期刊
JOURNAL OF MOLECULAR NEUROSCIENCE
卷 20, 期 3, 页码 425-429出版社
HUMANA PRESS INC
DOI: 10.1385/JMN:20:3:425
关键词
Alzheimer's disease; neurofibrillary degeneration; tauopathies; abnormal hyperphosphorylation; microtubules; tau
资金
- NIA NIH HHS [AG19158] Funding Source: Medline
Neurofibrillary degeneration has primary and pivotal involvement in the pathogenesis of Alzheimer disease (AD) and other tauopathies. The inhibition of this lesion offers a promising therapeutic approach. The microtubule-associated protein (MAP) tau is abnormally hyperphosphorylated in the brain of patients with AD, and in this form it is the major protein subunit of paired helical filaments/neurofibrillary tangles (PHF/NFT). The abnormal tau that is polymerized into PHF/NFT is apparently inert and has no effect on microtubule assembly in vitro. The cytosolic abnormally hyperphosphorylated tau from AD brain, the AD P-tau, does not promote in vitro microtubule assembly but, instead, sequesters normal tau, MAP1, and MAP2 and inhibits microtubule assembly. The AD P-tau readily self-assembles in vitro into tangles of PHF/straight filaments, and this self-assembly requires the abnormal hyperphosphorylation of this protein. Although, to date, an up-regulation of the activity of a tau kinase has not been established, the activity of phosphoseryl/ phosphothreonyl protein phosphatase (PP)-2A, which regulates the phosphorylation of tau, is compromised in AD brain. Thus, modulation of the activities of pp-2A and one or more tau kinases and inhibition of the sequestration of normal MAPs by AD P-tau offer promising therapeutic opportunities to inhibit neurofibrillary degeneration and the diseases characterized by this lesion. Development of high-throughput screening assays for potential drugs aimed at these therapeutic targets is currently under way.
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