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- W2981203239 abstract "Many neurodegenerative diseases share the feature that there is an accumulation of proteins which become neurotoxic. For example, amyloid-beta or tau in Alzheimer's Disease (AD), α-synuclein in Parkinson's disease (PD), or an overlapping of these proteins in Dementia with Lewy bodies (DLB). Although there have been a number of studies which explored targeting these neurotoxic proteins at their various stages of production and dysfunction none so far has led to a successful therapy for use in humans. Tyrosine kinases (TK) have increased activation in multiple neurodegenerative diseases including AD. Specific TKs, Abelson and Discoidin Domain Receptors 1 and 2 (DDR) are upregulated in the hippocampus in post-mortem AD brains. We have shown in preclinical models that Nilotinib, a preferential Abl inhibitor, penetrates the brain and activates parkin leading to Beclin-1 mediated autophagic clearance of aggregated tau and amyloid beta. In collaboration with the medicinal chemistry program, we developed a novel small molecule inhibitor of DDRs, BK40143. We screened this compound for safety and toxicity and its ability to reduce tau and amyloid beta in vitro. We then tested the ability of BK40143 to reduce levels of tau and amyloid beta in transgenic mouse models that overexpress tau as a result of the expression of familial APP mutations (TgAPP) and the human mutant P301L tau (RTG4510), respectively. Our data indicate that BK40143 significantly reduces tau and amyloid- beta, improves performance on the morris water maze test, and inhibits DDRs. Future studies aim to continue to understand the role of DDRs in neurodegeneration and develop BK40143 as a potential new therapy for AD." @default.
- W2981203239 created "2019-10-25" @default.
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- W2981203239 date "2019-07-01" @default.
- W2981203239 modified "2023-10-06" @default.
- W2981203239 title "DT-02-06: A NOVEL SMALL MOLECULE INHIBITOR OF THE DISCOIDIN DOMAIN RECEPTORS (DDR) REDUCES TAU AND AMYLOID-β AND IMPROVES COGNITION IN MODELS OF ALZHEIMER'S DISEASE" @default.
- W2981203239 doi "https://doi.org/10.1016/j.jalz.2019.08.015" @default.
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