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Authors: Wang, Jun | Santa-Maria, Ismael | Ho, Lap | Ksiezak-Reding, Hanna | Ono, Kenjiro | Teplow, David B. | Pasinetti, Giulio Maria

Article Type: Research Article

Abstract: Aggregation of microtubule-associated protein tau into insoluble intracellular neurofibrillary tangles is a characteristic hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases, including progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, frontotemporal dementias with Parkinsonism linked to chromosome 17, and Pick's disease. Tau is abnormally hyperphosphorylated in AD and aberrant tau phosphorylation contributes to the neuropathology of AD and other tauopathies. Anti-aggregation and anti-phosphorylation are main approaches for tau-based therapy. In this study, we report that a select grape-seed polyphenol extract (GSPE) could potently interfere with the assembly of tau peptides into neurotoxic aggregates. Moreover, oral administration of GSPE significantly …attenuated the development of AD type tau neuropathology in the brain of TMHT mouse model of AD through mechanisms associated with attenuation of extracellular signal-receptor kinase 1/2 signaling in the brain. Show more

Keywords: Aggregation, Alzheimer's disease, hyperphosphorylation, neurofibrillary tangles, tauopathies

DOI: 10.3233/JAD-2010-101074

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 653-661, 2010

Authors: Varghese, Merina | Santa-Maria, Ismael | Ho, Lap | Ward, Libby | Yemul, Shrishailam | Dubner, Lauren | Księżak-Reding, Hanna | Pasinetti, Giulio Maria

Article Type: Research Article

Abstract: The release of paired helical filaments (PHFs) from neurons into the extracellular space may contribute to the propagation of tau pathology across brain regions in Alzheimer’s disease (AD) and other tauopathies. The majority of available mechanistic studies exploring the pathologic role of extracellular PHFs are conducted in proliferating cell lines. Here, we compare how extracellular PHFs induce tauopathy in mitotic cells and in post-mitotic brain neurons. In a mitotic cell line (HEK 293T), extracellular exposure to AD PHFs leads to an intracellular “aggresomal” type deposition of tau, coincidental with redistribution of dynein, a retrograde motor protein. We also observed that …PHFs impaired proteasome degradation, but not autophagy. Exposure of cells to proteasome inhibitors was sufficient to induce intracellular tau aggregate formation as well as reorganization of dynein and the intermediate filament protein, vimentin. Thus, in mitotic cells, extracellular PHFs promote cellular tau aggregation, in part, by interfering with cellular proteasome degradation processes. In contrast with our observations with proliferating cells, exposure of post-mitotic primary neuronal cultures to AD PHFs did not promote “aggresomal” tau deposition, but instead resulted in a widespread accumulation of phosphorylated tau-immunoreactive swellings in neuritic processes, characterized by disturbed cytoskeletal organization of dynein and vimentin. Collectively, our observations suggest that extracellular PHFs may contribute to the propagation of tau pathology by independent mechanisms in post-mitotic and mitotic brain cells. These outcomes indicate that in addition to post-mitotic brain neurons, mitotic brain cells should also be considered as targets for therapeutic interventions to attenuate propagation of tauopathy. Show more

Keywords: Alzheimer’s disease, neuropathology, proteasome, tau

DOI: 10.3233/JAD-160166

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 477-496, 2016