including transcriptomics and lipidomics.
RESULTS
Lipidomics analysis detected altered lipid profiles in the brains and synaptosomes of 5×FAD; nAbca7−/− mice compared to controls. Transcriptomics profiling revealed that neuronal ABCA7 deficiency altered the expression of genes and pathways related to mitochondrial homeostasis and apoptosis, particularly in excitatory neurons. Consistently, synaptosomes isolated from 5×FAD; nAbca7−/− mice showed diminished mitochondria respiration and reduced synaptic protein levels, which is further supported by results from human AD brains.
DISCUSSION
Our findings reveal that neuronal ABCA7 plays a critical role in mitochondrial homeostasis important for neuronal function and survival in the presence of AD pathology.
Highlights
Neuronal ABCA7 deficiency exacerbates Aβ pathology and neuronal damage in 5×FAD mice.
Neuronal ABCA7 deficiency alters brain transcriptomes and lipidomes of 5×FAD mice.
Neuronal ABCA7 deficiency disturbs mitochondria functions in synaptosomes from 5×FAD mice.
Neuronal ABCA7 expression associates with genes and pathways related to mitochondrial homeostasis in AD brains.
期刊介绍：
Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.
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