title: Significance and mechanism of Alzheimer neurofibrillary degeneration and therapeutic targets to inhibit this lesion.
abstract: Abnormally hyperphosphorylated tau which is the major protein subunit of paired helical filaments (PHF)/neurofibrillary tangles is the pivotal lesion in Alzheimer disease (AD) and related tauopathies. The cosegregation of tau mutations with disease in inherited cases of frontotemporal dementia has confirmed that abnormalities in this protein can be a primary cause of neurodegeneration. Unlike normal tau that promotes assembly and maintains the structure of microtubules, the abnormally hyperphosphorylated protein sequesters normal tau, MAP1 and MAP2 and consequently disassembles microtubules. The abnormal hyperphosphorylation also promotes the self assembly of tau into tangles of PHF. The hyperphosphorylation of tau in AD is probably due to a protein phosphorylation/dephosphorylation imbalance produced by a decrease in the activity of protein phosphatase (PP)-2A and increase in the activities of tau kinases which are directly or indirectly regulated by PP-2A. Two of the most promising pharmacologic therapeutic approaches to AD are (1) the development of drugs that can inhibit the sequestration of normal MAPs by the abnormally hyperphosphorylated tau, and (2) the development of drugs that can reverse the abnormal hyperphosphorylation of tau by correcting the protein phosphorylation/dephosphorylation imbalance.
authors.affiliation: Department of Neurochemistry, New York State institute for Basic Research in Developmental Disabilities, Staten Island 10314-6399, USA. kiqbal@mail.con2.com
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
authors.forename: Alejandra del C
authors.initials: Adel C
authors.lastname: Alonso
authors.forename: Ezzat
authors.initials: E
authors.lastname: El-Akkad
authors.forename: Cheng-Xin
authors.initials: CX
authors.lastname: Gong
authors.forename: Niloufar
authors.initials: N
authors.lastname: Haque
authors.forename: Sabiha
authors.initials: S
authors.lastname: Khatoon
authors.forename: Jin-Jing
authors.initials: JJ
authors.lastname: Pei
authors.forename: Ichiro
authors.initials: I
authors.lastname: Tsujio
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
authors.forename: Inge
authors.initials: I
authors.lastname: Grundke-Iqbal
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D003704:Dementia / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016874:Neurofibrillary Tangles / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D016875:tau Proteins / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D008869:Microtubule-Associated Proteins; D016875:tau Proteins; D011494:Protein Kinases; D010749:Phosphoprotein Phosphatases