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P3‐038: TAU PROTEIN INDUCES INSULIN RESISTANCE THROUGH JNK PATHWAY
Author(s) -
Yin Jun
Publication year - 2014
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.2014.05.1125
Subject(s) - insulin resistance , insulin receptor , insulin , insulin receptor substrate , endocrinology , medicine , phosphorylation , irs1 , pi3k/akt/mtor pathway , insulin degrading enzyme , protein kinase b , kinase , tyrosine phosphorylation , irs2 , tau protein , signal transduction , chemistry , biology , microbiology and biotechnology , alzheimer's disease , disease
Background: Accumulating evidences indicate the amyloid cascade as the primary event in the pathogenesis of Alzheimer’s disease (AD). A disintegrin and metalloproteinase 10 (ADAM10) is the enzyme responsible for the a-secretase cleavage of the Amyloid Precursor Protein (APP), that prevents amyloid formation. ADAM10 is an integral component of postsynaptic density (PSD) of excitatory synapses and is active towards its substrates when properly inserted in the postsynaptic membranes. The Synapse-Associated Protein-97 (SAP97) mediates ADAM10 transport to the PSD: with its SH3 domain, SAP97 binds to the proline-rich sequences in the ADAM10 cytosolic domain, thereby driving the protease to the postsynaptic membrane and leading to an increased APP a-secretase cleavage. Although it is widely and long accepted that protein kinase C (PKC) is a key modulator of a-secretase activity and thereby of amyloid production, it still remains unclear through which downstream molecules PKC eventually mediates the increased a-secretase APP cleavage. Therefore, we asked whether SAP97 could be involved in PKC-induced ADAM10 activity.Methods:We used different approaches and cellularmodels to study the effects of PKC activation on ADAM10/SAP97 interaction and on ADAM10 trafficking in neuronal cells. Furthermore, we analysed this novel mechanism in AD patients’ hippocampi. Results: Here we clarify several important steps on PKC-regulated a-secretase activity. First, we identified a previously uncharacterized PKC phosphosite in SAP97 SH3 domain, which can modulate SAP97 association to ADAM10. Second, we showed that PKC phosphorylation of SAP97 is essential for efficient synaptic delivery of ADAM10, and thereby it can affect ADAM10 activity towards APP. Third, we described a pathological role of this mechanism, showing a significant reduction of SAP97 phosphorylation inADpatients. Finally, we disclosed a previously unknown aspect of ADAM10 trafficking in neuronal cells: ADAM10 transits through dendritic Golgi outposts where ADAM10/SAP97 complex formation occurs. Conclusions: These results helped in understanding the mechanism responsible for the modulation of ADAM10 intracellular path, and could constitute an innovative therapeutic strategy to finely tuneADAM10 shedding activity towards APP.