A Few More Mammalian Species Found to Exhibit Amyloid-β and Tau Pathology

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The primary challenge in Alzheimer's disease research has long been that short-lived laboratory species do not naturally exhibit any of the features of the condition. Thus all mouse models of the condition are highly artificial genetic constructs, and potential treatments and relevant mechanisms in these models have a high chance of being irrelevant to Alzheimer's disease as it exists in humans. Up until fairly recently it could be argued that humans were in fact the only species to exhibit full blown Alzheimer's disease, involving a lengthy increase in amyloid-β aggregation in the brain, followed by neuroinflammation, tau aggregation, and widespread cell death.

However, in recent years the study of chimpanzee brains - as well as a variety of other species - suggests that some might exhibit enough of the mechanisms of Alzheimer's disease to be said to suffer from it in old age. This is also the case in the aging of dolphins. In today's open access paper, researchers report on more signs of Alzheimer's mechanisms in the brains of sea lions, seals, and walrus. This is all interesting, but doesn't much help the state of Alzheimer's research in practice. None of these large mammal species are likely to be used in laboratories any time soon. Even if they were, it would not be for early stage discovery and exploration.

Amyloid β and tau pathology in brains of aged pinniped species (sea lion, seal, and walrus)

Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder and is characterized by the pathological aggregation of the amyloid-β (Aβ) and hyperphosphorylated tau (hp-tau) proteins in the form of senile plaques (SPs) and neurofibrillary tangles (NFTs), respectively. The accumulation of Aβ in the blood vessels of the brain, a condition known as cerebral amyloid angiopathy (CAA), is also detected in more than 80% of patients with AD. Humans appear to be uniquely susceptible to AD, potentially due to genetic differences, changes in cerebral structures and functions during evolution, and an increased lifespan. In the "amyloid hypothesis", the most acknowledged explanation for the pathogenesis of AD, the age-dependent accumulation of fibrillar insoluble Aβ peptides in the brain is considered to be the central and triggering event in AD pathology. Based on this hypothesis, various transgenic mouse models that produce human Aβ beyond physiological levels have been generated and exhibit the massive formation of SPs. However, they fail to develop NFTs and neuronal loss unless mutant tau is simultaneously introduced.

While AD appears to be a human-specific disease, age-dependent SP formation has been reported in several non-human primates, including chimpanzees, orangutans, and gorillas. The concomitant pathology with the formation of a small amount of NFTs was found in chimpanzees and rhesus macaques, while the oligodendroglial tau pathology was also detected in cynomolgus monkeys. Therefore, an AD-like pathology may occur during aging in primates. In contrast, non-primate animals, particularly Carnivora species, have exhibited species-specific patterns of Aβ and hp-tau accumulation. In the suborder Caniformia, aged dogs and bears developed SPs in their brains, but not NFTs, even in the oldest subjects. On the other hand, Feliformia species, such as cats, leopard cats, and cheetahs, exhibit NFTs without SP formation, although small granular deposits of Aβ were detected in the cerebral cortex.

Pinnipeds are semiaquatic carnivorans that spend most of their lives in water, and use coastal terrestrial environments and ice packs to breed, molt, and rest. They are currently classified into three families: Phocidae (seals), Otariidae (fur seals and sea lions), and Odobenidae (walruses). We herein describe the Aβ and hp-tau pathology in the brains of aged pinniped species. Molecular analyses revealed that the sequence of pinniped Aβ was identical to that of human Aβ. Histopathological examinations detected argyrophilic plaques composed of Aβ associated with dystrophic neurites in the cerebral cortex of aged pinnipeds. Astrogliosis and microglial infiltration were identified around Aβ plaques. Aβ deposits were observed in the blood vessel walls of the meninges and cerebrum.

Histopathological examinations revealed argyrophilic fibrillar aggregates composed of phosphorylated tau (hp-tau) in the neuronal somata and neurites of aged pinniped brains. Furthermore, the activation of GSK-3β was detected within cells containing hp-tau aggregates, and activated GSK-3β was strongly expressed in cases with severe hp-tau pathologies. The present results suggest that, in association with Aβ deposition, the activation of GSK-3β contributes to hp-tau accumulation in pinniped brains.

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source https://www.fightaging.org/archives/2021/01/a-few-more-mammalian-species-found-to-exhibit-amyloid-%CE%B2-and-tau-pathology/