Significance and mechanism of Alzheimer neurofibrillary degeneration and therapeutic targets to inhibit this lesion.
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.
Iqbal
Khalid
K
Department of Neurochemistry, New York State institute for Basic Research in Developmental Disabilities, Staten Island 10314-6399, USA. kiqbal@mail.con2.com
Alonso
Alejandra del C
Adel C
El-Akkad
Ezzat
E
Gong
Cheng-Xin
CX
Haque
Niloufar
N
Khatoon
Sabiha
S
Pei
Jin-Jing
JJ
Tsujio
Ichiro
I
Wang
Jian-Zhi
JZ
Grundke-Iqbal
Inge
I
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*
D008869:Microtubule-Associated Proteins; D016875:tau Proteins; D011494:Protein Kinases; D010749:Phosphoprotein Phosphatases