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Sienski G, Narayan P, Bonner JM, Kory N, Boland S, Arczewska AA, Ralvenius WT, Akay L, Lockshin E, He L, Milo B, Graziosi A, Baru V, Lewis CA, Kellis M, Sabatini DM, Tsai LH, Lindquist S. APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia. Sci Transl Med. 2021 Mar 3;13(583) PubMed.
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University of New South Wales
The work by Sienski and colleagues, demonstrating the perturbation of lipid homeostasis by APOE4, is of much interest because it suggests another pathway by which APOE polymorphisms may increase susceptibility to Alzheimer’s disease.
In particular, the authors showed an increase in unsaturated tricylglycerides and a higher phosphatidylcholine requirement in cultured human astrocytes with the APOE4 genotype, a defect reversed by choline supplementation. The focus on lipids is important since the brain is highly enriched for them, and several lipid changes have been demonstrated in AD brains and AD plasma (Wong et al., 2017).
Lipids change with age, and aging is the strongest risk factor for AD. Lipids can also be manipulated by alterations to the diet and gut microbiome, suggesting several therapeutic approaches. The work therefore needs to be taken further. Since APOE2 is known to offer some protection against AD, it would be interesting to study the impact of this genotype on lipids as well.
The authors focused on tricylglycerides and phospholipids and did not report other lipid species such as sphingolipids and ceramides, which are also of interest. The reversal with choline supplementation is interesting. There have been several trials of choline in mice models of AD, with reports of a protective effect (Velazquez et al., 2019). Several mechanisms for this have been suggested: an increase in levels of acetylcholine, reduced production of amyloid-β plaques, reduction in homocysteine levels, reduced activation of microglia, and even epigenetic alterations. Sienski et al. now add another potential mechanism to this list.
However, initial human trials of choline in AD were generally negative (Amenta et al., 2001). More recent multinutrient interventions have been more promising (Baumel et al., 2020), but better understanding of the mechanisms is needed so that appropriate intervention strategies can be developed.
Wong MW, Braidy N, Poljak A, Pickford R, Thambisetty M, Sachdev PS. Dysregulation of lipids in Alzheimer's disease and their role as potential biomarkers. Alzheimers Dement. 2017 Jul;13(7):810-827. Epub 2017 Feb 24 PubMed.
Velazquez R, Ferreira E, Winslow W, Dave N, Piras IS, Naymik M, Huentelman MJ, Tran A, Caccamo A, Oddo S. Maternal choline supplementation ameliorates Alzheimer's disease pathology by reducing brain homocysteine levels across multiple generations. Mol Psychiatry. 2019 Jan 8; PubMed.
Amenta F, Parnetti L, Gallai V, Wallin A. Treatment of cognitive dysfunction associated with Alzheimer's disease with cholinergic precursors. Ineffective treatments or inappropriate approaches?. Mech Ageing Dev. 2001 Nov;122(16):2025-40. PubMed.
Baumel BS, Doraiswamy PM, Sabbagh M, Wurtman R. Potential Neuroregenerative and Neuroprotective Effects of Uridine/Choline-Enriched Multinutrient Dietary Intervention for Mild Cognitive Impairment: A Narrative Review. Neurol Ther. 2021 Jun;10(1):43-60. Epub 2020 Dec 26 PubMed.View all comments by Perminder Sachdev
Henan University of Chinese Medicine
This study sheds more light on the role of ApoE in the brain. It is known that ApoE activates a range of growth-factor like receptors and plays a role in lipid metabolism (Liu et al., 2015; Zhao et al., 2017). APOE4 appears to be less able to activate these receptors. Therefore, the buildup of lipids in the microglia indicates a problem in processing lipids for energy production. This can explain why APOE4 carriers are more prone to develop AD, as we know that brain energy metabolism is increasingly challenged in AD, and that insulin signalling and glucose utilization is decreased (Talbot et al., 2012; Arnold et al., 2018). In APOE2 carriers, it might be possible to compensate for loss of glucose utilization, while in APOE4 carriers, this is not as effective.
Liu CC, Hu J, Tsai CW, Yue M, Melrose HL, Kanekiyo T, Bu G. Neuronal LRP1 regulates glucose metabolism and insulin signaling in the brain. J Neurosci. 2015 Apr 8;35(14):5851-9. PubMed.
Zhao N, Liu CC, Van Ingelgom AJ, Martens YA, Linares C, Knight JA, Painter MM, Sullivan PM, Bu G. Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes. Neuron. 2017 Sep 27;96(1):115-129.e5. PubMed.
Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, Fuino RL, Kawaguchi KR, Samoyedny AJ, Wilson RS, Arvanitakis Z, Schneider JA, Wolf BA, Bennett DA, Trojanowski JQ, Arnold SE. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012 Apr;122(4):1316-38. PubMed.
Arnold SE, Arvanitakis Z, Macauley-Rambach SL, Koenig AM, Wang HY, Ahima RS, Craft S, Gandy S, Buettner C, Stoeckel LE, Holtzman DM, Nathan DM. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol. 2018 Mar;14(3):168-181. Epub 2018 Jan 29 PubMed.View all comments by Christian Hoelscher
University of Arkansas for Medical Sciences
It would be very helpful if the authors, or other ApoE experts, could weigh in on the mechanism(s) by which ApoE secreted from yeast might interact with cellular processes. Does yeast have any surface receptors capable of binding ApoE? Or do we suppose that the effects are all due to mass-action effects by which ApoE, soluble in the growth medium, influences the availability of free lipids for uptake by other mechanisms?View all comments by Steve Barger
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