Cetaceans: Models for Alzheimer's Disease?

3 October 2022

Alzheimer's disease (AD), while being on one side the most frequently occurring dementia worldwide, cannot yet rely, conversely, on animal models encompassing the entire spectrum of its key pathological features, amyloid-β (Aβ) plaque-like aggregates and tau protein neurofibrillary tangles, in the brain tissue from affected patients [1].

Interestingly, AD-like neuropathological changes were reported some years ago in striped dolphins (Stenella coeruleoalba) and bottlenose dolphins (Tursiops truncatus) found stranded along the Spanish coastline [2]. Furthermore, AD-related immunohistomorphologic lesions have been recently described in stranded beaked whales (Ziphiidae), with such findings having been also linked to repetitive brain tissue hypoxia in these “big diver cetaceans” [3].

With reference to the etiology of AD-like pathological changes in cetacean brains, β-methylamino-L-alanine (BMAA), a cyanobacterial neurotoxin accumulating inside marine trophic chains, has been deemed responsible for Aβ plaques' and dystrophic neurites' occurrence in bottlenose dolphins and common dolphins (Delphinus delphis) stranded along the Atlantic USA coastline. Indeed, BMAA exposure had been previously associated with the occurrence of neurofibrillary tangles and Aβ plaques in nonhuman primates [4]. Based upon the “top predator position” of odontocete cetaceans in the marine food web, with subsequent bioaccumulation and biomagnification of a huge number of persistent environmental pollutants in their body tissues, the synergistic neurotoxicity of methylmercury (MeHg) and BMAA should be also taken into account [5]. Exposure to BMAA and MeHg, in fact, increased the magnitude and intensity of the aforementioned pathological processes in dolphins with AD-associated neuropathology [6].

Finally, given the critical role exerted by the host’s cellular prion protein (PrPc) as a high-affinity neuronal cell receptor for Aβ oligomers, alongside PrPc activity as a mediator of neurotoxic Aβ oligomer-induced synaptic dysfunction in AD [7], investigating PrPc expression in the brain tissue of cetaceans with AD-like pathological changes may shed additional light on their encephalopathy, thus providing further support to the relevance of dolphins as potentially useful “comparative neuropathology models” for AD in mankind [8].

Giovanni Di Guardo, DVM, Dipl. ECVP
Retired Professor of General Pathology and Veterinary Pathophysiology at the Veterinary Medical Faculty of the University of Teramo, 64100 Teramo, Italy
E-mail: gdiguardo[at]unite[dot]it

[1] Querfurth HW, LaFerla FM (2010) Alzheimer's disease. N Engl J Med 362, 329-344.
[2] Gunn-Moore D, Kaidanovich-Beilin O, Gallego Iradi MC, Gunn-Moore F, Lovestone S (2018) Alzheimer's disease in humans and other animals: A consequence of postreproductive life span and longevity rather than aging. Alzheimers Dement 14, 195-204.
[3] Sacchini S, Díaz-Delgado J, Espinosa de los Monteros A, Paz Y, Bernaldo de Quirós Y, Sierra E, Arbelo M, Herráez P, Fernández A (2020) Amyloid-beta peptide and phosphorylated tau in the frontopolar cerebral cortex and in the cerebellum of toothed whales: Aging versus hypoxia. Biol Open 9, bio054734.
[4] Davis DA, Mondo K, Stern E, Annor AK, Murch SJ, Coyne TM, Brand LE, Niemeyer ME, Sharp S, Bradley WG, Cox PA, Mash DC (2019) Cyanobacterial neurotoxin BMAA and brain pathology in stranded dolphins. PLoS One 14, e0213346.
[5] Rush T, Liu X, Lobner D (2012) Synergistic toxicity of the environmental neurotoxins methylmercury and beta-N-methylamino-L-alanine. Neuroreport 23, 216-219.
[6] Davis DA, Garamszegi SP, Banack SA, Dooley PD, Coyne TM, McLean DW, Rotstein DS, Mash DC, Cox PA (2021) BMAA, methylmercury, and mechanisms of neurodegeneration in dolphins: a natural model of toxin exposure. Toxins (Basel) 13, 697.
[7] Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers. Nature 457, 1128-1132.
[8] Di Guardo G (2018) Alzheimer’s disease, cellular prion protein, and dolphins. Alzheimers Dement 14, 259-260.