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Authors: Bocai, Nadia I. | Marcora, María S. | Belfiori-Carrasco, Lautaro F. | Morelli, Laura | Castaño, Eduardo M.

Article Type: Review Article

Abstract: The accumulation and spreading of protein tau in the human brain are major features of neurodegenerative disorders known as tauopathies. In addition to several subcellular abnormalities, tau aggregation within neurons seems capable of triggering endoplasmic reticulum (ER) stress and the consequent unfolded protein response (UPR). In metazoans, full activation of a complex ER-UPR network may restore proteostasis and ER function or, if stress cannot be solved, commit cells to apoptosis. Due to these alternative outcomes (survival or death), the pharmacological manipulation of ER-UPR has become the focus of potential therapies in many human diseases, including tauopathies. Here we update and …analyze the experimental data from human brain, cellular, and animal models linking tau accumulation and ER-UPR. We further discuss mechanistic aspects and put the ER-UPR into perspective as a possible therapeutic target in this group of diseases. Show more

Keywords: Dementia, endoplasmic reticulum stress, tau proteins, tauopathies, unfolded protein response

DOI: 10.3233/JAD-181021

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 439-458, 2019

Authors: Bulloj, Ayelén | Leal, María C. | Xu, Huaxi | Castaño, Eduardo M. | Morelli, Laura

Article Type: Research Article

Abstract: The accumulation of amyloid-β (Aβ) peptides in senile plaques is one of the hallmarks of Alzheimer's disease (AD) progression. The endocytic pathway has been proposed as a major subcellular site for Aβ generation while the compartments in which Aβ-degrading proteases interact with Aβ are still elusive. It was suggested that extracellular Aβ degradation may take place by plasma-membrane associated proteases or by extracellular proteases, among which insulin-degrading enzyme (IDE) is the most relevant. However, the mechanisms of IDE secretion are poorly understood. In the present study we used N2a cells to explore if IDE is indeed released through exosomes and …the effect of exosomes release on extracellular levels of Aβ. We demonstrated that proteolytically-active plasma membrane associated-IDE is routed in living N2a cells to multivesicular bodies and subsequently, a major fraction is sorted to exosomes. We described that extracellular IDE levels decrease if the generation of multivesicular bodies is interfered and may be positively modulated by exosomes release under stress-induced conditions. Our results reinforce the relevance of functional IDE in the catabolism of extracellular Aβ. Show more

Keywords: Alzheimer's disease, amyloid-β, calcium, exosomes, hypoxia, insulin-degrading enzyme, multivesicular bodies, peptide degradation, Rab11-GTPase, VPS4

DOI: 10.3233/JAD-2010-1206

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 79-95, 2010