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Dietary Exposure to an Environmental Toxin Triggers Neurofibrillary Tangles and Amyloid Deposits in the Brain

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Dietary Exposure to an Environmental Toxin Triggers Neurofibrillary Tangles and Amyloid Deposits in the Brain

Paul Alan Cox et al. Proc Biol Sci.

Abstract

Neurofibrillary tangles (NFT) and β-amyloid plaques are the neurological hallmarks of both Alzheimer's disease and an unusual paralytic illness suffered by Chamorro villagers on the Pacific island of Guam. Many Chamorros with the disease suffer dementia, and in some villages one-quarter of the adults perished from the disease. Like Alzheimer's, the causal factors of Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) are poorly understood. In replicated experiments, we found that chronic dietary exposure to a cyanobacterial toxin present in the traditional Chamorro diet, β-N-methylamino-l-alanine (BMAA), triggers the formation of both NFT and β-amyloid deposits similar in structure and density to those found in brain tissues of Chamorros who died with ALS/PDC. Vervets (Chlorocebus sabaeus) fed for 140 days with BMAA-dosed fruit developed NFT and sparse β-amyloid deposits in the brain. Co-administration of the dietary amino acid l-serine with l-BMAA significantly reduced the density of NFT. These findings indicate that while chronic exposure to the environmental toxin BMAA can trigger neurodegeneration in vulnerable individuals, increasing the amount of l-serine in the diet can reduce the risk.

Keywords: Alzheimer's; BMAA; amyotrophic lateral sclerosis; cyanobacteria; l-serine; tau.

Figures

Figure 1.
Figure 1.
Neuropathology of vervet brain tissue with chronic dietary BMAA exposures; a comparison of thioflavine-S and β-amyloid (1–42) immunoreactivity. (a) Thioflavine-S stained cells and neuropil threads in the motor cortex; scale bar, 150 µm. (b) Intraneuronal β-amyloid accumulation in neurons in motor cortex. (c) Vervet extracellular thioflavine-S deposits in the frontal cortex. (d) Localized β-amyloid immunostained neocortical deposits in vervet brains. (e) Thioflavine-S positive senile plaques and tangles in human AD temporal cortex. (f) β-amyloid senile plaques in human temporal cortex of AD patient (86-year-old male; 400× magnification). Human brain sections from AD patients were run as reference controls.
Figure 2.
Figure 2.
Microscopic pathology of chronic dietary l-BMAA exposures in vervets. Representative low-power images (5× magnification) of hyperphosphorylated tau (AT8) immunostained coronal hemisections from control (a,c) and l-BMAA-fed vervets (b,d). AT8 immunostaining is seen in the amygdala (Amy), entorhinal (EC), perirhinal (PrC), primary motor (M1) and temporal cortices of l-BMAA-fed vervets. Higher-power images show predominant tau AT8 staining in superficial cortical layers II and III with more robust staining over the entorhinal and perirhinal cortices (25× magnification) (d). Microscopic images (original magnification ×120) show NFT in vervets fed l-BMAA. Tangle-like tau aggregates are seen in the temporal gyrus (e,f). Dense intracellular tau immunolabelling (gi) and extracellular deposits (j,k) were seen in the parahippocampal gyrus. Abundant neuropil threads, tangles and dystrophic neuronal processes are observed in layers II and III of the perirhinal cortex (I, high-power images shown in l,m) and the paralaminar nucleus of the amygdala (n). Tau plaques were seen in l-BMAA-fed vervets ranging from large and diffuse (o) to small dense aggregates (p). ac, anterior commissure; Amy, amygdala; Bmc, basal nucleus of the amygdala, magnocellular region; Bpc, basal nucleus of the amygdala, parvicellular subdivision; Cd, caudate; cgs, cingulate gyrus sulcus; EC, entorhinal cortex; L, lateral nucleus of the amygdala; LF, lateral fissure; M1, primary motor cortex; PrC, perirhinal cortex; PL, paralaminar nucleus; Pu, putamen; STS, superior temporal sulcus.
Figure 3.
Figure 3.
Median counts for density of AT8 IHC positive staining inclusions plus NFT per brain area by treatment type. Each horizontal surface represents the median of an eight-vervet cohort statistically significant for dose using the Jonckheere–Terpstra trend test. (a) Brain regions in which AT8 IHC positive density counts from the 210 mg kg−1 d−1 BMAA treatment are greatest compared with other treatment types. (b) Brain regions in which AT8 IHC positive density counts from the 210 mg kg−1 d−1 BMAA plus 210 mg kg−1d−1 l-serine (high+SER) treatment is less than low-dose (low) BMAA (entorhinal cortex posterior) or in which low-dose NFT density is similar to controls (all other brain areas).
Figure 4.
Figure 4.
Theoretical pathways of development of ALS/PDC and AD neuropathology from chronic dietary BMAA exposure. (a) Tau proteins which bind microtubules become hyperphosphorylated, leading to dissociation of hyperphosphorylated tau fragments. These form paired helical filaments, leading to the formation of neurofibrillary tangles. (b) The APP is cleaved, producing β-amyloid (Aβ-42) fragments which are in an α-helix conformation. These change to a β-pleated sheet conformation, oligomerize, forming amyloid plaques.

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