Inflammation: Bridging Age, Menopause and APOEε4 Genotype to Alzheimer's Disease.
Inflammation: Bridging Age, Menopause and APOEε4 Genotype to Alzheimer's Disease.
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DOI：
10.3389/fnagi.2018.00312
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发表时间：
2018
影响因子：
4.8
通讯作者：
Brinton RD
中科院分区：
文献类型：
--
作者：
Mishra A;Brinton RD
导致阿尔茨海默病发展的神经炎症过程在潜伏前驱期早期就很明显，并在疾病过程中恶化。尽管有大量炎症的机制和临床证据，但针对炎症的治疗方法未能改变疾病的进程。针对炎症的流行病学和临床试验的不同结果凸显了炎症过程的复杂性。在此，我们回顾了衰老过程中炎症过程的动态、中年内分泌转变和 APOEε4 基因型及其对阿尔茨海默病 (AD) 进展的贡献。我们讨论了中年时期和内分泌衰老过程中激活的慢性炎症过程，这些过程最终限制了小胶质细胞的清除能力并导致免疫衰老。衰老、更年期和 APOEε4 结合了更年期生物能量系统受损、衰老引起的慢性低度先天性炎症、APOEε4 血脂异常和适应性免疫反应的三大打击。炎症免疫反应是连接 AD 各个危险因素的统一因素。针对疾病阶段和炎症表型的免疫系统调节剂将提供一种治疗策略，以断开驱动疾病的桥梁。这项分析的结果提供了阿尔茨海默氏症患者抗炎药物临床试验失败的合理机制。此外，他们强调需要根据炎症表型对 AD 临床试验队列进行分层。考虑采用联合疗法，包括有针对性地使用针对免疫表型的抗炎药物。
Neuro-inflammatory processes that contribute to development of Alzheimer’s are evident early in the latent prodromal phase and worsen during the course of the disease. Despite substantial mechanistic and clinical evidence of inflammation, therapeutic approaches targeting inflammation have failed to alter the course of the disease. Disparate results from epidemiological and clinical trials targeting inflammation, highlight the complexity of the inflammatory process. Herein we review the dynamics of the inflammatory process across aging, midlife endocrine transitions, and the APOEε4 genotype and their contribution to progression of Alzheimer’s disease (AD). We discuss the chronic inflammatory processes that are activated during midlife chronological and endocrine aging, which ultimately limit the clearance capacity of microglia and lead to immune senescence. Aging, menopause, and APOEε4 combine the three hits of a compromised bioenergetic system of menopause with the chronic low grade innate inflammation of aging with the APOEε4 dyslipidemia and adaptive immune response. The inflammatory immune response is the unifying factor that bridges across each of the risk factors for AD. Immune system regulators that are specific to stage of disease and inflammatory phenotype would provide a therapeutic strategy to disconnect the bridge that drives disease. Outcomes of this analysis provide plausible mechanisms underlying failed clinical trials of anti-inflammatory agents in Alzheimer’s patients. Further, they highlight the need for stratifying AD clinical trial cohorts based on inflammatory phenotype. Combination therapies that include targeted use of anti-inflammatory agent’s specific to the immune phenotype are considered.
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影响因子：
15.1
作者：
Brinkmalm A;Brinkmalm G;Honer WG;Frölich L;Hausner L;Minthon L;Hansson O;Wallin A;Zetterberg H;Blennow K;Öhrfelt A
通讯作者：
Öhrfelt A
影响因子：
6.2
作者：
Cerciat, M.;Unkila, M.;Arevalo, M. -A.
通讯作者：
Arevalo, M. -A.
DOI：
10.1016/j.jalz.2010.12.014
发表时间：
2011-07
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Breitner JC;Baker LD;Montine TJ;Meinert CL;Lyketsos CG;Ashe KH;Brandt J;Craft S;Evans DE;Green RC;Ismail MS;Martin BK;Mullan MJ;Sabbagh M;Tariot PN;ADAPT Research Group
通讯作者：
ADAPT Research Group
影响因子：
4.2
作者：
Brown, Candice M.;Choi, Emily;Colton, Carol A.
通讯作者：
Colton, Carol A.
影响因子：
4.8
作者：
Bruce-Keller, AJ;Keeling, JL;Mattson, MP
通讯作者：
Mattson, MP