Alzheimer's disease amyloid-β pathology in the lens of the eye.
Alzheimer's disease amyloid-β pathology in the lens of the eye.
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DOI：
10.1016/j.exer.2022.108974
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发表时间：
2022-08
影响因子：
3.4
通讯作者：
Goldstein, Lee E.
中科院分区：
文献类型：
--
作者：
Moncaster, Juliet A.;Moir, Robert D.;Burton, Mark A.;Chadwick, Oliver;Minaeva, Olga;Alvarez, Victor E.;Ericsson, Maria;Clark, John I.;McKee, Ann C.;Tanzi, Rudolph E.;Goldstein, Lee E.
关键词：
阿尔茨海默病（AD）的神经病理学特征包括淀粉样蛋白-β (Aβ)肽的致病性积累和大脑中淀粉样蛋白斑块的年龄依赖性形成。ad相关的Aβ神经病理在认知症状出现前几十年就开始了，并在疾病过程中缓慢进展。我们之前报道了在AD患者的晶状体中发现Aβ沉积、β-淀粉样变性和核上性白内障（SNC）共定位，但没有其他神经退行性疾病或正常衰老。我们通过免疫组织病理学、淀粉样蛋白组织化学、免疫印迹分析、表位定位、免疫金电子显微镜、定量免疫分析和胰蛋白酶消化质谱肽测序证实了晶状体中ad相关的Aβ分子病理学。超微结构分析表明，AD晶状体中AD相关的Aβ沉积在核上（深皮层）纤维细胞的细胞质中以电子密集微聚集体的形式存在。这些Aβ微聚集体还含有α b -晶体蛋白和散射光，从而将AD患者晶状体中的Aβ病理和SNC表型表达联系起来。随后的研究发现，a β晶状体病理是与唐氏综合征（DS， 21三体）相关的独特白内障的分子起源，唐氏综合征是一种与早发性a β积累和大脑中a β淀粉样变性始终相关的染色体疾病。弗雷明汉眼科研究对1249名参与者的调查发现，大脑和晶状体中与ad相关的数量特征是共同遗传的。此外，与AD相关的晶状体特征比MRI脑特征和认知缺陷早十年或更长时间，并预测未来的AD。一项针对同一受试者的双变量结果的全基因组关联研究发现，在编码δ-catenin的CTNND2基因中发现了一个新的AD危险因素位点，δ-catenin是一种调节大脑和晶状体中Aβ产生的蛋白质。在Tg2576转基因AD小鼠模型中，我们发现了AD相关的人Aβ (hAβ)晶状体病理和年龄依赖性SNC表型表达。Tg2576小鼠表达瑞典突变型人类淀粉样蛋白前体蛋白（APP-Swe），在大脑中积累hAβ肽和淀粉样蛋白病理，并表现出随着年龄增长缓慢进展的认知缺陷。我们发现Tg2576转基因（Tg+）小鼠，而非转基因（Tg−）对照小鼠，也表达人APP，积累hAβ肽，并在晶状体中出现hAβ分子和超微结构病变。Tg2576 Tg+小鼠表现出年龄依赖性的Aβ核上晶状体混浊，再现了人类AD的晶状体病理和SNC表型表达。此外，我们在Tg+小鼠制备的晶状体外植体培养物的条件培养基中检测到hAβ，而在Tg -对照小鼠中检测不到，这一发现与晶状体中本构性hAβ的产生一致。体外研究表明，准弹性光散射（QLS）光谱检测表明，hAβ促进小鼠晶状体蛋白聚集。这些结果支持晶状体和大脑中Aβ病理与ad相关表型之间的机制（基因型-表型）联系。总的来说，我们的研究结果在Tg2576转基因AD小鼠模型中确定了Aβ病理是两种年龄依赖性AD相关白内障的共同分子病因，这些白内障与两种人类疾病（AD， DS）和同源小鼠白内障相关。这些结果代表了大脑外AD相关的Aβ病理的第一个证据，并指出晶状体Aβ是一种光学可及的AD生物标志物，可用于这种破坏性神经退行性疾病的早期检测和纵向监测。
Neuropathological hallmarks of Alzheimer’s disease (AD) include pathogenic accumulation of amyloid-β (Aβ) peptides and age-dependent formation of amyloid plaques in the brain. AD-associated Aβ neuropathology begins decades before onset of cognitive symptoms and slowly progresses over the course of the disease. We previously reported discovery of Aβ deposition, β-amyloidopathy, and co-localizing supranuclear cataracts (SNC) in lenses from people with AD, but not other neurodegenerative disorders or normal aging. We confirmed AD-associated Aβ molecular pathology in the lens by immunohistopathology, amyloid histochemistry, immunoblot analysis, epitope mapping, immunogold electron microscopy, quantitative immunoassays, and tryptic digest mass spectrometry peptide sequencing. Ultrastructural analysis revealed that AD-associated Aβ deposits in AD lenses localize as electron-dense microaggregates in the cytoplasm of supranuclear (deep cortex) fiber cells. These Aβ microaggregates also contain αB-crystallin and scatter light, thus linking Aβ pathology and SNC phenotype expression in the lenses of people with AD. Subsequent research