Aβ43 levels determine the onset of pathological amyloid deposition.
Aβ43 levels determine the onset of pathological amyloid deposition.
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DOI：
10.1016/j.jbc.2023.104868
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发表时间：
2023-07
影响因子：
4.8
通讯作者：
D'Adamio, Luciano
中科院分区：
文献类型：
--
作者：
Tambini, Marc D.;Yin, Tao;Yesiltepe, Metin;Breuillaud, Lionel;Zehntner, Simone P.;d'Abramo, Cristina;Giliberto, Luca;D'Adamio, Luciano
大约2%的阿尔茨海默病（AD）病例具有早发性（FAD），并且由早老素（PSEN 1/2）或淀粉样蛋白-β前体蛋白（APP）中的突变引起。PSEN 1/2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的特征性病理损伤。PSEN 1/2和APP突变影响Aβ肽组成的机制分析表明，在淀粉样β斑块形成中Aβ42绝对或相对增加。在此，为了阐明导致淀粉样蛋白病理学的致病性Aβ鸡尾酒的形成，我们利用携带瑞典APP（Apps等位基因）和PSEN 1 L435 F（Psen 1 LF等位基因）突变的FAD大鼠基因敲入模型。为了适应啮齿类动物和人Aβ致病性的差异，这些大鼠模型经基因工程改造以表达人Aβ物种，因为Swedish突变等位基因和WT大鼠等位基因（称为Apph）均已在Aβ编码区进行人源化。对8种可能的FAD突变排列的分析表明，CNS中Aβ43的水平（而非Aβ42的绝对或相对增加）决定了FAD基因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基因敲入大鼠中启动淀粉样病变的机制反映了迟发性AD中驱动淀粉样病变的疾病机制。这项研究有助于阐明启动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。
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.
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影响因子：
82.9
作者：
Citron, M;Westaway, D;Selkoe, DJ
通讯作者：
Selkoe, DJ
影响因子：
30.8
作者：
MULLAN, M;CRAWFORD, F;LANNFELT, L
通讯作者：
LANNFELT, L
影响因子：
3.5
作者：
JOHNSTON, JA;COWBURN, RF;ONEILL, C
通讯作者：
ONEILL, C
影响因子：
4.8
作者：
Lauridsen, Camilla;Sando, Sigrid B.;White, Linda R.
通讯作者：
White, Linda R.
影响因子：
4.8
作者：
Fernandez, Marty A.;Klutkowski, Julia A.;Wolfe, Michael S.
通讯作者：
Wolfe, Michael S.