脂肪酸代谢与阿尔茨海默病联系的研究进展

doi:10.3969/j.issn.1003-9198.2025.04.019

摘要/Abstract

摘要： AD是一种与年龄相关的神经退行性疾病,其发病机制一直备受关注。AD的主流学说认为该病主要与淀粉样蛋白(Aβ)和tau蛋白相关。然而,越来越多的研究表明,脂肪酸代谢异常可能贯穿AD的疾病进程,并与其有特殊的病理生理联系。本文从脂肪酸的转运、降解、合成3个方面阐述其与AD的联系和研究新进展,以期为寻找新的潜在靶点提供新思路。

关键词: 阿尔茨海默病, 脂肪酸代谢, 神经炎症, 氧化应激

Abstract: Alzheimer’s disease(AD) is an age-associated neurodegenerative disorder, and its pathogenesis has been extensively studied. The mainstream theory shows AD is associated with amyloid-beta(Aβ) and tau protein. However, studies show that abnormal fatty acid metabolism may play a role throughout the progression of AD, with specific physiological and pathological connections. This article summarizes the associations and recent advances on fatty acid transport, degradation and synthesis in relation to AD, aiming to provide new insights for identifying potential therapeutic targets.

Key words: Alzheimer’s disease, fatty acid metabolism, neuroinflammation, oxidative stress

中图分类号:

R 749.16

王妍, 徐洁, 顾小萍. 脂肪酸代谢与阿尔茨海默病联系的研究进展[J]. 实用老年医学, 2025, 39(4): 415-419.

WANG Yan, XU Jie, GU Xiaoping. Research advances on association between fatty acid metabolism and Alzheimer’s disease[J]. Practical Geriatrics, 2025, 39(4): 415-419.

