AGING AND ALZHEIMER DEMENTIA--ROLE OF FIBROUS PROTEIN

衰老和阿尔茨海默氏痴呆——纤维蛋白的作用

• 批准号: 3114975
• 负责人: SHU-HUI C YEN
• 金额: $ 26.39万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-05-01 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3114975
• 关键词: Alzheimer's disease; SDS polyacrylamide gel electrophoresis; aging; antibody; autoradiography; calcium flux; calmodulin dependent protein kinase; chemical cleavage; embryo /fetus cell /tissue; enzyme linked immunosorbent assay; fibrous protein; gel electrophoresis; genetic manipulation; glutamates; hippocampus; histopathology; human genetic material tag; human tissue; immunocytochemistry; laboratory rabbit; laboratory rat; mass spectrometry; molecular cloning; molecular pathology; neurochemistry; neurofibrillary tangles; neurons; paired helical filament; pathologic process; phosphorylation; postmortem; posttranslational modifications; protein kinase; protein kinase A; protein kinase C; protein sequence; tau proteins; tissue /cell culture; western blottings

The long-term goal of this project is the understanding of the biology and molecular pathogenesis of Alzheimer's disease (AD), the most common organic dementia seen in old age. AD is characterized by the presence of neurofibrillary tangles which consist primarily of paired helical filaments (PHF). PHF preparations contain aberrant forms of tau named epitopes but differed in reactivity with a monoclonal anti-tau antibody (Tau-1) and antibodies to a region of bovine tau encoded by tau gene exon 2. A pretreatment of PHF-tau with phosphatase improved its binding with these antibodies, suggesting that PHF-tau differed from normal tau in the site/or the extent of phosphorylation. We have shown recently that PHF-tau also differed from normal tau in molecular mass and isoelectric charge. Dephosphorylation had very little effect on the biochemical properties of PHF tau, suggesting that post-translational modifications, besides phosphorylation, and/or alternative gene splicing play a role in the formation of PHF-tau. It remains to be determined if PHF-tau, besides the two regions mentioned above, contain other aberrant regions, and if phosphorylation is the only biochemical modification that distinguishes PHF-tau from normal tau. It is also unknown if PHF-tau contains additional phosphorylation sites and if the aberrant phosphorylation of PHF-tau is catalyzed via a protein kinase (s) in normal brains or only in AD brains. These questions will be answered by comparing PHF-tau, and tau proteins from normal and AD brains for their phosphate content, amino acid composition and sequences, post-translational modifications and by studying the rephosphorylation of dephosphorylated PHF-tau with known kinases and kinases from brain homogenates. A subtoxic level of glutamate or calcium ionophore A23187 was recently shown to alter the immunoreactivity of tau in cultured neurons. It is unclear whether this alteration is similar to that in PHF-tau. Our last specific aim is to study the effect of these treatments on the biochemical and immunocytochemical properties of tau, and on the ultrastructure of the affected neurons.

这个项目的长期目标是了解生物学和