Abstract
The microtubule (MT) binding protein tau is the major constituent of neurofibrillary tangles (NFTs), a hallmark of AD and other related disorders including neurodegenerative tauopathies that manifest as sporadic and familial frontotemporal dementias (FTDs). Thus, tau pathology is a critical underlying abnormality that links AD and these disorders to a shared mechanism of neurodegeneration. NFTs are composed of tau assembled into paired helical filaments (PHFs) known as PHFtau, and when tau is transformed into PHFtau, less normal tau is available to stabilize MTs. Since MTs are essential for intracellular transport, when MTs are destabilized and axonal transport is compromised, neurodegeneration follows. Several interventions focusing on correcting losses of normal tau function and reversing gains of toxic function by PHFs/NFTs have been suggested for development as disease modifying therapies for AD and related FTD tauopathies. Plausible targets for tau focused drug discovery are briefly summarized, and recent efforts to develop MT stabilizing, PHFtau anti-fibrillization and neuroprotection compounds as disease modifying therapy for AD and related FTD tauopathies are reviewed. In vitro tau fibrillization assays are used to identify compounds that inhibit tau fibril formation and the PS 19 mouse model is used for neuroprotection studies. Potential identification of compounds that inhibit tau fibrillization and efficacy dose that confer neuroprotection in PS19 mouse model. It is possible to identify lead compounds that inhibit tau fibrillization and the efficacy dose for neuroprotection in a mouse model of tauopathy.
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