APOLIPOPROTEINA Ɛ4 NA DOENÇA DE ALZHEIMER, SUA RELAÇÃO COM A OBESIDADE E FUTUROS TRATAMENTOS:
UMA REVISÃO DA LITERATURA
DOI:
https://doi.org/10.56238/rebeisv1n5-002Palavras-chave:
APOE4, Alvo terapêutico, Estilo de vida, Demência, FisiopatologiaResumo
O presente estudo teve o objetivo de identificar por meio de uma revisão de literatura, a apolipoproteína ɛ4 (APOE4) na Doença do Alzheimer (DA), apresentando sua relação com a obesidade e futuros tratamentos. Para a investigação, foram utilizados artigos de revisão publicados na base de dados PubMed, dos últimos 5 (cinco) anos (2018 a 2023). Identificou-se que na fisiopatologia da DA, a APOE4 está associada à cascata da apolipoproteína (APOE), acúmulo das proteínas beta-amiloide (Aβ) e tau, neuroinflamação crônica, perda da integridade da barreira hematoencefálica e disfunção da rede inibitória e fragmentação da APOE. Nesse sentido, 5 (cinco) abordagens terapêuticas utilizando a APOE como alvo foram desenvolvidas: 1) interação da APOE com Aβ; 2) edição genética da APOE; 3) receptores da APOE; 4) anticorpos APOE; e 5) terapia não farmacológica. Dentre estas, destaca-se o estilo de vida, no qual, ao investigar acerca da obesidade, estudos evidenciaram que a APOE4 provoca alterações metabólicas, podendo ser um fator interferente na obesidade, e que ambos em conjunto, podem apresentar riscos ou progressão à DA. Portanto, se faz necessário novos estudos para melhor compreensão dessa relação e aprimoramento dos tratamentos para a DA.
Referências
AMPONSAH, A. E. et al. Fragmentation of brain apolipoprotein E (ApoE) and its relevance in Alzheimer’s disease. Reviews in the Neurosciences, v. 31, n. 6, p. 589–603, 27 ago. 2020.
ANGELOPOULOU, E. et al. APOE genotype and Alzheimer’s disease: the influence of lifestyle and environmental factors. ACS Chemical Neuroscience, v. 12, n. 15, p. 2749–2764, 4 ago. 2021.
ARBONES-MAINAR, J. M. et al. Differential modulation of diet-induced obesity and adipocyte functionality by human apolipoprotein E3 and E4 in mice. International Journal of Obesity, v. 32, n. 10, p. 1595–1605, out. 2008.
ARNOLD, S. E. et al. High fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behavior in mice. Neurobiology of Disease, v. 67, p. 79–87, jul. 2014.
AVILA-MUÑOZ, E.; ARIAS, C. When astrocytes become harmful: functional and inflammatory responses that contribute to Alzheimer’s disease. Ageing Research Reviews, v. 18, p. 29–40, nov. 2014.
BONDI, M. W.; EDMONDS, E. C.; SALMON, D. P. Alzheimer’s disease: past, present, and future. Journal of the International Neuropsychological Society: JINS, v. 23, n. 9–10, p. 818–831, out. 2017.
BUCKMAN, L. B. et al. Obesity induced by a high-fat diet is associated with increased immune cell entry into the central nervous system. Brain, Behavior, and Immunity, v. 35, p. 33–42, jan. 2014.
CHANG, C. Y.; SILVERMAN, D. H. S. Accuracy of early diagnosis and its impact on the management and course of Alzheimer’s disease. Expert Review of Molecular Diagnostics, v. 4, n. 1, p. 63–69, jan. 2004.
COLTON, C. A. et al. APOE genotype-specific differences in human and mouse macrophage nitric oxide production. Journal of Neuroimmunology, v. 147, n. 1–2, p. 62–67, fev. 2004.
CORDEIRO, A. M. et al. Revisão sistemática: uma revisão narrativa. Revista do Colégio Brasileiro de Cirurgiões, v. 34, p. 428–431, dez. 2007.
CORDER, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science (New York, N.Y.), v. 261, n. 5123, p. 921–923, 13 ago. 1993.
DE-PAULA, V. J. et al. Alzheimer’s disease. Sub-cellular biochemistry, v. 65, p. 329–352, 2012.
DRAKE, J. A. et al. Reduced brain activity during a working memory task in middle-aged apolipoprotein E ε4 carriers with overweight/obesity. Frontiers in Human Neuroscience, v. 16, p. 1001229, 2022.
