Targeting tau protein in Alzheimer's disease.
Alzheimer's disease (AD) is characterized histopathologically by numerous neurons with neurofibrillary tangles and neuritic (senile) amyloid-beta (Abeta) plaques, and clinically by progressive dementia. Although Abeta is the primary trigger of AD according to the amyloid cascade hypothesis, neurofibrillary degeneration of abnormally hyperphosphorylated tau is apparently required for the clinical expression of this disease. Furthermore, while approximately 30% of normal aged individuals have as much compact plaque burden in the neocortex as is seen in typical cases of AD, in several tauopathies, such as cortical basal degeneration and Pick's disease, neurofibrillary degeneration of abnormally hyperphosphorylated tau in the absence of Abeta plaques is associated with dementia. To date, all AD clinical trials based on Abeta as a therapeutic target have failed. In addition to the clinical pathological correlation of neurofibrillary degeneration with dementia in AD and related tauopathies, increasing evidence from in vitro and in vivo studies in experimental animal models provides a compelling case for this lesion as a promising therapeutic target. A number of rational approaches to inhibiting neurofibrillary degeneration include inhibition of one or more tau protein kinases, such as glycogen synthase kinase-3beta and cyclin-dependent protein kinase 5, activation of the major tau phosphatase protein phosphatase-2A, elevation of beta-N-acetylglucosamine modification of tau through inhibition of beta-N-acetylglucosaminidase or increase in brain glucose uptake, and promotion of the clearance of the abnormally hyperphosphorylated tau by autophagy or the ubiquitin proteasome system.
Gong
Cheng-Xin
CX
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA.
Grundke-Iqbal
Inge
I
Iqbal
Khalid
K
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D009454:Neurofibrils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017510:Protein Folding / Q000187:drug effects; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
D004791:Enzyme Inhibitors; D016875:tau Proteins
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