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[FTS3–02–01]: 2017 NIA‐AA RESEARCH FRAMEWORK TO INVESTIGATE THE ALZHEIMER's DISEASE CONTINUUM
Author(s) -
Jack Clifford R.,
Bennett David A.,
Blennow Kaj,
Carrillo Maria C.,
Dunn Billy,
Elliott Cerise L.,
Haeberlein Samantha Budd,
Holtzman David M.,
Jagust William J.,
Jessen Frank,
Karlawish Jason,
Liu Enchi,
Molinuevo José Luis,
Montine Thomas J.,
Phelps Creighton,
Rankin Katherine,
Rowe Christopher C.,
Ryan Laurie M.,
Scheltens Philip,
Siemers Eric R.,
Silverberg Nina,
Snyder Heather M.,
Sperling Reisa A.
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.07.294
Subject(s) - workgroup , disease , dementia , context (archaeology) , psychology , medicine , gerontology , pathology , computer science , computer network , paleontology , biology
the transcription factor TFEB, its mRNA transcripts, and their principle autophagy proteins – LC3B, p62, and LAMP2 – by immunohistochemistry and computational modeling of ApoE protein-DNA interactions. Results: Levels of the three key TFEB-regulated mRNA transcripts were lower in the brains of Alzheimer patient carriers of APOE ε4,4 than those of APOE ε3,3 carriers, despite similar nuclear levels of TFEB. This was due to specific binding of ApoE4 to TFEB-regulated CLEAR DNA motifs and was dependent on the presence of Arg112 and Arg61 as was shown to be the case by preclusion of such binding by computational substitution of Ala for Arg at 112 and 61. Conclusions: ApoE4-CLEAR motif interactions may account for elevated aggregation in ApoE4 carriers, and this in turn, account for increased risk for disease development. ApoE4 increases risk for development of AD in part by weakening the autophagy response, specifically by direct binding of ApoE4 to the CLEAR motif, which is recognized by the master autophagy regulator TFEB. The close relationship between inflammation and autophagy suggests that therapies targeting both pathways might be beneficial in treating Alzheimer patients.