ELOSUA, R. et al. Obesity modulates the association among APOE genotype, insulin, and glucose in men. Obesity Research, v. 11, n. 12, p. 1502–1508, dez. 2003.
EMRANI, S. et al. APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer’s disease: a systematic review. Alzheimer’s Research & Therapy, v. 12, n. 1, p. 141, 4 nov. 2020.
ERATNE, D. et al. Alzheimer’s disease: clinical update on epidemiology, pathophysiology and diagnosis. Australasian Psychiatry: Bulletin of Royal Australian and New Zealand College of Psychiatrists, v. 26, n. 4, p. 347–357, ago. 2018.
ESSER, K.-H.; MARX, W. H.; LISOWSKY, T. MaxXbond: first regeneration system for DNA binding silica matrices. Nature Methods, v. 3, n. 1, p. i–ii, jan. 2006.
FERNÁNDEZ-CALLE, R. et al. APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases. Molecular Neurodegeneration, v. 17, n. 1, p. 62, 24 set. 2022.
GALE, S. C. et al. APOε4 is associated with enhanced in vivo innate immune responses in human subjects. Journal of Allergy and Clinical Immunology, v. 134, n. 1, p. 127- 134.e9, jul. 2014.
GHOSAL, K. et al. A randomized controlled study to evaluate the effect of bexarotene on amyloid-β and apolipoprotein E metabolism in healthy subjects. Alzheimer’s & Dementia (New York, N. Y.), v. 2, n. 2, p. 110–120, jun. 2016.
GUEST, P. C. (ED.). Reviews on new drug targets in age-related disorders. Cham: Springer International Publishing, 2020. v. 1260
HALLIDAY, M. R. et al. Relationship between cyclophilin a levels and matrix metalloproteinase 9 activity in cerebrospinal fluid of cognitively normal apolipoprotein e4 carriers and blood-brain barrier breakdown. JAMA Neurology, v. 70, n. 9, p. 1198–1200, 1 set. 2013.
HEBERT, L. E. et al. Is the risk of developing Alzheimer’s disease greater for women than for men? American Journal of Epidemiology, v. 153, n. 2, p. 132–136, 15 jan. 2001.
HENEKA, M. T. et al. Neuroinflammation in Alzheimer’s disease. The Lancet Neurology, v. 14, n. 4, p. 388–405, abr. 2015.
JEONG, W. et al. ApoE4 induced cholesterol dysregulation and its brain cell type-specific implications in the pathogenesis of alzheimer’s disease. Molecules and Cells, v. 42, n. 11, p. 739–746, 30 nov. 2019.
JONES, N.; REBECK, G. The synergistic effects of APOE genotype and obesity on Alzheimer’s disease risk. International Journal of Molecular Sciences, v. 20, n. 1, p. 63, 24 dez. 2018.
KLOSKE, C. M.; WILCOCK, D. M. The important interface between Apolipoprotein E and neuroinflammation in alzheimer’s disease. Frontiers in Immunology, v. 11, p. 754, 2020.
KOTHARI, V. et al. High fat diet induces brain insulin resistance and cognitive impairment in mice. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, v. 1863, n. 2, p. 499–508, fev. 2017.
KOUTSODENDRIS, N. et al. Apolipoprotein E and alzheimer’s disease: findings, hypotheses, and potential mechanisms. Annual Review of Pathology: Mechanisms of Disease, v. 17, n. 1, p. 73–99, 24 jan. 2022.
KUSZCZYK, M. A. et al. Blocking the interaction between apolipoprotein E and Aβ reduces intraneuronal accumulation of Aβ and inhibits synaptic degeneration. The American Journal of Pathology, v. 182, n. 5, p. 1750–1768, maio 2013.
LANFRANCO, M. F.; NG, C. A.; REBECK, G. W. ApoE lipidation as a therapeutic target in Alzheimer’s disease. International Journal of Molecular Sciences, v. 21, n. 17, p. 6336, 1 set. 2020.
LEWANDOWSKI, C. T.; LAHAM, M. S.; THATCHER, G. R. J. Remembering your A, B, C’s: Alzheimer’s disease and ABCA1. Acta Pharmaceutica Sinica. B, v. 12, n. 3, p. 995–1018, mar. 2022.
LI, L. et al. A gene-environment interplay between omega-3 supplementation and APOE ε4 provides insights for Alzheimer’s disease precise prevention amongst high-genetic-risk population. European Journal of Neurology, v. 29, n. 2, p. 422–431, fev. 2022.
