title: Tau pathology in Alzheimer disease and other tauopathies.
abstract: Just as neuronal activity is essential to normal brain function, microtubule-associated protein tau appears to be critical to normal neuronal activity in the mammalian brain, especially in the evolutionary most advanced species, the homo sapiens. While the loss of functional tau can be compensated by the other two neuronal microtubule-associated proteins, MAP1A/MAP1B and MAP2, it is the dysfunctional, i.e., the toxic tau, which forces an affected neuron in a long and losing battle resulting in a slow but progressive retrograde neurodegeneration. It is this pathology which is characteristic of Alzheimer disease (AD) and other tauopathies. To date, the most established and the most compelling cause of dysfunctional tau in AD and other tauopathies is the abnormal hyperphosphorylation of tau. The abnormal hyperphosphorylation not only results in the loss of tau function of promoting assembly and stabilizing microtubules but also in a gain of a toxic function whereby the pathological tau sequesters normal tau, MAP1A/MAP1B and MAP2, and causes inhibition and disruption of microtubules. This toxic gain of function of the pathological tau appears to be solely due to its abnormal hyperphosphorylation because dephosphorylation converts it functionally into a normal-like state. The affected neurons battle the toxic tau both by continually synthesizing new normal tau and as well as by packaging the abnormally hyperphosphorylated tau into inert polymers, i.e., neurofibrillary tangles of paired helical filaments, twisted ribbons and straight filaments. Slowly but progressively, the affected neurons undergo a retrograde degeneration. The hyperphosphorylation of tau results both from an imbalance between the activities of tau kinases and tau phosphatases and as well as changes in tau's conformation which affect its interaction with these enzymes. A decrease in the activity of protein phosphatase-2A (PP-2A) in AD brain and certain missense mutations seen in frontotemporal dementia promotes the abnormal hyperphosphorylation of tau. Inhibition of this tau abnormality is one of the most promising therapeutic approaches to AD and other tauopathies.
authors.affiliation: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314-6399, USA. iqbalk@worldnet.att.net
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
authors.forename: Alejandra del C
authors.initials: Adel C
authors.lastname: Alonso
authors.forename: She
authors.initials: S
authors.lastname: Chen
authors.forename: M Omar
authors.initials: MO
authors.lastname: Chohan
authors.forename: Ezzat
authors.initials: E
authors.lastname: El-Akkad
authors.forename: Cheng-Xin
authors.initials: CX
authors.lastname: Gong
authors.forename: Sabiha
authors.initials: S
authors.lastname: Khatoon
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Abdur
authors.initials: A
authors.lastname: Rahman
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tanimukai
authors.forename: Inge
authors.initials: I
authors.lastname: Grundke-Iqbal
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D009410:Nerve Degeneration / Q000378:metabolism; D016874:Neurofibrillary Tangles / Q000378:metabolism*; D009454:Neurofibrils / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation; D011494:Protein Kinases / Q000378:metabolism; D054648:Protein Phosphatase 2; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D016875:tau Proteins; D011494:Protein Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2