TDP-43 and Alzheimer’s Disease Pathology in the Brain of a Harbor Porpoise Exposed to the Cyanobacterial Toxin BMAA

Abstract

Cetaceans are well-regarded as sentinels for toxin exposure. Emerging studies suggest that cetaceans can also develop neuropathological changes associated with neurodegenerative disease. The occurrence of neuropathology makes cetaceans an ideal species for examining the impact of marine toxins on the brain across the lifespan. Here, we describe TAR DNA-binding protein 43 (TDP-43) proteinopathy and Alzheimer’s disease (AD) neuropathological changes in a beached harbor porpoise (Phocoena phocoena) that was exposed to a toxin produced by cyanobacteria called β-N-methylamino-L-alanine (BMAA). We found pathogenic TDP-43 cytoplasmic inclusions in neurons throughout the cerebral cortex, midbrain and brainstem. P62/sequestosome-1, responsible for the autophagy of misfolded proteins, was observed in the amygdala, hippocampus and frontal cortex. Genes implicated in AD and TDP-43 neuropathology such as APP and TARDBP were expressed in the brain. AD neuropathological changes such as amyloid-β plaques, neurofibrillary tangles, granulovacuolar degeneration and Hirano bodies were present in the hippocampus. These findings further support the development of progressive neurodegenerative disease in cetaceans and a potential causative link to cyanobacterial toxins. Climate change, nutrient pollution and industrial waste are increasing the frequency of harmful cyanobacterial blooms. Cyanotoxins like BMAA that are associated with neurodegenerative disease pose an increasing public health risk.

Evaluation of cyanotoxin L-BMAA effect on α-synuclein and TDP43 proteinopathy

“…Taken together, all our results support a significant role of L-BMAA and LCS-MaCe exposure in α-synuclein and TDP43 proteinopathy and neurodegeneration. Our findings align with the recent discovery that prolonged exposure to L-BMAA in cetaceans, as evidenced by both epidemiological and biochemical observations, triggers distinct indicators of Alzheimer’s Disease (Aβ+ plaques and neurofibrillary tangles in the hippocampus) and TDP-43 proteinopathy (TDP-43 cytoplasmic inclusions in cerebral cortex, midbrain and brainstem) ( 76 ). Human beings can be, via dietary sources, chronically exposed to cyanotoxins, that can alter specific cellular pathways leading to protein misfolding and aggregation likely associated to autophagy impairment.…”

Editorial: New insights in the neuroanatomy and neuropathology of marine mammals

“…Given its association with organ system damage and disease, cyanotoxin exposures are a public health concern. As previously shown, BMAA overexposure was associated with β-amyloid+ plaques, dystrophic neurites, and TDP-43 proteinopathy in the brain of stranded dolphins, resembling AD-like pathology (Davis et al, 2019 ; Garamszegi et al, 2024 ). Lastly, Liu et al studied two characteristic genes subtypes, in the large yellow croaker ( Larimichthys crocea ) genome, of the corticotropin-releasing hormone, the neuropeptide in the hypothalamus that is most important for the stress response.…”

“…The distribution pattern of neurofibrillary pathological alterations serves as the basis for the Braak staging, as follows: first entorhinal cortex (Braak I and II), followed by the limbic (Braak III and IV), and finally the isocortical (Braak V and VI). The entorhinal cortex has only been recently explored in a beached harbor porpoise ( Phocoena phocoena ; Family Phocoenidae ), exposed to cyanobacterial β- N-methylamino-L-alanine (BMAA) toxin (Garamszegi et al, 2024 ). After the animal's brain was examined for signs of AD-like disease, Aβ+ plaques were found in the entorhinal cortex and the amygdaloid complex along with other neurodegenerative alterations.…”

“…Through the use of calbindin-D28k immunohistochemistry, the authors emphasize the structure of the its central nucleus in the overall description of the amygdaloid body. The manuscript does not address the involvement of the amygdala in neurodegenerative processes, but it is well recognized in human medicine that these processes have an impact on the amygdaloid body and have been also demonstrated in one species of cetacean, the harbor porpoise (Garamszegi et al, 2024 ). Research on fish models has revealed additional significant facets of the neuropathological mechanisms impacting cetaceans and marine mammals overall.…”