LIAO, F. et al. Anti-ApoE antibody given after plaque onset decreases Aβ accumulation and improves brain function in a mouse model of Aβ amyloidosis. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, v. 34, n. 21, p. 7281–7292, 21 maio 2014.
LIU, C.-C. et al. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature Reviews. Neurology, v. 9, n. 2, p. 106–118, fev. 2013.
LYNCH, J. R. et al. APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response. The Journal of Biological Chemistry, v. 278, n. 49, p. 48529–48533, 5 dez. 2003.
MAHONEY-SANCHEZ, L. et al. The complex role of apolipoprotein E in Alzheimer’s disease: an overview and update. Journal of Molecular Neuroscience, v. 60, n. 3, p. 325–335, nov. 2016.
MAMUN, A. A. et al. Molecular insight into the therapeutic promise of targeting APOE4 for Alzheimer’s disease. Oxidative Medicine and Cellular Longevity, v. 2020, p. 5086250, 2020.
MANTZAVINOS, V.; ALEXIOU, A. Biomarkers for Alzheimer’s disease diagnosis. Current Alzheimer Research, v. 14, n. 11, p. 1149–1154, 2017.
OBOUDIYAT, C. et al. Alzheimer’s disease. Seminars in Neurology, v. 33, n. 4, p. 313–329, set. 2013.
MARTENS, Y. A. et al. ApoE cascade hypothesis in the pathogenesis of Alzheimer’s disease and related dementias. Neuron, v. 110, n. 8, p. 1304–1317, abr. 2022.
MATHIEU, P. et al. Visceral obesity: the link among inflammation, hypertension, and cardiovascular disease. Hypertension (Dallas, Tex.: 1979), v. 53, n. 4, p. 577–584, abr. 2009.
MONTAGNE, A. et al. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature, v. 581, n. 7806, p. 71–76, maio 2020.
MOON, W.-J. et al. Hippocampal blood-brain barrier permeability is related to the APOE4 mutation status of elderly individuals without dementia. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism, v. 41, n. 6, p. 1351–1361, jun. 2021.
MORRILL, S. J.; GIBAS, K. J. Ketogenic diet rescues cognition in ApoE4+ patient with mild Alzheimer’s disease: A case study. Diabetes & Metabolic Syndrome, v. 13, n. 2, p. 1187–1191, 2019.
NAJM, R.; JONES, E. A.; HUANG, Y. Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease. Molecular Neurodegeneration, v. 14, n. 1, p. 24, 11 jun. 2019.
NETH, B. J.; CRAFT, S. Insulin Resistance and Alzheimer’s disease: bioenergetic linkages. Frontiers in Aging Neuroscience, v. 9, p. 345, 31 out. 2017.
OBOUDIYAT, C. et al. Alzheimer’s disease. Seminars in Neurology, v. 33, n. 4, p. 313–329, set. 2013.
OJOPI, E. P. B.; BERTONCINI, A. B.; DIAS NETO, E. Apolipoproteína E e a doença de Alzheimer. Archives of Clinical Psychiatry (São Paulo), v. 31, n. 1, p. 26–33, 2004.
OPHIR, G. et al. Apolipoprotein E4 enhances brain inflammation by modulation of the NF-κB signaling cascade. Neurobiology of Disease, v. 20, n. 3, p. 709–718, dez. 2005.
OSIECKA, Z. et al. Obesity reduces hippocampal structure and function in older African Americans with the APOE-ε4 Alzheimer’s disease risk allele. Frontiers in Aging Neuroscience, v. 15, p. 1-12, 2023.
PARHIZKAR, S.; HOLTZMAN, D. M. APOE mediated neuroinflammation and neurodegeneration in Alzheimer’s disease. Seminars in Immunology, v. 59, p. 101594, jan. 2022.
PRADO, D.; CARDOSO, I. L. Apolipoproteína E e doença de alzheimer. Revista de Neurociências, v. 21, n. 1, p. 118–125, 2013.
QUINN, J. F. et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA, v. 304, n. 17, p. 1903–1911, 3 nov. 2010.
RAFNSSON, S. B. et al. Cognitive decline and markers of inflammation and hemostasis: the edinburgh artery study. Journal of the American Geriatrics Society, v. 55, n. 5, p. 700–707, maio 2007.
RASLAU, F. D. et al. Memory part 2: the role of the medial temporal lobe. AJNR. American journal of neuroradiology, v. 36, n. 5, p. 846–849, maio 2015.
