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，进化保留了有利于形成人类Aβ42肽的氨基酸序列， 大的同源寡聚体。人们普遍认为这些不寻常的分子是致病的。这些低聚物 在人类和动物模型脑组织中以阿尔茨海默病依赖性方式积累。他们有 实验表明，它以一种导致记忆功能障碍和重演的方式影响中枢神经系统。 AD神经病理学（例如，tau蛋白过度磷酸化，神经炎症，突触丢失，选择性神经细胞 死亡）。病理性AβO积聚开始于疾病早期，在斑块之前，但在健康人群中并不明显， 非痴呆的成年人在体外，有毒的Aβ O很容易从纳摩尔浓度的合成人 Aβ。在某些动物物种中发现了相同的寡聚体形成序列（例如，非人类灵长类动物，兔子， 鸡，但不是啮齿动物）。奇怪的是，这些物种保留了明显危险的能力， 形成引发神经损伤导致AD痴呆的分子。目前的项目涉及 AβOs在功能性、生理性方面存在的可能性。在漫长的- 运行，确定这种情况预计将提供一个新的视角到触发器， AD中毒性AβO积聚的机制。检验的工作假设是AβOs具有短暂的功能性 在中枢神经系统发育过程中的作用，初步研究结果强烈支持的可能性。蛋白质印迹和 免疫组化显示发育中的鸡存在AβOs，其Aβ序列与 人类胚胎视网膜中的AβOs选择性地由神经节细胞表达，这在某种程度上值得注意， 同样显示在AD丝氨酸-396位点磷酸化的tau的存在。关于这个函数，我们一无所知。 发育调节的AβOs，但它是可行的，发育的影响可能类似于 在成人大脑中观察到的病理影响。从另一个角度来看，当Aβ O在 成年人，他们影响脑组织的方式重新投降的发展功能。发展功能 因此，Aβ O可能包括，例如，刺激tau过度磷酸化、小胶质增生、突触修剪或 选择性神经细胞死亡本研究以发育中的鸡视网膜为实验材料，对上述假说进行了验证。 目的1.确定特定AβO种类的发病、峰值表达和消失模式 视网膜发育过程中AD样tau蛋白过度磷酸化和小胶质细胞分化。 目的2.探讨短暂性AβOs对视网膜细胞发育的影响，尤其是AβOs对视网膜细胞发育的影响。 小胶质细胞和tau蛋白过度磷酸化。 结果预计将确定阿尔茨海默病相关的Aβ O在发育过程中发挥生理作用。 鸡胚是研究AβO调控的理想模型 表达和正常AβO功能，包括其与tau蛋白和小胶质细胞的关系。通过实现第一次洞察 通过对正常AβO生物学的深入研究，有望对AβO病理生物学有新的、更深入的认识。

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