identified Aβ lens pathology as the molecular origin of the distinctive cataracts associated with Down syndrome (DS, trisomy 21), a chromosomal disorder invariantly associated with early-onset Aβ accumulation and Aβ amyloidopathy in the brain. Investigation of 1249 participants in the Framingham Eye Study found that AD-associated quantitative traits in brain and lens are co-heritable. Moreover, AD-associated lens traits preceded MRI brain traits and cognitive deficits by a decade or more and predicted future AD. A genome-wide association study of bivariate outcomes in the same subjects identified a new AD risk factor locus in the CTNND2 gene encoding δ-catenin, a protein that modulates Aβ production in brain and lens. Here we report identification of AD-related human Aβ (hAβ) lens pathology and age-dependent SNC phenotype expression in the Tg2576 transgenic mouse model of AD. Tg2576 mice express Swedish mutant human amyloid precursor protein (APP-Swe), accumulate hAβ peptides and amyloid pathology in the brain, and exhibit cognitive deficits that slowly progress with increasing age. We found that Tg2576 trangenic (Tg+) mice, but not non-transgenic (Tg−) control mice, also express human APP, accumulate hAβ peptides, and develop hAβ molecular and ultrastructural pathologies in the lens. Tg2576 Tg+ mice exhibit age- dependent Aβ supranuclear lens opacification that recapitulates lens pathology and SNC phenotype expression in human AD. In addition, we detected hAβ in conditioned medium from lens explant cultures prepared from Tg+ mice, but not Tg− control mice, a finding consistent with constitutive hAβ generation in the lens. In vitro studies showed that hAβ promoted mouse lens protein aggregation detected by quasi-elastic light scattering (QLS) spectroscopy. These results support mechanistic (genotype-phenotype) linkage between Aβ pathology and AD-related phenotypes in lens and brain. Collectively, our findings identify Aβ pathology as the shared molecular etiology of two age-dependent AD-related cataracts associated with two human diseases (AD, DS) and homologous murine cataracts in the Tg2576 transgenic mouse model of AD. These results represent the first evidence of AD-related Aβ pathology outside the brain and point to lens Aβ as an optically-accessible AD biomarker for early detection and longitudinal monitoring of this devastating neurodegenerative disease.
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DOI：
10.3233/jad-2012-120730
发表时间：
2012
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Chhatwal JP;Sperling RA
通讯作者：
Sperling RA
影响因子：
3.4
作者：
Augusteyn, Robert C.
通讯作者：
Augusteyn, Robert C.
影响因子：
2.1
作者：
Camarda, Cecilia;Torelli, Paola;Camarda, Rosolino
通讯作者：
Camarda, Rosolino
影响因子：
56.9
作者：
BUSH, AI;PETTINGELL, WH;TANZI, RE
通讯作者：
TANZI, RE
影响因子：
82.9
作者：
Backskai, BJ;Kajdasz, ST;Hyman, BT
通讯作者：
Hyman, BT