Modulation of Protein-Protein Interactions as a Therapeutic Strategy for the Treatment of Neurodegenerative Tauopathies

C.      Ballatore; K.      R. Brunden; J.      Q. Trojanowski; V.      M.-Y. Lee; A.      B. Smith; D.      M. Huryn

doi:10.2174/156802611794072605

Abstract

The recognition that malfunction of the microtubule (MT) associated protein tau is likely to play a defining role in the onset and/or progression of a number of neurodegenerative diseases, including Alzheimers disease, has resulted in the initiation of drug discovery programs that target this protein. Tau is an endogenous MT-stabilizing agent that is highly expressed in the axons of neurons. The MT-stabilizing function of tau is essential for the axonal transport of proteins, neurotransmitters and other cellular constituents. Under pathological conditions, tau misfolding and aggregation results in axonal transport deficits that appear to have deleterious consequences for the affected neurons, leading to synapse dysfunction and, ultimately, neuronal loss. This review focuses on both progress and unresolved issues surrounding the development of novel therapeutics for the treatment of neurodegenerative tauopathies, which are based on (A) MT-stabilizing agents to compensate for the loss of normal tau function and (B) small molecule inhibitors of tau aggregation.

Keywords: Protein-protein interaction, tau, Alzheimer's disease, neurodegenerative tauopathies, microtubule-stabilizing agents, aggregation inhibitors, microtubule, neuronal loss, cyclosporine A, FK506, taxanes, vinca alkaloids, RGD-mimetics, central nervous system, Pick's disease, frontotemporal dementia, neurofibrillary tangles, frontotemporal lobar degeneration, tau-MT complex, phosphorylation, antineoplastic agents, rheumatoid arthritis, psoriasis, paclitaxel, blood-brain barrier, P-glycoprotein, ATP-binding cassette, IDN5109, brain to plasma ratio, TXD258, Larotaxel, ANG1005, Angiopep-2, Epothilones, Ixabepilone, desoxyepothilones, discodermolide, dictyostatin, cyclostreptin, davunetide, N-methyl-D-aspartate, phenothiazines, anthraquinones, N-phenylamines, thiazolyl-hydrazides, rhodanines, quinoxalines, aminothienopyridazines