Serial key for idm. In Alzheimer’s disease (AD) most hippocampal and cortical neurons show increased staining with anti-transthyretin (TTR) antibodies. Genetically programmed over-expression of wild type human TTR suppressed the neuropathologic and behavioral abnormalities in APP23 AD model mice and TTR-Aβ complexes have been isolated from some human AD brains and those of APP23 transgenic mice. Zip code list by dmaic. In the present study in vitro NMR analysis showed interaction between the hydrophobic thyroxine binding pocket of TTR and the cytoplasmic loop of the C99 fragment released by β-secretase cleavage of AβPP with K d = 86±9 µM. In cultured cells expressing both proteins the interaction reduced phosphorylation of C99 (at T668) and suppressed its cleavage by γ-secretase significantly decreasing Aβ secretion. Max B Domain Diego Zip LinesCoupled with its previously demonstrated capacity to inhibit Aβ aggregation (with the resultant cytotoxicity in tissue culture) and its regulation by HSF1 these findings indicate that TTR can behave as a stress responsive multimodal suppressor of AD pathogenesis. The majority of neurons in the brains of patients with Alzheimer’s disease (AD) stain with antibodies specific for the protein transthyretin (TTR) a systemic amyloid precursor [–]. Similarly immunohistochemistry of the brains in transgenic murine models of human Aβ deposition show diffuse TTR staining in cortical and hippocampal neurons and focal staining of plaques and vessels [,]. Studies in our laboratory demonstrated that the positive TTR staining reflected neuronal TTR synthesis rather than uptake of TTR released from the choroid plexus and that neuronal TTR gene expression was regulated in a stress responsive manner by the transcription factor heat shock factor 1 (HSF1) [,]. A beneficial function of neuronal TTR in vivo was strongly indicated in the APP23 murine model of human Aβ deposition in which mice bearing a multi-copy construct of a wild type human TTR (wt h TTR) gene with tissue specific overexpression had substantially reduced neuropathologic and behavioral manifestations of Aβ deposition []. Consistent with those studies is the earlier observation in the Tg2576 transgenic AD model that unilateral intraventricular injection of an anti-TTR antibody increased ipsilateral Aβ deposition when compared with the opposite hemisphere and the more recent demonstration that co-injection of TTR reduces the AD like pathology induced in a rodent model in which preformed oligomeric Aβ1-42 complexes are injected intracerebrally [,].
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