Interplay between microglia and environmental risk factors in Alzheimer's disease

Abstract

Alzheimer's disease, among the most common neurodegenerative disorders, is characterized by progressive cognitive impairment. At present, the Alzheimer's disease main risk remains genetic risks, but major environmental factors are increasingly shown to impact Alzheimer's disease development and progression. Microglia, the most important brain immune cells, play a central role in Alzheimer's disease pathogenesis and are considered environmental and lifestyle "sensors." Factors like environmental pollution and modern lifestyles (e.g., chronic stress, poor dietary habits, sleep, and circadian rhythm disorders) can cause neuroinflammatory responses that lead to cognitive impairment via microglial functioning and phenotypic regulation. However, the specific mechanisms underlying interactions among these factors and microglia in Alzheimer's disease are unclear. Herein, we: discuss the biological effects of air pollution, chronic stress, gut microbiota, sleep patterns, physical exercise, cigarette smoking, and caffeine consumption on microglia; consider how unhealthy lifestyle factors influence individual susceptibility to Alzheimer's disease; and present the neuroprotective effects of a healthy lifestyle. Toward intervening and controlling these environmental risk factors at an early Alzheimer's disease stage, understanding the role of microglia in Alzheimer's disease development, and targeting strategies to target microglia, could be essential to future Alzheimer's disease treatments.

Figure 1

Possible mechanisms by which microglia detect PM_2.5 and some AD-related neuropathologic consequences of this exposure. Microglia detect PM_2.5 entering the brain via the nasal route. These particles can directly damage neurons, activating microglia and causing cytokine release via the peripheral systemic inflammatory system through the respiratory tract and activated microglia. AD biomarkers changes from PM_2.5 exposure include: 1) high amyloid PET scan positivity; 2) low DNA methylation; 3) cerebrospinal fluid (reduced Aβ₄₂, Aβ₄₀, and BDNF; increased t-tau, p-tau, and inflammatory cytokines IL-1β, IL-6, and TNF-α). Created with Adobe Illustrator CS6. AD: Alzheimer's disease; Aβ: amyloid-β; BDNF: brain-derived neurotrophic factor; DNA: deoxyribonucleic acid; IL-1β: interleukin-1β; IL-6: interleukin-6; PET: positron emission tomography; PM_2.5: particulate matter (PM) with diameter < 2.5 µm; TNF-α: tumor necrosis factor.

Figure 2

Microglia as stress response sensors. Stress induces a series of alterations in microglial morphology, function, and immunophenotype through stress hormones/transmitters. These changes allow microglia to undergo a markedly increased proinflammatory response, leading to increased levels of neurotoxic cytokines and accumulating Aβ and neurofibrillary tangles. These combined factors may accelerate AD onset. Created with Adobe Illustrator CS6. ACTH: Adrenocorticotropic hormone; ADX: adrenalectomy; Aβ: amyloid-β; DAMP: danger-associated molecular patterns; HPA: hypothalamic-pituitary-adrenal; PAMP: pathogen-associated molecular patterns; RU486: glucocorticoid receptor GR antagonist.

Figure 3

Postulated links between gut microbiota dysregulation and AD pathology, and microbiota-gut-brain axis reconditioning with antibiotic treatment and probiotic supplementation. Intestinal flora dysregulation in patients with AD allows increased intestinal barrier permeability, leading to microglial activation and neuroinflammation, which promotes Aβ plaque accumulation and tau hyperphosphorylation, ultimately leading to cognitive impairment. Antibiotics can modulate microbiota composition and probiotics can normalize intestinal bacteria. Created with Adobe Illustrator CS6. AD: Alzheimer's disease; Aβ: amyloid-β; IL-1β: interleukin-1β; IL-6: interleukin-6; TNF-α: tumor necrosis factor.