Unraveling Alzheimer's: ABCA7's Key Role in Neuronal Health and Cardiolipin Metabolism
In the research article ‘ABCA7 deficiency causes neuronal dysregulation by altering mitochondrial lipid metabolism’, the authors provide an explanation for how the presence or absence of ABCA7 alters neuronal function by influencing mitochondrial lipid metabolism. ABCA7 is an ATP-binding cassette (ABC) transporter, a type of molecule that governs traffic into and out of cells. It is a known risk gene for Alzheimer’s disease (AD). However, little is known about the specific role ABCA7 has in neuronal physiology, and little progress has been made in understanding how individuals vary in their susceptibility to Alzheimer’s disease. There have also been few efforts to determine if the differing susceptibility can help scientists learn more about the disease’s progressive nature. Patients with Alzheimer’s disease have impaired transport of cholesterol out of neurons and experience abnormalities and a breakdown of neuronal networks. These characteristics share elements with neuroendocrine tumours, where ABCA7 shows response to drug therapy. Non-pharmacological intervention in neuroendocrine tumours has provided more options for treatment and slowed disease progression. Considering these clinical observations, Jaishankar and colleagues hypothesise that ABCA7 may provide specificity in neuronal health and dysfunction, and could play a role in the pathology of Alzheimer’s disease.
Major findings include the discovery that ABCA7 is abundantly expressed in the brain, in particular in neurons, and plays a crucial role in promoting neuronal homeostasis. When ABCA7 levels drop, many neurons reorganise to restore achieve normal function, as demonstrated by dysregulated mitochondria and lipid flow. The study shows that ABCA7 deficiency disrupts normal mitochondrial function, resulting in impaired mitochondrial respiration, reduction in ATP synthesis, and increased oxidative damage.
Moreover, ABCA7 deficiency disrupts mitochondrial lipid composition, involved in maintaining the membrane integrity and function of mitochondria. Several lipid species, including phosphatidylcholines, phosphatidylethanolamines and cardiolipins, were affected, which could interfere with the function of mitochondrial proteins and perhaps affect their stability. Changes in cardiolipin composition can also lead to cell death due to dysfunctional mitochondria. The work also shows that ABCA7 directs lipid homeostasis by controlling the activity of enzymes that control lipid synthesis and remodelling, such as acyl-CoA synthetase and phospholipase A2, important for mitochondrial lipid homeostasis.
Dysregulation of lipid metabolism leads to synaptic dysfunction and to cell death of ABCA7 knockout neurons, and that deficiency in ABCA7 is the result of broader neurodegenerative processes with similarities to AD. In order to guide the discovery of how ABCA7-deficient neuronal lipid and mitochondrial misregulation leads to dysfunction and cellular death, the authors relied on a variety of experimental approaches including genetic models for mice that allowed them to knock out the ABCA7 gene, biochemical analyses of mitochondrial respiration and lipidomics, and primary neuronal culture from ABCA7 knockout mice.
These results provide important new hints to how ABCA7 deficiency can result in AD pathogenesis. Alterations in mitochondrial lipid metabolism, especially involving cardiolipins, and the resultant neuronal dysfunction provide a mechanistic rationale for its role in AD. Targeting lipid metabolic pathways in neurons could provide new therapeutic approaches to AD and other neurodegenerative diseases involving mitochondrial dysfunction. Improving ABCA7 function or its compensation could alleviate mitochondrial and neuronal dysfunctions.
As a conclusion, this study brings novel and clear support for the neuroprotective effect of ABCA7, by maintaining mitochondrial lipid metabolism, and keeping neuronal vitality, integrity and functionality. Presumably, the dysfunction of ABCA7 would lead to dramatic disturbance of mitochondrial physiology, lipid constitution, and neuronal wellbeing, contributing to neuropathological progression of the AD. This brings new molecular clues for AD and also adds a neuronal lipid metabolic pathway for novel therapeutic approaches.
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Click here for the full article: Kawatani, K., Holm, M.-L., Starling, S. C., Martens, Y. A., Zhao, J., Lu, W., Ren, Y., Li, Z., Jiang, P., Jiang, Y., Baker, S. K., Wang, N., Roy, B., Parsons, T. M., Perkerson, R. B., Bao, H., Han, X., Bu, G., & Kanekiyo, T. (2023). ABCA7 deficiency causes neuronal dysregulation by altering mitochondrial lipid metabolism. Molecular Psychiatry, 29(3), 809–819. https://doi.org/10.1038/s41380...