Significance and Mechanism of Alzheimer Neurofibrillary Degeneration and Therapeutic Targets to Inhibit This Lesion

Overview

Journal J Mol Neurosci

Specialties Molecular Biology
Neurology

Date 2002 Sep 6

PMID 12212801

Citations 13

Authors

Khalid Iqbal

Alejandra Del C Alonso

Ezzat El-Akkad

Cheng-Xin Gong

Niloufar Haque

Sabiha Khatoon

Jin-Jing Pei

Ichiro Tsujio

Jian-Zhi Wang

Inge Grundke-Iqbal

Affiliations

Soon will be listed here.

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.

Citing Articles

Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer's Disease.

Panza F, Solfrizzi V, Seripa D, Imbimbo B, Lozupone M, Santamato A Biomed Res Int. 2016; 2016:3245935.

PMID: 27429978 PMC: 4939203. DOI: 10.1155/2016/3245935.

Escitalopram Ameliorates Forskolin-Induced Tau Hyperphosphorylation in HEK239/tau441 Cells.

Ren Q, Wang Y, Gong W, Zhou Q, Xu L, Zhang Z J Mol Neurosci. 2015; 56(2):500-8.

PMID: 25687330 DOI: 10.1007/s12031-015-0519-4.

Spectral Analysis of EEG in Familial Alzheimer's Disease with E280A Presenilin-1 Mutation Gene.

Rodriguez R, Lopera F, Alvarez A, Fernandez Y, Galan L, Quiroz Y Int J Alzheimers Dis. 2014; 2014:180741.

PMID: 24551475 PMC: 3914466. DOI: 10.1155/2014/180741.

MicroRNAs and the Regulation of Tau Metabolism.

Hebert S, Sergeant N, Buee L Int J Alzheimers Dis. 2012; 2012:406561.

PMID: 22720189 PMC: 3374946. DOI: 10.1155/2012/406561.

Electroencephalographic rhythms in Alzheimer's disease.

Lizio R, Vecchio F, Frisoni G, Ferri R, Rodriguez G, Babiloni C Int J Alzheimers Dis. 2011; 2011:927573.

PMID: 21629714 PMC: 3100729. DOI: 10.4061/2011/927573.

References

Katzman R, Terry R, DeTeresa R, Brown T, Davies P, Fuld P . Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol. 1988; 23(2):138-44. DOI: 10.1002/ana.410230206. View

Ulitzur N, Rancano C, Pfeffer S . Biochemical characterization of mapmodulin, a protein that binds microtubule-associated proteins. J Biol Chem. 1997; 272(48):30577-82. DOI: 10.1074/jbc.272.48.30577. View

Dickson D, Farlo J, Davies P, Crystal H, Fuld P, Yen S . Alzheimer's disease. A double-labeling immunohistochemical study of senile plaques. Am J Pathol. 1988; 132(1):86-101. PMC: 1880629. View

Morsch R, Simon W, Coleman P . Neurons may live for decades with neurofibrillary tangles. J Neuropathol Exp Neurol. 1999; 58(2):188-97. DOI: 10.1097/00005072-199902000-00008. View

Cohen P . The structure and regulation of protein phosphatases. Annu Rev Biochem. 1989; 58:453-508. DOI: 10.1146/annurev.bi.58.070189.002321. View

Cohen P, Alemany S, Hemmings B, Resink T, Stralfors P, Tung H . Protein phosphatase-1 and protein phosphatase-2A from rabbit skeletal muscle. Methods Enzymol. 1988; 159:390-408. DOI: 10.1016/0076-6879(88)59039-0. View

Gong C, Lidsky T, Wegiel J, Zuck L, Grundke-Iqbal I, Iqbal K . Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer's disease. J Biol Chem. 2000; 275(8):5535-44. DOI: 10.1074/jbc.275.8.5535. View

Spillantini M, Murrell J, Goedert M, Farlow M, Klug A, Ghetti B . Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A. 1998; 95(13):7737-41. PMC: 22742. DOI: 10.1073/pnas.95.13.7737. View

Bennecib M, Gong C, Grundke-Iqbal I, Iqbal K . Inhibition of PP-2A upregulates CaMKII in rat forebrain and induces hyperphosphorylation of tau at Ser 262/356. FEBS Lett. 2001; 490(1-2):15-22. DOI: 10.1016/s0014-5793(01)02127-5. View

10.

Wang J, Gong C, Zaidi T, Grundke-Iqbal I, Iqbal K . Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B. J Biol Chem. 1995; 270(9):4854-60. DOI: 10.1074/jbc.270.9.4854. View

11.

Grundke-Iqbal I, Iqbal K, Tung Y, Quinlan M, Wisniewski H, Binder L . Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986; 83(13):4913-7. PMC: 323854. DOI: 10.1073/pnas.83.13.4913. View

12.

Alonso A, Grundke-Iqbal I, Iqbal K . Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat Med. 1996; 2(7):783-7. DOI: 10.1038/nm0796-783. View

13.

Li M, Makkinje A, Damuni Z . Molecular identification of I1PP2A, a novel potent heat-stable inhibitor protein of protein phosphatase 2A. Biochemistry. 1996; 35(22):6998-7002. DOI: 10.1021/bi960581y. View

14.

Alonso A, Grundke-Iqbal I, Barra H, Iqbal K . Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau. Proc Natl Acad Sci U S A. 1997; 94(1):298-303. PMC: 19321. DOI: 10.1073/pnas.94.1.298. View

15.

Li M, Makkinje A, Damuni Z . The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A. J Biol Chem. 1996; 271(19):11059-62. DOI: 10.1074/jbc.271.19.11059. View

16.

Walaas S, Greengard P . Protein phosphorylation and neuronal function. Pharmacol Rev. 1991; 43(3):299-349. View

17.

von Lindern M, Van Baal S, Wiegant J, Raap A, Hagemeijer A, Grosveld G . Can, a putative oncogene associated with myeloid leukemogenesis, may be activated by fusion of its 3' half to different genes: characterization of the set gene. Mol Cell Biol. 1992; 12(8):3346-55. PMC: 364582. DOI: 10.1128/mcb.12.8.3346-3355.1992. View

18.

Alafuzoff I, Iqbal K, Friden H, Adolfsson R, Winblad B . Histopathological criteria for progressive dementia disorders: clinical-pathological correlation and classification by multivariate data analysis. Acta Neuropathol. 1987; 74(3):209-25. DOI: 10.1007/BF00688184. View

19.

Iqbal K, Grundke-Iqbal I, Smith A, George L, Tung Y, Zaidi T . Identification and localization of a tau peptide to paired helical filaments of Alzheimer disease. Proc Natl Acad Sci U S A. 1989; 86(14):5646-50. PMC: 297681. DOI: 10.1073/pnas.86.14.5646. View

20.

Finch C, Tanzi R . Genetics of aging. Science. 1997; 278(5337):407-11. DOI: 10.1126/science.278.5337.407. View