Alzheimer's disease‐like neuropathology in three species of oceanic dolphin

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease and the primary cause of disability and dependency among elderly humans worldwide. AD is thought to be a disease unique to humans although several other animals develop some aspects of AD-like pathology. Odontocetes (toothed whales) share traits with humans that suggest they may be susceptible to AD. The brains of 22 stranded odontocetes of five different species were examined using immunohistochemistry to investigate the presence or absence of neuropathological hallmarks of AD: amyloid-beta plaques, phospho-tau accumulation and gliosis. Immunohistochemistry revealed that all aged animals accumulated amyloid plaque pathology. In three animals of three different species of odontocete, there was co-occurrence of amyloid-beta plaques, intraneuronal accumulation of hyperphosphorylated tau, neuropil threads and neuritic plaques. One animal showed well-developed neuropil threads, phospho-tau accumulation and neuritic plaques, but no amyloid plaques. Microglia and astrocytes were present as expected in all brain samples examined, but we observed differences in cell morphology and numbers between individual animals. The simultaneous occurrence of amyloid-beta plaques and hyperphosphorylated tau pathology in the brains of odontocetes shows that these three species develop AD-like neuropathology spontaneously.

Of dolphins, humans, other long‐lived animals and Alzheimer's disease (Commentary on Vacher et al.)

“…These three cetaceans belonged to three different species: Lagenorhynchus albirostris , Globicephala melas and Tursiops truncates , all of which have an Aβ peptide amino acid sequence identical to that of humans, as also observed in other mammals in which AP accumulation has been detected. Analysis of additional brain regions from the same animals confirmed the variable presence of both Aβ and p‐Tau aggregates, which were never found in brain samples from younger animals of the same species (Vacher et al, 2022).…”

“…Somewhat surprisingly, in this issue, Vacher and colleagues demonstrate the notable coexistence of AP deposition and hyperphosphorylated tau in the brains of dolphins (Vacher et al, 2022), mammals that have undergone considerable anatomical adaptations to their aquatic environment, including in their brain organization. The authors analysed brain samples from 22 dolphins of five different species, which were found stranded along the Scottish coast.…”

“…Indeed, the ‘sick leader’ hypothesis speculates that members of a pod would also strand when following a leader with cognitive decline. Furthermore, Vacher et al (2022) found only mild evidence of reactive astrogliosis or activated microglia surrounding the plaques, a characteristic that is common to AD pathology, although this may again indicate that the brains analysed were at an early stage of AD‐like pathology.…”

“…Independently of these considerations, this study shows the susceptibility of odontocetes to develop spontaneous and concomitant aggregates of APs and pre‐NFT, the coexistence of which in humans has been always associated with AD. There are previous reports describing the presence of amyloid aggregates and a few neurofibrillary threads or phosphor‐tau‐positive granules in the neurons of cetaceans' brains (Gunn‐Moore et al, 2018; Sacchini et al, 2020), but Vacher et al (2022) are the first to establish a clear correlation between the presence of APs and pTau aggregates with old age and to identify accumulations that resemble NFTs. In an interesting discussion, the authors review the idea that cetaceans possess some physiological and behavioural traits that may make them a more accurate, spontaneous model for studying AD than non‐human primates.…”

“…Nevertheless, longitudinal PET imaging studies indicate that Tau accumulation precedes amyloid pathology, whereas amyloid, once it has reached a threshold concentration, seems to foster the spread of tau aggregates and neuronal death (rev in (Karran & De Strooper, 2022). Notably, Vacher et al (2022) found abundant pTau-positive granules within neuronal cell bodies, axons and dendrites as well as accumulations consistent with pre-NFT in additional brain regions of the same individuals, where AP were either absent or very sparse. PhosphoTau-immunolabelling consistent with intracellular neuronal tangles was also found in an additional Globicephala melas in which APs were absent.…”