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的人类Aβ42肽的氨基酸序列

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