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Aβ43 levels determine the onset of pathological amyloid deposition
Journal of Biological Chemistry ( IF 5.5 ) Pub Date : 2023-05-29 , DOI: 10.1016/j.jbc.2023.104868
Marc D Tambini 1 , Tao Yin 1 , Metin Yesiltepe 1 , Lionel Breuillaud 2 , Simone P Zehntner 2 , Cristina d'Abramo 3 , Luca Giliberto 4 , Luciano D'Adamio 1
Affiliation  

About 2% of Alzheimer’s disease (AD) cases have early onset (FAD) and are caused by mutations in either Presenilins (PSEN1/2) or amyloid-β precursor protein (APP). PSEN1/2 catalyze production of Aβ peptides of different length from APP. Aβ peptides are the major components of amyloid plaques, a pathological lesion that characterizes AD. Analysis of mechanisms by which PSEN1/2 and APP mutations affect Aβ peptide compositions lead to the implication of the absolute or relative increase in Aβ42 in amyloid-β plaques formation. Here, to elucidate the formation of pathogenic Aβ cocktails leading to amyloid pathology, we utilized FAD rat knock-in models carrying the Swedish APP (Apps allele) and the PSEN1 L435F (Psen1LF allele) mutations. To accommodate the differences in the pathogenicity of rodent and human Aβ, these rat models are genetically engineered to express human Aβ species as both the Swedish mutant allele and the WT rat allele (called Apph) have been humanized in the Aβ-coding region. Analysis of the eight possible FAD mutant permutations indicates that the CNS levels of Aβ43, rather than absolute or relative increases in Aβ42, determine the onset of pathological amyloid deposition in FAD knock-in rats. Notably, Aβ43 was found in amyloid plaques in late onset AD and mild cognitive impairment cases, suggesting that the mechanisms initiating amyloid pathology in FAD knock-in rat reflect disease mechanisms driving amyloid pathology in late onset AD. This study helps clarifying the molecular determinants initiating amyloid pathology and supports therapeutic interventions targeting Aβ43 in AD.



中文翻译:

Aβ43 水平决定病理性淀粉样蛋白沉积的发生

大约 2% 的阿尔茨海默病 (AD) 病例为早发 (FAD),由早老素( PSEN1/2)淀粉样蛋白-β 前体蛋白 (APP )突变引起。PSEN1/2 催化 APP 产生不同长度的 Aβ 肽。Aβ 肽是淀粉样斑块的主要成分,淀粉样斑块是 AD 的一种病理病变。对 PSEN1/2 和 APP 突变影响 Aβ 肽组成的机制的分析表明,淀粉样蛋白斑块形成中 Aβ42 的绝对或相对增加。在这里,为了阐明导致淀粉样蛋白病理学的致病性 Aβ 混合物的形成,我们利用携带瑞典APPApp s等位基因)和PSEN1 L435FPsen1 LF等位基因)突变的FAD 大鼠敲入模型。为了适应啮齿动物和人类 Aβ 致病性的差异,这些大鼠模型经过基因工程改造以表达人类 Aβ 物种,因为瑞典突变等位基因和 WT 大鼠等位基因(称为 App h )已在 Aβ 编码区人。对八种可能的 FAD 突变排列的分析表明,Aβ43 的 CNS 水平,而不是 Aβ42 的绝对或相对增加,决定了 FAD 敲入大鼠中病理性淀粉样蛋白沉积的发生。值得注意的是,在迟发性 AD 和轻度认知障碍病例的淀粉样斑块中发现了 Aβ43,这表明 FAD 敲入大鼠中淀粉样蛋白病理的启动机制反映了晚发性 AD 中驱动淀粉样蛋白病理的疾病机制。这项研究有助于阐明引发淀粉样蛋白病理学的分子决定因素,并支持针对 AD 中 Aβ43 的治疗干预措施。

更新日期:2023-05-29
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