Abca7-KO Mouse

Abca7, an ATP-binding cassette transporter, is a member of the ABC transporter gene superfamily [3]. It plays a role in lipid homeostasis, phagocytosis, and is involved in pathways related to cholesterol metabolism and amyloid-β (Aβ) processing [2,3,4,5,6]. ABCA7 is most abundantly expressed in microglial cells in the brain, and its gene variants are associated with late-onset Alzheimer's disease (LOAD), making it an important genetic determinant for LOAD [3,6]. Genetic models, such as knockout (KO) mouse models, have been crucial in studying its function.

ABCA7 deficiency in KO models has been shown to have multiple effects. In human iPSC-derived models, it leads to reduced mitochondria-related phospholipids, altered mitochondrial morphology, reduced ATP synthase activity, exacerbated oxidative damage, compromised mitochondrial respiration, excess ROS generation, and decreased spontaneous synaptic firing and network formation [1]. These effects were rescued by phosphatidylglycerol or NAD+ precursor supplementation [1]. In neuron-specific Abca7 knockout mice, similar effects on mitochondria morphology and synapses were observed in synaptosomes [1]. Additionally, ABCA7 deficiency in vitro and in vivo exacerbates Aβ pathology, likely by facilitating endocytosis and/or processing of APP, and impairs microglial Aβ clearance [4].

In conclusion, Abca7 is essential for normal mitochondrial lipid metabolism, synaptic function, and Aβ clearance. Studies using Abca7 KO mouse models have significantly contributed to understanding its role in Alzheimer's disease, highlighting its importance in disease pathogenesis and suggesting it as a potential therapeutic target for AD [1,4].

References:

1. Kawatani, Keiji, Holm, Marie-Louise, Starling, Skylar C, Bu, Guojun, Kanekiyo, Takahisa. 2023. ABCA7 deficiency causes neuronal dysregulation by altering mitochondrial lipid metabolism. In Molecular psychiatry, 29, 809-819. doi:10.1038/s41380-023-02372-w. https://pubmed.ncbi.nlm.nih.gov/38135757/

2. Stepler, Kaitlyn E, Gillyard, Taneisha R, Reed, Calla B, Davis, Jamaine S, Robinson, Renã A S. . ABCA7, a Genetic Risk Factor Associated with Alzheimer's Disease Risk in African Americans. In Journal of Alzheimer's disease : JAD, 86, 5-19. doi:10.3233/JAD-215306. https://pubmed.ncbi.nlm.nih.gov/35034901/

3. Zhao, Qing-Fei, Yu, Jin-Tai, Tan, Meng-Shan, Tan, Lan. 2014. ABCA7 in Alzheimer's Disease. In Molecular neurobiology, 51, 1008-16. doi:10.1007/s12035-014-8759-9. https://pubmed.ncbi.nlm.nih.gov/24878767/

4. Aikawa, Tomonori, Holm, Marie-Louise, Kanekiyo, Takahisa. 2018. ABCA7 and Pathogenic Pathways of Alzheimer's Disease. In Brain sciences, 8, . doi:10.3390/brainsci8020027. https://pubmed.ncbi.nlm.nih.gov/29401741/

5. Abe-Dohmae, Sumiko, Yokoyama, Shinji. 2020. ABCA7 links sterol metabolism to the host defense system: Molecular background for potential management measure of Alzheimer's disease. In Gene, 768, 145316. doi:10.1016/j.gene.2020.145316. https://pubmed.ncbi.nlm.nih.gov/33221536/

6. Dib, Shiraz, Pahnke, Jens, Gosselet, Fabien. 2021. Role of ABCA7 in Human Health and in Alzheimer's Disease. In International journal of molecular sciences, 22, . doi:10.3390/ijms22094603. https://pubmed.ncbi.nlm.nih.gov/33925691/