title: Microtubule-associated protein tau as a therapeutic target in Alzheimer's disease.
abstract: BACKGROUND
  Alzheimer's disease (AD) is a major public health problem in modern society and as yet, other than a few symptomatic drugs, there is no disease-modifying treatment for this disease available.
  
  
  METHODS
  Neurofibrillary pathology, which is made up from abnormally hyperphosphorylated microtubule-associated protein tau, is both a hallmark and key lesion of AD and related tauopathies. The density of neurofibrillary pathology in the cerebral cortex correlates with the degree of dementia. Both experimental and transgenic animal studies have consistently shown that abnormal hyperphosphorylation of tau causes cognitive impairment. Abnormal hyperphosphorylation of tau converts it from a microtubule assembly-promoting to a microtubule-disrupting protein and promotes its self-assembly into paired helical filaments. To date, the bulk of studies have shown that abnormal hyperphosphorylation is the key gain of toxic function step though some cell culture and transgenic mouse studies have also reported that aggregated tau can lead to neurodegeneration. In this article, we have reviewed data from our lab and that from PubMed search on the molecular mechanism of tau pathology and the potential of tau as a therapeutic target for AD and related disorders.
  
  
  CONCLUSIONS
  In our opinion, inhibition of abnormal hyperphosphorylation of tau is the most rational therapeutic target. Therapeutic approaches include restoration of the activity of protein phosphatase-2A, which is the major regulator of tau phosphorylation and the activity of which is compromised in AD brain, inhibition of one or more tau protein kinases which include GSK-3β, cyclin-dependent protein kinase-5, dual-specificity tyrosine phosphorylated-regulated kinase 1A, Ca(2+)/calmodulin-activated protein kinase II and casein kinase I, enhancement of O-GlcNAcylation of tau, and tau immunization.
authors.affiliation: New York State Institute for Basic Research in Developmental Disabilities, Department of Neurochemistry, Inge Grundke-Iqbal Research Floor , 1050 Forest Hill Road, Staten Island, NY 10314 , USA +1 718 494 5259 ; khalid.iqbal.ibr@gmail.com.
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
authors.forename: Cheng-Xin
authors.initials: CX
authors.lastname: Gong
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D009410:Nerve Degeneration / Q000378:metabolism; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology
chemical_list: D038362:Glycogen Synthase Kinase 3; C080888:tau-protein kinase