An Essential Role for Alzheimer's-Linked Amyloid Beta Oligomers in Neurodevelopment: Transient Expression of Multiple Proteoforms during Retina Histogenesis.
An Essential Role for Alzheimer's-Linked Amyloid Beta Oligomers in Neurodevelopment: Transient Expression of Multiple Proteoforms during Retina Histogenesis.
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DOI：
10.3390/ijms23042208
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发表时间：
2022-02-17
影响因子：
5.6
通讯作者：
Klein WL
中科院分区：
文献类型：
--
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
人淀粉样β蛋白(Aβ)是一种脑部分解代谢产物，在纳摩尔浓度下可形成神经毒性寡聚体(AβOs)，已知在阿尔茨海默病中积累。由于形成神经毒素的倾向似乎令人惊讶，我们调查了是否存在AβO积聚实际上可能有益的情况。我们的研究集中在鸡的胚胎视网膜上，它表达与人类相同的Aβ。利用构象选择抗体、免疫印迹、质谱学和荧光显微镜，我们发现AβOs确实存在于发育中的视网膜中，在那里多种蛋白形式以高度调控的细胞特异性方式表达。AβO蛋白形式的表达选择性地与瞬时表达的磷酸化Tau蛋白形式有关，与AβO蛋白形式一样，与阿尔茨海默病(AD)有关。为了测试AβOs在发育过程中是否起作用，对胚胎进行体外培养，然后在玻璃体内注射β位点裂解酶1抑制剂或AβO选择性抗体，以过早降低AβOs的水平。其结果是扰乱了组织发生，导致了类似于各种视网膜病理的异常增生。我们提出的假设是，胚胎AβOs是一种新型的短命多肽能激素，在神经发育中起作用。这样的作用可以帮助解释为什么在老化的大脑中寡聚时表现出有害的功能获得活性的多肽在进化上是保守的。
Human amyloid beta peptide (Aβ) is a brain catabolite that at nanomolar concentrations can form neurotoxic oligomers (AβOs), which are known to accumulate in Alzheimer’s disease. Because a predisposition to form neurotoxins seems surprising, we have investigated whether circumstances might exist where AβO accumulation may in fact be beneficial. Our investigation focused on the embryonic chick retina, which expresses the same Aβ as humans. Using conformation-selective antibodies, immunoblots, mass spectrometry, and fluorescence microscopy, we discovered that AβOs are indeed present in the developing retina, where multiple proteoforms are expressed in a highly regulated cell-specific manner. The expression of the AβO proteoforms was selectively associated with transiently expressed phosphorylated Tau (pTau) proteoforms that, like AβOs, are linked to Alzheimer’s disease (AD). To test whether the AβOs were functional in development, embryos were cultured ex ovo and then injected intravitreally with either a beta-site APP-cleaving enzyme 1 (BACE-1) inhibitor or an AβO-selective antibody to prematurely lower the levels of AβOs. The consequence was disrupted histogenesis resulting in dysplasia resembling that seen in various retina pathologies. We suggest the hypothesis that embryonic AβOs are a new type of short-lived peptidergic hormone with a role in neural development. Such a role could help explain why a peptide that manifests deleterious gain-of-function activity when it oligomerizes in the aging brain has been evolutionarily conserved.
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影响因子：
5.6
作者：
Cohn W;Melnik M;Huang C;Teter B;Chandra S;Zhu C;McIntire LB;John V;Gylys KH;Bilousova T
通讯作者：
Bilousova T
大脑中淀粉样β低聚物的生物发生和生物学。
DOI：
10.1002/alz.12084
发表时间：
2020-11
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Ashe KH
通讯作者：
Ashe KH
DOI：
10.3233/jad-179941
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Cline EN;Bicca MA;Viola KL;Klein WL
通讯作者：
Klein WL
DOI：
10.1046/j.1432-1327.1999.00886.x
发表时间：
1999-12-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Caswell, MD;San Mok, S;Small, DH
通讯作者：
Small, DH
老年痴呆症中肾上腺素能投射到大脑皮层（脑室核）的起源神经元的缺失
影响因子：
9.9
作者：
BONDAREFF, W;MOUNTJOY, CQ;ROTH, M
通讯作者：
ROTH, M