Biotic/Abiotic Stress-Driven Alzheimer's Disease

摘要

Introduction Alzheimer's disease (AD), a neurodegenerative condition, is characterized by deficient synaptic plasticity, dramatic neuronal dysfunction, and massive neuronal loss. Apart from familial or early-onset AD (5–10%), most AD cases are non-familial or late-onset/sporadic (90–95%; Ballard et al., 2011 ) with a complicated etiology. Some competing theories have been suggested regarding the cause of AD, such as the amyloid hypothesis (Hardy and Allsop, 1991 ) and tau hypothesis (Mudher and Lovestone, 2002 ), but minimal data on initial triggers are available despite intensive explorations over recent decades. We summarized the published evidence into an opinion that deciphers how the multifaceted adverse environmental factors drive the onset and development of AD. Etiological drivers can be categorized as biotic stressors and abiotic stressors, with the latter category divided into physical stressors and chemical stressors. Ultimately, biotic/abiotic stressors can be integrated into reactive oxygen species (ROS)/oxidative stressors and reactive nitrogen species (RNS)itrosative stressors that impact the transition of neurons from dysfunction to death (Barone et al., 2011a , b ; Butterfield et al., 2014 ). Our opinion on biotic/abiotic stress-triggered AD links the various stressors to the genesis and progression of AD through a neuroinflammatory signaling cascade, which initiates nuclear factor κB (NF-κB) and induces pro-inflammatory cytokines that evoke potent ROS/RNS burst for neuronal/glial killing. To trigger AD, biotic stressors convey the external biological signals via lipopolysaccharide (LPS)-toll-like receptor 4 (TLR4), LPS-receptor of advanced glycation end products (RAGE), and amyloid β peptide (Aβ)/senile plaques (SP)-RAGE interactions (Yan et al., 1996 ; Yamamoto et al., 2011 ). Alternatively, abiotic stressors transduce the external non-biological signals via AGEs-RAGE, high-mobility group protein B1 (HMGB1)-RAGE, and Aβ/SP-RAGE interactions (Mazarati et al., 2011 ; Horst et al., 2016 ). Specifically, hypothermia, as well as anesthesia and aging that induce hypothermia, can execute a neurotoxic role to kill neurons and glia via neurofibrillary tangles (NFTs) derived from hyperphosphorylated Tau (p-Tau) (Carrettiero et al., 2015 ; Figure 1 ). Figure 1 A hypothetical schematic of biotic/abiotic stress-triggered AD . Biotic stress from brain, oral, or gut infection can activate NF-κB-primed neuroinflammatory cascades, elicit ROS/RNS burst, and kill neurons and glia via LPS-TLR4/RAGE and Aβ/SP-RAGE interactions and subsequent signaling. Abiotic stress encompassing physical stress (e.g., head trauma, stroke, or irradiation) and chemical stress (e.g., metals, pesticides, solvents, or neurotoxins) can also activate NF-κB-primed neuroinflammatory cascades, elicit ROS/RNS burst, and kill neurons and glia via AGEs-RAGE, HMGB1-RAGE/TLR4, and Aβ/SP-RAGE interactions and downstream signaling. Hypothermia, anesthetics, and aging, can exert a neurotoxic effect upon exposure of neurons and glia to NFTs (the background figure was adopted from the website https://zhidao.baidu.com/daily/view?id=5979 ). Mounting evidence supports that LPS and interferon γ (IFN-γ) activate microglia to induce a pro-inflammatory neurotoxic M1 phenotype, whereas interleukin 4 (IL-4), IL-10, IL-13, and transforming growth factor β (TGF-β) activate microglia to give rise to an anti-inflammatory neuroprotective M2 phenotype (Tang and Le, 2016 ). Interestingly, we found that electric acupuncture can mimic mechanical wounding to firstly deteriorate LPS-induced AD-like brain pathogenesis, but secondly ameliorate the progressive neurodegeneration in a wounding-healing manner, suggesting a putative conversion from M1 microglia to M2 microglia (He, 2016 ). Biotic stress and AD Biotic stressors refer to any potential infectious pathogens or opportunistic infectious microbes, including Chlamydophila pneumoniae (Balin et al., 1998 ), Helicobacter pylori (Kountouras et al., 2012 ), Toxoplasma gondii (Prandota, 2014 ), human immunodeficiency virus (HIV; Borjabad and Volsky, 2012 ), and human cytomegalovirus (HCMV; Lurain et al., 2013 ). An international team recently urged that cerebral pathogenic infections by herpes simplex virus type 1 (HSV-1), C. pneumoniae , spirochetes, and fungi be considered as candidate AD initiators (Itzhaki et al., 2016 ). Similarly, extracerebral infectious pathogens were also considered as AD triggers; for example, oral pathogenic infections by the periodontal bacteria Porphyromonas gingivalis and Actinomyces naeslundii were identified as high-risk factors driving development toward AD (Noble et al., 2014 ; Singhrao et al., 2015 ). A recent study on gut microbiota dysbiosis indicated that intestinal microbiome alterations are related to the malfunctional motor phenotypes, suggesting the overgrowth of intestinal commensal microbes (i.e., opportunistic infection) acting as a neurodegenerative driver (Scheperjans