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Accumulation of cellular prion protein within β-amyloid oligomer plaques in aged human brains.

ABSTRACT: Alzheimer's disease (AD) is the main cause of dementia, and β-amyloid (Aβ) is a central factor in the initiation and progression of the disease. Different forms of Aβ have been identified as monomers, oligomers, and amyloid fibrils. Many proteins have been implicated as putative receptors of respective forms of Aβ. Distinct forms of Aβ oligomers are considered to be neurotoxic species that trigger the pathophysiology of AD. It was reported that cellular prion protein (PrP^C ) is one of the most selective and high-affinity binding partners of Aβ oligomers. The interaction of Aβ oligomers with PrP^C is important to synaptic dysfunction and loss. The binding of Aβ oligomers to PrP^C has mostly been studied with synthetic peptides, cell culture, and murine models of AD by biochemical and biological methods. However, the molecular mechanisms underlying the relationship between Aβ oligomers and PrP^C remain unclear, especially in the human brain. We immunohistochemically investigated the relationship between Aβ oligomers and PrP^C in human brain tissue with and without amyloid pathology. We histologically demonstrate that PrP^C accumulates with aging in human brain tissue even prior to AD mainly within diffuse-type amyloid plaques, which are composed of more soluble Aβ oligomers without stacked β-sheet fibril structures. Our results suggest that PrP^C accumulating plaques are associated with more soluble Aβ oligomers, and appear even prior to AD. The investigation of PrP^C accumulating plaques may provide new insights into AD.

SUBMITTER: Takahashi RH

PROVIDER: S-EPMC8412093 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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Accumulation of cellular prion protein within β-amyloid oligomer plaques in aged human brains.

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