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O3–02–08: The phosphorylation state of Tyr687 on APP contributes to protein–protein interactions and Abeta production
Author(s) -
Rebelo Sandra,
Domingues Sara S.,
Vieira Sandra I.,
Esselman Hermann,
Wiltfang Jens,
Cruz e Silva Edgar F.,
da Cruz e Silva Odete A.
Publication year - 2006
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.2006.05.203
Subject(s) - phosphorylation , dephosphorylation , green fluorescent protein , protein phosphorylation , amyloid precursor protein , microbiology and biotechnology , fusion protein , chemistry , transmembrane protein , biology , biochemistry , alzheimer's disease , phosphatase , gene , protein kinase a , recombinant dna , medicine , receptor , disease
insulin receptors (IR), major Akt-activating receptors in brain. Results discovered a disease-stage related loss of Akt containing neurons selective to areas of the brain that degenerate in AD. This was detected together with a significantly increased Akt activity in AD, and hyperphosphorylation of many Akt downstream targets, including GSK3 , tau, mTOR and p27. Hyperphosphorylation of tau occurs at Ser214, an optimal consensus sequence for Akt, important for PHF formation, linking Akt activation to tau pathology. Mechanistically, increased Akt activation may be due to a significant loss of PTEN, and its altered subcellular localization, which was detected in neurons that degenerate in AD. We also discovered key defects in IGF-1R and IR, upstream to Akt signalling, indicating impaired normal growth factor activation of Akt in AD. This included a significant loss of IRS1/2, key adaptor proteins for IR and IGF-1R-activation of PI3-kinase, and loss of p85 and p100 subunits of PI3-kinase. Importantly, in other systems downregulation of IRS1/2 is a feedback response to heightened Akt activity, with resultant inhibition of normal receptor responses through PI3kinase-Akt. Further work detected more pronounced defects in IGF-1R status in AD compared to IR, including increased IGF-1R levels in glia, and within and surrounding A plaques. Together results indicate that Akt is hyper-activated in AD neurons, and that loss of normal regulated Akt target phosphorylation in AD may link to loss of Akt neurons, and impaired normal growth factor and insulin responses through this pathway in AD.