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P4‐007: Interaction between SORLA and adaptor proteins in Alzheimer's disease
Author(s) -
Burgert Tilman,
Caglayan Safak,
Schmidt Vanessa,
Willnow Thomas
Publication year - 2012
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.2012.05.1708
Subject(s) - retromer , endosome , microbiology and biotechnology , golgi apparatus , sorting nexin , receptor , transport protein , intracellular , signal transducing adaptor protein , amyloid precursor protein , biology , chemistry , biochemistry , signal transduction , alzheimer's disease , endoplasmic reticulum , medicine , disease , pathology
disease (AD). APP cleavage is a fundamental event in AD and it is mediated by several proteolytic enzymes. Two of these, ADAM10 and BACE1, mediate the non-amyloidogenic and the amyloidogenic cleavages of APP respectively. TrkB FL has been shown to increase the non-amyloidogenic cleavage of APP. We hypothesized that TrkB isoforms can alter APP levels and ADAM10/BACE1 levels or activity and therefore contribute to the pathology of AD. Methods:We tested our hypothesis by over-expressing the different isoforms of the receptor and some point mutants in two different human cell lines: HEK293 and SH-SY5Y cells. We then measured endogenous levels of APP, BACE1 and ADAM10.We also measured ADAM10 activity. Finally we employed a luciferase reporter assay to test TrkB FL mediated transcriptional activation. Results: We found that TrkB FL increased APP endogenous levels in both human cell lines while TrkB T did not alter these levels. Surprisingly, we did not find a significant difference in ADAM10 activity but an increase in BACE1 levels when over-expressing the TrkB FL receptor. This was not observed with the truncated counterparts or when mutating the SHC binding site of the TrkB FL receptor. We also found that NFAT3 activation mediated by TrkB FL signaling might explain the increase in BACE1 levels. Conclusions: We conclude that TrkB isoforms are involved in AD molecular mechanisms by directly affecting endogenous APP and BACE1 levels. TrkB FL increases BACE1 levels in vitro and this effect is SHC mediated. All these mechanisms need to be better elucidated before implementing successful BDNF based therapies for AD.