Abstract
Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) as senile plaques and cerebral amyloid angiopathy, and hyperphosphorylated tau (hp-tau) as neurofibrillary tangles in the brain. The AD-related pathology has been reported in several non-human animals, and most animals develop only the Aβ or tau pathology. We herein describe the Aβ and hp-tau pathology in the brains of aged pinniped species (seal, sea lion, and walrus). 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. Pinniped tau protein was physiologically subjected to alternative splicing at exons 2, 3, and 10, and presented as five isoforms: two 3-repeat tau isoforms (1N3R, 2N3R) and three 4-repeat tau isoforms (0N4R, 1N4R, 2N4R); 0N3R tau isoform was absent. Histopathological examinations revealed argyrophilic fibrillar aggregates composed of hp-tau in the neuronal somata and neurites of aged pinniped brains. Few hp-tau aggregates were found in oligodendrocytes and microglia. Biochemically, hp-tau of the 3-repeat and 4-repeat isoforms was detected in brain sarkosyl-insoluble fractions. Aβ and hp-tau both predominantly accumulated in the neocortex, particularly the frontal cortex. 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. Here, we report that pinniped species naturally accumulate Aβ and tau with aging, similar to the human AD pathology.
Highlights
Alzheimer’s disease (AD) is the most prevalent agerelated neurodegenerative disorder and is characterized by the pathological aggregation of the amyloid-β (Aβ) and hyperphosphorylated tau proteins in the form of senile plaques (SPs) and neurofibrillary tangles (NFTs), respectively [1]
We detected amyloid plaque formation in aged pinniped brains, and their Aβ peptide amino acid sequence was the same as that of human Aβ, providing support for spontaneous amyloid plaque formation developing in animals that express the human type Aβ
Immunohistochemistry for Aβ revealed that Aβ42 more prominently accumulated than Aβ40 in the parenchyma of pinniped brains, and some amyloid plaques were positive for AβpN3, suggesting the presence of Aβ species with a higher aggregation capability and neurotoxicity in pinniped brains
Summary
Alzheimer’s disease (AD) is the most prevalent agerelated 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 [1]. The accumulation of Aβ in the blood vessels of the brain, a condition known as cerebral amyloid angiopathy (CAA) [2], is detected in more than 80% of patients with AD [3]. Takaichi et al acta neuropathol commun (2021) 9:10 pathology [8]. 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. 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 They fail to develop NFTs and neuronal loss unless mutant tau is simultaneously introduced [9]
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