RAUCH, J. N. et al. LRP1 is a master regulator of tau uptake and spread. Nature, v. 580, n. 7803, p. 381–385, abr. 2020.
RODA, A. R.; MONTOLIU-GAYA, L.; VILLEGAS, S. The role of apolipoprotein E isoforms in Alzheimer’s disease. Journal of Alzheimer’s Disease, v. 68, n. 2, p. 459–471, 29 mar. 2019.
ROSTAGNO, A. A. Pathogenesis of Alzheimer’s disease. International Journal of Molecular Sciences, v. 24, n. 1, p. 107, 21 dez. 2022.
SAFIEH, M.; KORCZYN, A. D.; MICHAELSON, D. M. ApoE4: an emerging therapeutic target for Alzheimer’s disease. BMC medicine, v. 17, n. 1, p. 64, 20 mar. 2019.
SCHMID, B. et al. Generation of a set of isogenic, gene-edited iPSC lines homozygous for all main APOE variants and an APOE knock-out line. Stem Cell Research, v. 34, p. 101349, jan. 2019.
SCHNEEBERGER, M.; GOMIS, R.; CLARET, M. Hypothalamic and brainstem neuronal circuits controlling homeostatic energy balance. The Journal of Endocrinology, v. 220, n. 2, p. T25-46, fev. 2014.
SORIA LOPEZ, J. A.; GONZÁLEZ, H. M.; LÉGER, G. C. Alzheimer’s disease. Handbook of Clinical Neurology, v. 167, p. 231–255, 2019.
STRITTMATTER, W. J. et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America, v. 90, n. 5, p. 1977–1981, 1 mar. 1993.
SUN, Y.-Y.; WANG, Z.; HUANG, H.-C. Roles of ApoE4 on the pathogenesis in alzheimer’s disease and the potential therapeutic approaches. Cellular and Molecular Neurobiology, v. 43, n. 7, p. 3115–3136, out. 2023.
TAN, C.-C.; YU, J.-T.; TAN, L. Biomarkers for preclinical Alzheimer’s disease. Journal of Alzheimer’s disease: JAD, v. 42, n. 4, p. 1051–1069, 2014.
TAN, S. C.; YIAP, B. C. DNA, RNA, and protein extraction: the past and The present. Journal of Biomedicine and Biotechnology, v. 2009, p. 1–10, 2009.
TAN, Z. S. et al. Inflammatory markers and the risk of Alzheimer disease: the Framingham Study. Neurology, v. 68, n. 22, p. 1902–1908, 29 maio 2007.
TREVIÑO, S. et al. A high calorie diet causes memory loss, metabolic syndrome and oxidative stress into hippocampus and temporal cortex of rats. Synapse (New York, N.Y.), v. 69, n. 9, p. 421–433, set. 2015.
UDDIN, M. S. et al. APOE and alzheimer’s disease: evidence mounts that targeting APOE4 may combat alzheimer’s pathogenesis. Molecular Neurobiology, v. 56, n. 4, p. 2450–2465, abr. 2019.
VITEK, M. P.; BROWN, C. M.; COLTON, C. A. APOE genotype-specific differences in the innate immune response. Neurobiology of Aging, v. 30, n. 9, p. 1350–1360, set. 2009.
WHO. Obesity: preventing and managing the global epidemic. World Health Organization Technical Report Series, v. 894, p. 1–253, 2000.
WYSS-CORAY, T.; ROGERS, J. Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harbor Perspectives in Medicine, v. 2, n. 1, p. a006346, jan. 2012.
XU, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. The Journal of Clinical Investigation, v. 112, n. 12, p. 1821–1830, dez. 2003.
XU, Q. et al. Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, v. 26, n. 19, p. 4985–4994, 10 maio 2006.
ZHANG, L.; XIA, Y.; GUI, Y. Neuronal ApoE4 in Alzheimer’s disease and potential therapeutic targets. Frontiers in Aging Neuroscience, v. 15, p. 1199434, 2023.
ZHAO, T. et al. Alzheimer’s disease: causal effect between obesity and APOE gene polymorphisms. International Journal of Molecular Sciences, v. 24, n. 17, p. 13531, 31 ago. 2023.
ZHOU, X. et al. ApoE4-mediated blood-brain barrier damage in Alzheimer’s disease: Progress and prospects. Brain Research Bulletin, v. 199, p. 110670, jul. 2023.
ZLOKOVIC, B. V. Cerebrovascular effects of apolipoprotein E: implications for Alzheimer disease. JAMA Neurology, v. 70, n. 4, p. 440, 1 abr. 2013.
