Cortical Astrocytes Acutely Exposed to the Monomethylarsonous Acid (MMAIII) Show Increased Pro-inflammatory Cytokines Gene Expression that is Consistent with APP and BACE-1: Over-expression

Abstract

Long-term exposure to inorganic arsenic (iAs) through drinking water has been associated with cognitive impairment in children and adults; however, the related pathogenic mechanisms have not been completely described. Increased or chronic inflammation in the brain is linked to impaired cognition and neurodegeneration; iAs induces strong inflammatory responses in several cells, but this effect has been poorly evaluated in central nervous system (CNS) cells.Because astrocytes are the most abundant cells in the CNS and play a critical role in brain homeostasis, including regulation of the inflammatory response, any functional impairment in them can be deleterious for the brain. We propose that iAs could induce cognitive impairment through inflammatory response activation in astrocytes. In the present work, rat cortical astrocytes were acutely exposed in vitro to the monomethylated metabolite of iAs (MMA III ), which accumulates in glial cells without compromising cell viability. MMA III LD 50 in astrocytes was 10.52 μM, however, exposure to sub-toxic MMA III concentrations (50 to 1000 nM) significantly increased IL-1β, IL-6, TNF-α, COX-2, and MIF-1 gene expression. These effects were consistent with amyloid precursor protein (APP) and β-secretase (BACE-1) increased gene expression, mainly for those MMA III concentrations that also induced TNF-α over-expression. Other effects of MMA III on cortical astrocytes included increased proliferative and metabolic activity. All tested MMA III concentrations led to an inhibition of intracellular lactate dehydrogenase (LDH) activity. Results suggest that MMA III induces important metabolic and functional changes in astrocytes that may affect brain homeostasis and that inflammation may play a major role in cognitive impairment-related pathogenicity in As-exposed populations.

The role of astrocytes in amyloid production and Alzheimer's disease

“…Primary rat astrocytes exposed to MMA III have increased mRNA levels of a plethora of AD-related cytokines including IL-1β, IL-6 and TNF α . Additionally, MMA III induces a roughly threefold increase in APP and BACE1 mRNA expression [ 180 ].…”

Environmental exposures and the etiopathogenesis of Alzheimer's disease: The potential role of BACE1 as a critical neurotoxic target

“…Environmental neurotoxicants upregulate the expression and activity of BACE1, with some increasing BACE1 mRNA level, [ 21,22,24,27,37,41,167,170,171 ] whereas others do not affect BACE1 mRNA. [ 35,266 ] Transcriptional and posttranscriptional control is implicated in BACE1 modulation by oxidative stress.…”

“…Aluminum Aluminum exposure increased BACE1 activity in aged New Zealand rabbits and rats, elevated BACE1 levels in rats, and increased BACE1 mRNA in rats and SH-SY5Y cells [18][19][20][21][22]167,168] Arsenic Developmental exposure of rats to arsenic increased BACE1 enzymatic activity and BACE1 protein; gene expression of BACE-1 increased in astrocytes exposed to arsenic [25,169,170] Copper…”

“…[25] Developmental arsenic exposure also induces behavioral deficits accompanied by an increase in BACE1 enzymatic activity, Aβ, and receptor for advanced glycation end products (RAGE) [169] Gene expression of APP, BACE-1, TNF-α, IL-1β, IL-6, COX-2, and MIF-1 increased significantly in rat cortical astrocytes exposed to a subtoxic monomethylated metabolite of inorganic arsenic. [170] Zinc: Zinc exposure could also be a risk factor for AD. Zinc is found in Aβ senile plaques and neurofibrillary tangles in AD.…”

Astrocytes Are More Vulnerable than Neurons to Silicon Dioxide Nanoparticle Toxicity in Vitro

“…We isolated rat astrocyte-rich secondary cultures following a previously reported protocol with minor modifications [ 15 ]. In brief, astrocytes were isolated from the cerebellum of 7-9-days-old male/female Wistar rats.…”