Hippocampal neural stem cells are more susceptible to the neurotoxin BMAA than primary neurons: effects on apoptosis, cellular differentiation, neurite outgrowth, and DNA methylation

Abstract

Developmental exposure to the environmental neurotoxin β-N-methylamino-l-alanine (BMAA), a proposed risk factor for neurodegenerative disease, can induce long-term cognitive impairments and neurodegeneration in rats. While rodent studies have demonstrated a low transfer of BMAA to the adult brain, this toxin is capable to cross the placental barrier and accumulate in the fetal brain. Here, we investigated the differential susceptibility of primary neuronal cells and neural stem cells from fetal rat hippocampus to BMAA toxicity. Exposure to 250 µM BMAA induced cell death in neural stem cells through caspase-independent apoptosis, while the proliferation of primary neurons was reduced only at 3 mM BMAA. At the lowest concentrations tested (50 and 100 µM), BMAA disrupted neural stem cell differentiation and impaired neurite development in neural stem cell-derived neurons (e.g., reduced neurite length, the number of processes and branches per cell). BMAA induced no alterations of the neurite outgrowth in primary neurons. This demonstrates that neural stem cells are more susceptible to BMAA exposure than primary neurons. Importantly, the changes induced by BMAA in neural stem cells were mitotically inherited to daughter cells. The persistent nature of the BMAA-induced effects may be related to epigenetic alterations that interfere with the neural stem cell programming, as BMAA exposure reduced the global DNA methylation in the cells. These findings provide mechanistic understanding of how early-life exposure to BMAA may lead to adverse long-term consequences, and potentially predispose for neurodevelopmental disorders or neurodegenerative disease later in life.

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“…Sections of one testis per animal were lysed with RIPA buffer (150 mM NaCl, 0.1% triton X-100, 0.5% sodium deoxycholate, 0.1% SDS, 50 mM Tris-HCl, 1% protease inhibitors pH 8). The protein content was measured by the Lowry assay [ 57 ] and 20 µg of protein per sample was separated by SDS-page and Western blot was performed as previously described [ 58 ]. The primary antibodies ( Supplementary information, Table S3 ) were diluted in TTBS with 5% of dry milk and incubated overnight.…”

Freshwater Cyanobacterial Toxins, Cyanopeptides and Neurodegenerative Diseases

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“…[115] [144] primary cerebellar granule cells colture, rat up to 3 mM 24-48h L-BMAA induced both necrotic-and apoptotic-like cell death [145] primary neurons and astrocytes cortical cell cultures, fetal mouse 3-10 mM 3-24h 0.1 mM 48h enhancement death of cortical neurons damaged by other insults; oxidative stress, Wallerian-Like Degeneration [146][147][148] neural stem cells 50 µM-3 mM 24 h apoptosis, cellular differentiation, neurite outgrowth, and DNA methylation [133] The production of L-BMAA is not limited to cycad seeds, and the risk to exposure to this neurotoxin is not confined to Guam. In some locations, cyanobacteria are directly consumed by people.…”