A Single Neonatal Exposure to BMAA in a Rat Model Produces Neuropathology Consistent with Neurodegenerative Diseases

Abstract

Although cyanobacterial β-N-methylamino-l-alanine (BMAA) has been implicated in the development of Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and Amyotrophic Lateral Sclerosis (ALS), no BMAA animal model has reproduced all the neuropathology typically associated with these neurodegenerative diseases. We present here a neonatal BMAA model that causes β-amyloid deposition, neurofibrillary tangles of hyper-phosphorylated tau, TDP-43 inclusions, Lewy bodies, microbleeds and microgliosis as well as severe neuronal loss in the hippocampus, striatum, substantia nigra pars compacta, and ventral horn of the spinal cord in rats following a single BMAA exposure. We also report here that BMAA exposure on particularly PND3, but also PND4 and 5, the critical period of neurogenesis in the rodent brain, is substantially more toxic than exposure to BMAA on G14, PND6, 7 and 10 which suggests that BMAA could potentially interfere with neonatal neurogenesis in rats. The observed selective toxicity of BMAA during neurogenesis and, in particular, the observed pattern of neuronal loss observed in BMAA-exposed rats suggest that BMAA elicits its effect by altering dopamine and/or serotonin signaling in rats.

Experimental evidence challenges the presumed defensive function of a “slow toxin” in cycads

“…These caveats notwithstanding, we feel the weight of available evidence bears strongly against an anti-herbivore function of BMAA, based both on the absence of short-term effects in the current study and on the extensive latency between exposure and the onset of toxic effects observed in other animals 28 . In mammals, for example, BMAA exposure at a young age can cause neurological symptoms that become apparent only much later in life 11 , 39 . Similarly, fruit fly larvae reared on BMAA-laced diet exhibited delayed locomotive impairment as adults, even though BMAA did not negatively affect larval survival 23 .…”

“…In general, the biological and ecological functions of BMAA for cycads remain uncertain: although some metabolic and signaling functions have been proposed, the most prevalent hypothesis for an adaptive function of BMAA in cycads is that it confers protection against herbivory, consistent with its demonstrated toxicity to diverse organisms including non-human primates and other mammals 9 – 11 , crustaceans 3 , fish 12 , and microbes 13 . Indeed, numerous papers implicitly or explicitly refer to BMAA as an anti-herbivore compound 14 – 22 .…”

Amyotrophic Lateral Sclerosis: A Diet Review

“…Although more studies are needed, recently Martin and colleagues showed a relation between BMAA and microcystin leucine and arginine (other cyanotoxins) with the neurodegeneration, using a larval zebrafish model [ 42 ]. In addition, new-born rats exposed to BMAA were affected by motor defects, suggesting that exposure during neural development could lead to develop ALS [ 43 ]. Previous studies investigated the mechanisms of action of BMAA on the neurodegeneration: BMAA kills NADPH-diaphorase-positive motor neurons and plays a toxic role to glial cells affecting motor neuron injury [ 44 , 45 ].…”

Targeting TDP‐43 proteinopathy with drugs and drug‐like small molecules

“…For example, Vitamin D has been proposed as a potential treatment to delay ALS although a definitive answer with regard to its effectiveness is yet to be reached (Libonati et al, 2017). Another example is represented by pioglitazone, a compound that protected against neurodegeneration in SOD1 G93A transgenic mice (Schutz et al, 2005) but was eventually found ineffective in a double blind, placebo controlled study as add-on therapy with riluzole in ALS patients (Dupuis et al, 2012). The observation that some of these molecules can affect TDP-43 functions might therefore represent an opportunity to re-evaluate their usefulness in the fight against ALS.…”