Calcineurin Inhibition for Reversing the Cognitive Effects of Amyloid

抑制钙调神经磷酸酶可逆转淀粉样蛋白的认知影响

• 批准号: 7584444
• 负责人: Giulio Taglialatela
• 金额: $ 42.08万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7584444
• 关键词: Achievement; Acute; Affect; Age; Age-Months; Aging; Alzheimer' s Disease; American; Amino Acids; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animals; Apoptotic; Appearance; Autopsy; Behavior; Behavioral; Biochemical; Biochemistry; Brain; Breeding; Calcineurin; Calcineurin inhibitor; Cessation of life; Cognition; Cognitive; Cognitive deficits; Consensus; Data; Data Analyses; Dementia; Deposition; Development; Diagnostic; Disease; Elderly; Elements; Environment; Event; Functional disorder; Future; Goals; Health; Histology; Human; Immunohistochemistry; Impaired cognition; Impairment; Knowledge; Laboratories; Life; Link; Long-Term Potentiation; Longitudinal Studies; Manuscripts; Mediating; Memory; Memory impairment; Mind; Molecular; Monoclonal Antibodies; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Outcome; Pathway interactions; Patients; Peptides; Performance; Play; Production; Proteins; Psyche structure; Publications; Publishing; Research; Research Personnel; Rodent; Role; Sampling; Senile Plaques; Severities; Severity of illness; Signal Transduction; Societies; Staging; Suggestion; Synaptic plasticity; Testing; Tg2576; Therapeutic; TimeLine; Tissues; Toxic effect; Transgenic Mice; Western Blotting; Work; abeta accumulation; base; behavior test; calcineurin phosphatase; conditioned fear; cost; depressed; depression; effective therapy; follow-up; inhibitor/antagonist; member; mouse model; multidisciplinary; neuron loss; neurotoxic; neurotoxicity; novel; object recognition; offender; prevent; protein aggregate; research study; secretase; therapeutic target; tool

Alzheimer's Disease (AD) is an age-associated dementia for which there is currently no cure. AD is characterized by memory deficits, loss of CNS neurons, and eventually death. One of the prominent events in AD is the CNS presence of plaques that are mostly formed by large macromolecular aggregates of insoluble fibrillar amyloid beta (Aj3), a 40 or 42 aminoacid-Iong peptide resulting from atypical cleavage of the larger amyloid precursor protein (APP). However, mouse models of AD have shown that memory deficits occur in the absence of neuronal loss and long before plaque deposition; furthermore in humans, total CNS levels of Aj3, rather than number of amyloid plaques, correlate with the degree of disease severity, thus suggesting that soluble, non plaque associated, small forms of Aj3 may be the principal offender in the AD brain. Indeed, recent evidence has shown that specific oligomeric forms of Aj3 perturb synaptic plasticity, depress long term potentiation (L TP) and induce transient memory deficits in rodents. On this basis, there is consensus that preventing oligomeric Aj3 toxicity would be a significant therapeutic step to reverse cognitive deficits and hopefully prevent later neurodegeneration in AD. Thus, understanding the yet unclear cellular mechanisms mediating oligomeric Aj3-promoted memory deficits, the overall goal of this research, is important for the development of future therapies for AD. The central hypothesis of this project is that a key mechanism mediating oligomeric Aft neurotoxicity is the aberrant activation of the phosphatase calcineurin (CaN), a signaling element abundant in the CNS that plays a fundamental role in memory function. This hypothesis has been formulated based on preliminary data and published results showing that CaN is up-regulated in the CNS of APP transgenic mice (Tg2576), coincident with the appearance of oligomeric Aj3 and memory impairments, and that acute inhibition of CaN reverses memory deficits in these mice. The objective of this project is therefore to determine the role played by CaN in mediating the cognitive effects of oligomeric Aj3. This objective will be achieved by pursuing the following specific aim: test the hypothesis that there exist a causal link between the occurrence of oligomeric Aj3 and increased CaN activity in the CNS of ageing Tg2576 APP transgenic mice as a function of age, deteriorating cognitive performance and appearance of amyloid plaques. Once completed, this project will have identified CaN as a crucial element mediating the cognitive outcomes of oligomeric Aj3. Acquiring this new knowledge is important for the future development of effective therapies for AD.

阿尔茨海默氏病（AD）是一种与年龄相关的痴呆症，目前无法治愈。 AD的特征是记忆缺陷，中枢神经系统神经元的丧失以及最终死亡。 AD中的一个突出事件之一是CNS存在斑块，这些斑块主要由不溶性纤维纤维淀粉样β（AJ3）（40或42个氨基酸二离子肽）的大型大分子骨料形成，这是由较大淀粉样蛋白蛋白质蛋白（App）的非典型裂解而产生的。但是，AD的小鼠模型表明，记忆缺陷在没有神经元丧失的情况下发生，并且在斑块沉积之前很久。此外，在人类中，总CNS水平 AJ3而不是数量的淀粉样斑块与疾病的严重程度相关，因此表明可溶性，非斑块相关的AJ3的小型AJ3可能是AD大脑中的主要罪犯。实际上，最近的证据表明，AJ3的特定寡聚形式均匀突触可塑性，降低长期增强（L TP）并诱导啮齿动物中的短暂记忆缺陷。在此基础上，有共识，预防寡聚AJ3毒性将是逆转认知缺陷的重要治疗步骤，并希望防止AD中后来的神经变性。因此，理解介导的寡聚AJ3促进记忆缺陷的尚未清晰的细胞机制，这是这项研究的总体目标，对于开发AD的未来疗法至关重要。该项目的中心假设是介导寡聚后的神经毒性的关键机制是磷酸酶钙调蛋白（CAN）的异常激活，CNS中丰富的信号传导元件在记忆功能中起着基本作用。该假设是根据初步数据和发布结果提出的，表明可以在 APP转基因小鼠的中枢神经系统（TG2576），与寡聚AJ3和记忆障碍的出现相吻合，并且对急性抑制可以逆转这些小鼠的记忆缺陷。因此，该项目的目的是确定CAN在介导寡聚AJ3的认知作用中所起的作用。这一目标将通过追求以下特定目的来实现：检验以下假设：寡聚AJ3的发生与衰老TG2576的中枢神经系统的发生之间存在因果关系。 APP转基因小鼠随着年龄的函数，淀粉样斑块的认知性能和外观恶化。完成后，该项目将确定可以将可以作为介导的寡聚AJ3认知结果的关键要素。获取这种新知识对于未来开发AD疗法的发展很重要。