Physiological role of naturally-occuring amyloid beta oligomers

天然存在的β淀粉样蛋白寡聚体的生理作用

• 批准号: 9759747
• 负责人: WILLIAM L KLEIN
• 金额: $ 19.29万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759747
• 关键词: Address; Adult; Alzheimer' s Disease; Amino Acid Sequence; Amyloid beta-Protein; Animal Model; Animals; Biology; Brain; Brain Diseases; Chickens; Dangerousness; Dementia; Development; Disease; Embryo; Etiology; Evolution; Experimental Models; Eye diseases; Glaucoma; Homo; Human; Immunohistochemistry; In Vitro; Link; Macular degeneration; Memory impairment; Microglia; Modeling; Nature; Neurologic; Oryctolagus cuniculus; Pathogenicity; Pathologic; Pathology; Pattern; Peptides; Physiological; Regulation; Retina; Role; Serine; Site; Synapses; Testing; Therapeutic; Time; Western Blotting; abeta oligomer; brain tissue; cellular development; experimental study; ganglion cell; human model; insight; nanomolar; neuroinflammation; neuron loss; neuropathology; non-demented; nonhuman primate; relating to nervous system; selective expression; synaptic pruning; tau Proteins; tau phosphorylation; tau-1

Surprisingly, evolution has retained an amino acid sequence for the human Aβ42 peptide that favors formation of large homo-oligomers. It is widely regarded that these unusual molecules are pathogenic. These oligomers accumulate in human and animal model brain tissue in an Alzheimer's disease-dependent manner. They have been shown experimentally to impact the CNS in a manner that causes memory dysfunction and recapitulates AD neuropathology (e.g., tau hyperphosphorylation, neuroinflammation, synapse loss, selective nerve cell death). Pathological AβO buildup begins early in the disease, before plaques, but it is not evident in healthy, non-demented adults. In vitro, toxic AβOs readily assemble from nanomolar concentrations of synthetic human Aβ. The same oligomer-forming sequence is found in certain animal species (e.g., nonhuman primates, rabbit, chicken, but not rodents). It is peculiar that these species have retained the apparently dangerous capacity to form molecules that instigate the neural damage leading to AD dementia. The current project addresses the possibility that circumstances exist whereupon AβOs manifest a functional, physiological presence. In the long- run, determining such circumstances is expected to give a significantly new perspective into the triggers and mechanisms of toxic AβO buildup in AD. The working hypothesis tested is that AβOs have a transient, functional role during CNS development, a possibility strongly supported by preliminary findings. Western blots and immunohistochemistry show the presence of AβOs in the developing chick, whose Aβ sequence is the same as humans. AβOs in embryonic retina are selectively expressed by ganglion cells, which, somewhat remarkably, likewise show a presence of tau phosphorylated at the AD serine-396 site. Nothing is known about the function of the developmentally-regulated AβOs, but it is feasible that the developmental impact may resemble the pathological impact observed in adult brain. Looked at another way, when AβOs re-emerge pathologically in adults, they impact brain tissue in a manner re-capitulating developmental functions. Developmental functions of AβOs thus might comprise, e.g., stimulation of tau hyperphosphorylation, microgliosis, synaptic pruning or selective nerve cell death. The Aims test the hypothesis using developing chick retina for experimentation. Aim 1  Determine the onset, peak expression and disappearance pattern for particular AβO species relative to AD-like tau hyperphosphorylation and microglial differentiation during retina development. Aim 2  Determine the influence that transient AβOs exert on cellular development of retina, particularly with respect to microglia and tau hyperphosphorylation. Results are expected to establish that Alzheimer's-related AβOs serve a physiological role during development. Embryonic chick will be introduced as an exceptionally well-suited model for investigating the regulation of AβO expression and normal AβO function, including its relationship to tau and microglia. By achieving the first insights into normal AβO biology, it is expected that new and deeper insight into AβO pathobiology will be achieved.

令人惊讶的是，进化保留了人类Aβ42胡椒的氨基酸序列，该序列有利于形成 大型同源物。人们普遍认为这些不寻常的分子是致病性的。这些低聚物 以阿尔茨海默氏病的依赖性方式积聚在人类和动物模型的脑组织中。他们有 我们通过实验向我们展示了以导致记忆功能障碍和概括的方式影响中枢神经系统 AD神经病理学（例如Tau高磷酸化，神经炎症，突触丧失，选择性神经细胞 死亡）。病理AβO的积累开始于疾病早期，在斑块之前开始，但不是健康的证据，而是证据 非痴呆的成年人。在体外，有毒Aβ很容易从合成人的纳摩尔浓度组装 Aβ。在某些动物物种（例如，非人类灵长类动物，兔子，， 鸡，但不是啮齿动物）。这些物种保留了明显危险的能力，这是奇特的 形成分子，引起神经损伤导致痴呆症。当前的项目解决了 存在情况的可能性，因此AβOS表现出功能性的物理存在。长期 跑步，确定这种情况有望给触发器和 AD中有毒AβO积累的机制。测试的工作假设是AβOS具有瞬态，功能性 在CNS开发过程中的作用，初步发现强烈支持了这种可能性。蛋白质印迹和 免疫组织化学显示了发育中的小鸡中AβOS的存在，其Aβ序列与 人类。胚胎视网膜中的AβOS由神经节细胞选择性地表达，在某种程度上，它有些明显地表达 同样，在AD丝氨酸-396位点显示了Tau磷酸化的存在。对功能一无所知 在开发的AβOS中，可行的发育影响可能类似于 在成人大脑中观察到的病理影响。望去另一种方式，当AβOS在病理上重新出现在 成年人，他们以一种重新计算发育功能的方式影响脑组织。发展功能 因此，AβOS的刺激可能包括刺激tau高磷酸化，小胶质细胞增多，突触修剪或 选择性神经细胞死亡。目的是使用开发的雏鸡进行实验检验假设。 AIM1确定特定AβO物种相对的发作，峰值表达和消失模式 在视网膜发育过程中进行广告样的tau高磷酸化和小胶质细胞分化。 AIM2确定瞬态AβOS对视网膜细胞发育的影响，特别是在 相对于小胶质细胞和tau高磷酸化。 预计结果将确定阿尔茨海默氏症相关的AβOS在发育过程中发挥了身体作用。 胚胎小鸡将作为一个非常适合研究AβO调节的模型。 表达和正常的AβO功能，包括其与TAU和小胶质细胞的关系。通过实现第一个见解 进入正常的AβO生物学，可以预期将实现对AβO病理生物学的新的和更深入的洞察力。

项目成果

An Essential Role for Alzheimer's-Linked Amyloid Beta Oligomers in Neurodevelopment: Transient Expression of Multiple Proteoforms during Retina Histogenesis.

• DOI: 10.3390/ijms23042208
• 发表时间: 2022-02-17
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Bartley SC;Proctor MT;Xia H;Ho E;Kang DS;Schuster K;Bicca MA;Seckler HS;Viola KL;Patrie SM;Kelleher NL;De Mello FG;Klein WL
• 通讯作者: Klein WL