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Role of Fibrinogen in Alzheimer's Disease

纤维蛋白原在阿尔茨海默病中的作用

基本信息

批准号：
10737135
负责人：
ERIN H NORRIS
金额：
$ 77.37万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737135
关键词：
Affect Affinity Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid beta-42 Amyloid beta-Protein Binding Blood Proteins Blood coagulation Blood flow Brain Brain Pathology Cell Communication Cells Coagulation Process Complex Culture Techniques Cytolysis Disease Elements Fibrin Fibrinogen Functional disorder Goals Hippocampus Human Imaging Techniques Impaired cognition In Vitro Inflammation Injections Measures Molecular Mus Nerve Degeneration Neuronal Dysfunction Pathogenesis Pathogenicity Pathway interactions Peptides Physiological Population Dynamics Property Proteins Protocols documentation Resistance Role Sampling Severity of illness Slice Structure Synapses System Toxic effect Variant Vascular Diseases Vascular System abeta toxicity biophysical properties biophysical techniques improved in vivo mouse model mutant negative affect neuroinflammation neuron loss novel novel diagnostics novel therapeutics pharmacologic protective effect protein purification single nucleus RNA-sequencing small molecule vascular contributions

项目摘要

PROJECT SUMMARY Alzheimer's disease (AD) is a multifactorial disorder with many pathogenic elements. One contributing factor is vascular dysfunction, which can be both a result of the primary AD pathogenesis and a cause of neuronal loss and subsequent cognitive impairment. The molecular mechanisms by which AD and the vascular system intersect and influence each other are still unclear. We have been working for two decades to try to better define this molecular interaction. We have shown that beta amyloid (Aβ), the peptide that is a driver of AD, interacts with fibrinogen and increases blood clot formation. These clots have an altered structure and are resistant to lysis. These abnormal clots can contribute to reduced blood flow and increased inflammation, both of which could contribute to vascular contributions to AD. We have now found that the Aβ/fibrinogen complexes can have toxic effects independent of clotting. In hippocampal slice cultures, Aβ/fibrinogen complexes are more toxic than either Aβ or fibrinogen alone. These results identify a new mechanism by which the interaction of Aβ and fibrinogen can lead to neuronal dysfunction. Mutant and longer forms of Aβ are sometimes much more toxic that the classical Aβ42 and Aβ40 species. We show that some mutant forms of Aβ that are more toxic interact much more strongly with fibrinogen. These Aβ variants provide an entrée for studying the mechanisms by which Aβ/fibrinogen complexes are toxic in AD. Therefore, our main goal is to explore the cellular and molecular mechanisms by which Aβ variants and their fibrinogen complexes negatively affect the brain.

项目概要阿尔茨海默病（AD）是一种多因素疾病，具有多种致病因素。一个影响因素是血管功能障碍，这既可能是原发性 AD 发病机制的结果，也可能是神经元损失的原因以及随后的认知障碍。 AD 和血管系统的分子机制相互交叉、相互影响尚不清楚。二十年来，我们一直在努力，力求做得更好定义这种分子相互作用。我们已经证明，β 淀粉样蛋白 (Aβ)（AD 的驱动肽）与纤维蛋白原相互作用，并且增加血凝块的形成。这些凝块具有改变的结构并且能够抵抗溶解。这些异常血栓会导致血流量减少和炎症增加，这两者都可能有助于 AD 的血管贡献。我们现在发现 Aβ/纤维蛋白原复合物可以产生与凝血无关的毒性作用。在海马切片培养物中，Aβ/纤维蛋白原复合物比单独的 Aβ 或纤维蛋白原毒性更大。这些结果确定了一种新机制，通过该机制 Aβ 和纤维蛋白原的相互作用可以导致神经元功能障碍。突变型和较长形式的 Aβ 有时比经典的 Aβ42 和 Aβ40 物种毒性更大。我们表明一些毒性更强的 Aβ 突变体与纤维蛋白原的相互作用更强。这些Aβ 变体为研究 Aβ/纤维蛋白原复合物在 AD 中的毒性机制提供了一个切入点。因此，我们的主要目标是探索Aβ变体及其相关的细胞和分子机制。纤维蛋白原复合物会对大脑产生负面影响。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Vascular Dysfunction in Alzheimer's Disease: Alterations in the Plasma Contact and Fibrinolytic Systems.

DOI：
10.3390/ijms24087046
发表时间：
2023-04-11
期刊：
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
影响因子：
5.6
作者：
Badimon, Ana;Torrente, Daniel;Norris, Erin H.
通讯作者：
Norris, Erin H.

The protective effect of early dietary fat consumption on Alzheimer's disease-related pathology and cognitive function in mice.

DOI：
10.1002/trc2.12173
发表时间：
2021
期刊：
Alzheimer's & dementia (New York, N. Y.)
影响因子：
0
作者：
Amelianchik A;Merkel J;Palanisamy P;Kaneki S;Hyatt E;Norris EH
通讯作者：
Norris EH

Vascular endothelial growth factor associated dissimilar cerebrovascular phenotypes in two different mouse models of Alzheimer's Disease.

DOI：
10.1016/j.neurobiolaging.2021.07.015
发表时间：
2021-11
期刊：
Neurobiology of aging
影响因子：
4.2
作者：
Tataryn NM;Singh V;Dyke JP;Berk-Rauch HE;Clausen DM;Aronowitz E;Norris EH;Strickland S;Ahn HJ
通讯作者：
Ahn HJ

The contact activation system and vascular factors as alternative targets for Alzheimer's disease therapy.