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

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß (Aß) 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 Aß or tau pathology. We herein describe the Aß and hp-tau pathology in the brains of aged pinniped species (seal, sea lion, and walrus). Molecular analyses revealed that the sequence of pinniped Aß was identical to that of human Aß. Histopathological examinations detected argyrophilic plaques composed of Aß associated with dystrophic neurites in the cerebral cortex of aged pinnipeds. Astrogliosis and microglial infiltration were identified around Aß plaques. Aß 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. Aß and hp-tau both predominantly accumulated in the neocortex, particularly the frontal cortex. Furthermore, the activation of GSK-3ß was detected within cells containing hp-tau aggregates, and activated GSK-3ß was strongly expressed in cases with severe hp-tau pathologies. The present results suggest that, in association with Aß deposition, the activation of GSK-3ß contributes to hp-tau accumulation in pinniped brains. Here, we report that pinniped species naturally accumulate Aß and tau with aging, similar to the human AD pathology.