Abstract
Human epidemiological evidence and animal experimental data suggest that chronic manganese (Mn) exposure increases the risk of Alzheimer’s disease (AD) and amyloid plaques, a hallmark of AD brain pathology, but the underlying mechanisms were not fully understood. Using the transgenic APP/PS1/Tau triple transgenic AD (3×Tg-AD) mouse model and mouse-derived microglia and neuroblastoma cell lines, we found that chronic 5-month Mn treatment increased beta amyloid peptide (Aβ) expression and Aβ plaques in the cerebral cortex and hippocampus in these 3×Tg-AD mice. Furthermore, we found that the β- and γ-secretase cleavage activities were markedly increased, while α-secretase cleavage activity was reduced in the brain of Mn-treated AD mice; these effects increase Aβ production and thus are amyloidogenic. Equally important, Mn treatment alone did not alter β-secretase 1 (BACE1) gene expression or Aβ production in amyloidogenic mutant amyloid precursor protein (APP) gene hAPPsw-transfected N2a cells (APPsw-N2a), but in APPsw-N2a cells either co-cultured with microglia or cultured with microglia-conditioned media, Mn exposure increased BACE1 expression and amyloidogenesis. We further determined that Mn exposure promoted the activation of microglia both in 3×Tg-AD mouse brains and in cultured microglia cells, and increased the secretion of the inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Taken together, these results suggest that Mn may increase the release of IL-1β and TNF-α from microglia that in turn stimulates the expression of BACE1 gene and protein and consequently Aβ production; this novel molecular mechanism not only advances our understanding about the amyloidogenic effect of chronic Mn exposure reported for special human populations but also indicates Mn dyshomeostasis as a potential contributor to AD pathogenesis.
Highlights
Alzheimer’s disease (AD) is the most common dementia-causing neurodegenerative disease that inflicts 5.8 million senior people in the United States alone and 40 million senior people worldwide, and the patient population is increasing as the life expectancy increases (Alzheimer’s Association, 2020)
To further determine Mn’s potential enhancement of AD pathology and the underlying molecular mechanisms, our present study investigates the effects of chronic Mn exposure on amyloid plaque formation in mutant APP/PS1/Tau triple transgenic AD mice and cultured cells expressing mutant amyloidogenic amyloid precursor protein (APP) and the involvement of brain innate immune cells, microglia; this combined approach enables us to study the potential Mn effects in intact brain tissues—conferring more pathophysiological relevance, and in isolated cultured cells—allowing more detailed cellular and molecular analyses
A similar drinking water Mn-induced body weight loss was reported in normal mice in a previous study (Krishna et al, 2014) that showed that drinking water Mn initially reduced water intake and body weight, but these effects disappeared after 7 weeks
Summary
Alzheimer’s disease (AD) is the most common dementia-causing neurodegenerative disease that inflicts 5.8 million senior people in the United States alone and 40 million senior people worldwide, and the patient population is increasing as the life expectancy increases (Alzheimer’s Association, 2020). While old age is a key risk factor and abnormal Aβ and tau are key molecules causing AD neurodegeneration (Selkoe and Hardy, 2016; Forner et al, 2017; Walsh and Selkoe, 2020), other factors may contribute to AD pathogenesis. One such contributing factor is a dyshomeostasis of essential biometals (e.g., iron, zinc, copper, and manganese; Jucker and Walker, 2013; Ciechanover and Kwon, 2015; Adlard and Bush, 2018; Soto and Pritzkow, 2018; Lermyte et al, 2019). Studies have found cognitive deficits in human populations living near refineries with high Mn levels (Guarneros et al, 2013), and there is dose–effect relationships between Mn exposure and cognitive decline (Bowler et al, 2007; Ellingsen et al, 2008)
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