参考文献

[1] 2023 Alzheimer’s disease facts and figures[J].Alzheimers Dement, 2023, 19(4): 1598-1695.
[2] GDB 2019 Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019[J].Lancet Public Health, 2022, 7(2): e105-e125.
[3] ALZHEIMER A, STELZMANN R A, SCHNITZLEIN H N,et al. An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”[J].Clin Anat, 1995, 8(6): 429-431.
[4] YIN F. Lipid metabolism and Alzheimer’s disease: clinical evidence, mechanistic link and therapeutic promise[J].FEBS J, 2023, 290(6): 1420-1453.
[5] MUKHERJEE S, SURESH S N. Neuron-astrocyte liaison to maintain lipid metabolism of brain[J].Trends Endocrinol Metab, 2019, 30(9): 573-575.
[6] ERASO-PICHOT A, BRASÓ-VIVES M, GOLBANO A, et al. GSEA of mouse and human mitochondriomes reveals fatty acid oxidation in astrocytes[J].Glia, 2018, 66(8): 1724-1735.
[7] IOANNOU M S, JACKSON J, SHEU S H, et al. Neuron-astrocyte metabolic coupling protects against activity-induced fatty acid toxicity[J].Cell, 2019, 177(6): 1522-1535.e14.
[8] KARCH C M, GOATE A M. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis[J].Biol Psychiatry, 2015, 77(1): 43-51.
[9] QI G, MI Y, SHI X, et al. ApoE4 impairs neuron-astrocyte coupling of fatty acid metabolism[J].Cell Rep, 2021, 34(1): 108572.
[10]BOGIE J F J, HAIDAR M, KOOIJ G, et al. Fatty acid metabolism in the progression and resolution of CNS disorders[J].Adv Drug Deliv Rev, 2020, 159: 198-213.
[11]THANGAVEL R, KEMPURAJ D, ZAHEER S, et al. Glia maturation factor and mitochondrial uncoupling proteins 2 and 4 expression in the temporal cortex of Alzheimer’s disease brain[J].Front Aging Neurosci, 2017, 9: 150.
[12]ATES G, GOLDBERG J, CURRAIS A, et al. CMS121, a fatty acid synthase inhibitor, protects against excess lipid peroxidation and inflammation and alleviates cognitive loss in a transgenic mouse model of Alzheimer’s disease[J].Redox Biol, 2020, 36: 101648.
[13]DIMAS P, MONTANI L, PEREIRA J A, et al. CNS myelination and remyelination depend on fatty acid synthesis by oligodendrocytes[J].eLife, 2019, 8: e44702.
[14]CAMARGO N, GOUDRIAAN A, VAN DEIJK A F, et al. Oligodendroglial myelination requires astrocyte-derived lipids[J].PLoS Biol, 2017, 15(5): e1002605.
[15]GUTTENPLAN K A, WEIGEL M K, PRAKASH P, et al. Neurotoxic reactive astrocytes induce cell death via saturated lipids[J].Nature, 2021, 599(7883): 102-107.
[16]NASRABADY S E, RIZVI B, GOLDMAN J E, et al. White matter changes in Alzheimer’s disease: a focus on myelin and oligodendrocytes[J].Acta Neuropathol Commun, 2018, 6(1): 22.
[17]OPERTO G, CACCIAGLIA R, GRAU-RIVERA O, et al. White matter microstructure is altered in cognitively normal middle-aged APOE-ε4 homozygotes[J].Alzheimers Res Ther, 2018, 10(1): 48.
[18]CRISTOFANO A, SAPERE N, LA MARCA G, et al. Serum levels of acyl-carnitines along the continuum from normal to Alzheimer’s dementia[J].PLoS One, 2016, 11(5): e0155694.
[19]CIAVARDELLI D, PIRAS F, CONSALVO A, et al. Medium-chain plasma acylcarnitines, ketone levels, cognition, and gray matter volumes in healthy elderly, mildly cognitively impaired, or Alzheimer’s disease subjects[J].Neurobiol Aging, 2016, 43: 1-12.
[20]SCHÖNFELD P, REISER G. Brain energy metabolism spurns fatty acids as fuel due to their inherent mitotoxicity and potential capacity to unleash neurodegeneration[J].Neurochem Int, 2017, 109: 68-77.
[21]WILSOND M 3rd, COOKSONM R, VANDENBOSCHL, et al. Hallmarks of neurodegenerative diseases[J].Cell, 2023, 186(4): 693-714.
[22]HENEKA M T, CARSON M J, EL KHOURY J, et al. Neuroinflammation in Alzheimer’s disease[J].Lancet Neurol, 2015, 14(4): 388-405.
[23]LENG F, EDISON P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?[J].Nat Rev Neurol, 2021, 17(3): 157-172.
[24]MI Y, QI G, VITALI F, et al. Loss of fatty acid degradation by astrocytic mitochondria triggers neuroinflammation and neurodegeneration[J].Nat Metab, 2023, 5(3): 445-465.
[25]LIDDELOW S A, GUTTENPLAN K A, CLARKE L E, et al. Neurotoxic reactive astrocytes are induced by activated microglia[J].Nature, 2017, 541(7638): 481-487.
[26]PATEL N S, PARIS D, MATHURA V, et al. Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer’s disease[J].J Neuroinflammation, 2005, 2(1): 9.
[27]FÜNFSCHILLING U, SUPPLIEL M, MAHAD D, et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity[J].Nature, 2012, 485(7399): 517-521.
[28]EBERT D, HALLER R G, WALTON M E. Energy contribution of octanoate to intact rat brain metabolism measured by ¹³C nuclear magnetic resonance spectroscopy[J].J Neurosci, 2003, 23(13): 5928-5935.
[29]KNOBLOCH M, PILZ G A, GHESQUIÈRE B, et al. A fatty acid oxidation-dependent metabolic shift regulates adult neural stem cell activity[J].Cell Rep, 2017, 20(9): 2144-2155.
[30]HAMILTON L K, DUFRESNE M, JOPPÉ S E, et al. Aberrant lipid metabolism in the forebrain niche suppresses adult neural stem cell proliferation in an animal model of Alzheimer’s disease[J].Cell Stem Cell, 2015, 17(4): 397-411.
[31]NOLFI-DONEGAN D, BRAGANZA A, SHIVA S. Mitochondrial electron transport chain: oxidative phosphorylation, oxidant production, and methods of measurement[J].Redox Biol, 2020, 37: 101674.
[32]PLASCENCIA-VILLA G, PERRY G. Roles of oxidative stress in synaptic dysfunction and neuronal cell death in Alzheimer’s disease[J].Antioxidants, 2023, 12(8): 1628.
[33]BRADLEY M A, MARKESBERY W R, LOVELL M A. Increased levels of 4-hydroxynonenal and acrolein in the brain in preclinical Alzheimer disease[J].Free Radic Biol Med, 2010, 48(12): 1570-1576.
[34]CRIVELLI S M, GIOVAGNONI C, VISSEREN L, et al. Sphingolipids in Alzheimer’s disease, how can we target them?[J].Adv Drug Deliv Rev, 2020, 159: 214-231.
[35]GIORGI C, MISSIROLI S, PATERGNANI S, et al. Mitochondria-associated membranes: composition, molecular mechanisms, and physiopathological implications[J].Antioxid Redox Signal, 2015, 22(12): 995-1019.
[36]BHATTACHARYYA R, BLACK S E, LOTLIKAR M S, et al. Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes[J].Cell Rep, 2021, 35(7): 109134.
[37]SIEGEL S J, BIESCHKE J, POWERSE T, et al. The oxidative stress metabolite 4-hydroxynonenal promotes Alzheimer protofibril formation[J].Biochemistry, 2007, 46(6): 1503-1510.
[38]OWEN J B, SULTANA R, ALUISE C D, et al. Oxidative modification to LDL receptor-related protein 1 in hippocampus from subjects with Alzheimer disease: implications for Aβ accumulation in AD brain[J].Free Radic Biol Med, 2010, 49(11): 1798-1803.
[39]DO K V, KAUTZMANN M I, JUN B, et al. Elovanoids counteract oligomeric β-amyloid-induced gene expression and protect photoreceptors[J].Proc Natl Acad Sci USA, 2019, 116(48): 24317-24325.
[40]FONTEH A N, CIPOLLA M, CHIANG J, et al. Human cerebrospinal fluid fatty acid levels differ between supernatant fluid and brain-derived nanoparticle fractions, and are altered in Alzheimer’s disease[J].PLoS One, 2014, 9(6): e100519.
[41]WEI B Z, LI L, DONG C W, et al. The relationship of omega-3 fatty acids with dementia and cognitive decline: evidence from prospective cohort studies of supplementation, dietary intake, and blood markers[J].Am J Clin Nutr, 2023, 117(6): 1096-1109.