Inflammation: Bridging Age, Menopause and APOEε4 Genotype to Alzheimer’s Disease

Abstract

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.

Women’s brain aging: effects of sex-hormone exposure, pregnancies, and genetic risk for Alzheimer’s disease

“…Positive effects of parity on the brain may thus reflect mechanisms related to immune factors rather than estrogen fluctuations involved in pregnancy (40). The cessation of ovarian hormone function during menopause has been linked to altered inflammatory processes, increase in cytokine levels, and changes in T cell biology (reviewed by (71)). These processes might constitute a menopausal immune senescence that may increase the risk for AD, of which the pathogenesis is known to involve inflammatory processes (40,72).…”

Towards an understanding of women's brain aging: the immunology of pregnancy and menopause

“…Aging has been linked to a plethora of broad systems-level effects on human biology including extensive and complex effects on immune responses [39]. Immunosenescence, a term coined to describe the deterioration of human immunity with aging, comprises both increased inflammation and diminished protective immunity [138].…”

“…Recent studies have shown that pregnancy-related endocrinological fluctuations influence neural plasticity and brain structure in animals [28,29,30,31,32] and humans [33,34,35,36], and that biological processes related to menopause can have significant effects on brain health [37]. During pregnancy and menopause, the female immune system undergoes substantial changes [38,39], and evidence suggests that the immune regulations that occur during these major transitional phases may play an important part in women's brain aging trajectories [40,41,42]. However, the long-term implications of these complex immune processes are far from fully understood.…”

A Unique GSK-3β inhibitor B10 Has a Direct Effect on Aβ, Targets Tau and Metal Dyshomeostasis, and Promotes Neuronal Neurite Outgrowth

“…These drugs provide only limited efficiency and curable drugs remain lacking. Several hypotheses are put forth to explain the causes of AD, mainly including the amyloid cascade hypothesis [6,7], tau pathology [8,9], cholinergic hypothesis [10,11], inflammatory [12,13], metal ion dyshomeostasis [14][15][16][17], and oxidative stress [18,19]; however, the exact AD etiology is still unclear. Since AD is a complicated disease with multifaceted pathogenesis, the one-drug-one-target strategy is not very effective, and therefore, the multitarget-directed ligands that simultaneously interfere with the multiple processes of AD progression are more hopeful [20][21][22][23].…”

“…H NMR (400 MHz, DMSO) δ 12.13 (d, J = 2.2 Hz, 1H), 8.78 (dd, J = 4.1, 1.6 Hz, 1H), 8.59 (s, 2H), 8.43 (dd, J = 8.4, 1.5 Hz, 1H), 8.32 (t, J = 5.6 Hz, 1H), 8.11 (d, J = 6.8 Hz, 2H), 8.08 (d, J = 2.6 Hz, 1H), 7.84 (d, J = 1.6 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.58-7.52 (m, 2H), 7.49 (d, J = 8.2 Hz, 2H), 6.78 (d, J = 6.8 Hz, 2H), 4.52 (d, J = 5.6 Hz, 2H);13 C NMR (100 MHz, DMSO) δ 171.39, 155.36, 152.92, 148.17, 146.64, 143.55, 141.50, 137.43, 136.92, 136.16, 135.35, 133.50, 128.86, 128.10, 127.42, 126.81, 125.14, 125.03, 121.44, 116.74, 113.73, 113.44, 109.84, 44.43; HRMS (ESI): Calcd. for C 28 H 21 N 5 O [M+H] + : 444.1819, found: 444.1835.…”