Developing therapeutic approaches to tau, selected kinases, and related neuronal protein targets.
A hallmark of the Alzheimer disease (AD) brain is the presence of inclusions within neurons that are comprised of fibrils formed from the microtubule-stabilizing protein tau. The formation of misfolded multimeric tau species is believed to contribute to the progressive neuron loss and cognitive impairments of AD. Moreover, mutations in tau have been shown to cause a form of frontotemporal lobar degeneration in which tau neuronal inclusions observed in the brain are similar to those seen in AD. Here we review the more compelling strategies that are designed to reduce the contribution of misfolded tau to AD neuropathology, including those directed at correcting a possible loss of tau function resulting from sequestration of cellular tau and to minimizing possible gain-of-function toxicities caused by multimeric tau species. Finally, we discuss the challenges and potential benefits of tau-directed drug discovery programs.
Center for Neurodegenerative Disease Research, Institute on Aging, Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Virginia M-Y
VM
Lee
Kurt R
KR
Brunden
Michael
M
Hutton
John Q
JQ
Trojanowski
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000737:chemistry / Q000378:metabolism; D002491:Central Nervous System Agents / Q000627:therapeutic use*; D055808:Drug Discovery; D005819:Genetic Markers; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D016874:Neurofibrillary Tangles / Q000737:chemistry / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D002491:Central Nervous System Agents; D005819:Genetic Markers; C054369:MAPT protein, human; D047428:Protein Kinase Inhibitors; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3; C080888:tau-protein kinase