Familial forms of Alzheimer’s disease (AD) are caused by mutations in the presenilin genes or in the gene encoding for the amyloid precursor protein (APP). Proteolytic cleavage of APP generates the β-amyloid peptide (Aβ), which aggregates into amyloid plaques, one of the major hallmarks of AD. APP mutations within the Aβ sequence, so-called intra-Aβ mutations, cluster around position E693 of APP, which corresponds to position E22 in the Aβ sequence. One of these mutations is the Osaka mutation, E693Δ, which has unique aggregation properties with patients showing unusually low brain amyloid levels on amyloid PET scans. Despite intense research on the pathomechanisms of different intra-Aβ mutants, our knowledge is limited due to controversial findings in various studies. Here, we investigated in an ex vivo experimental system the neuro- and synaptotoxic properties of two intra-Aβ mutants with different intrinsic aggregation propensities, the Osaka mutation E22Δ and the Arctic mutation E22G, and compared them to wild-type (wt) Aβ. Experiments in hippocampal slice cultures from transgenic mice were complemented by treating wild-type slices with recombinantly produced Aβ40 or Aβ42 containing the respective intra-Aβ mutations. Our analyses revealed that wt Aβ and E22G Aβ, both recombinant and transgenic, caused a loss of dendritic spines along with an increase in tau phosphorylation and tau-dependent neurodegeneration. In all experiments, the 42-residue variants of wt and E22G Aβ showed stronger effects than the respective Aβ40 isoforms. In contrast, E22Δ Aβ neither reduced dendritic spine density nor resulted in increased tau phosphorylation or neuronal cell death in our ex vivo system. Our findings suggest that the previously reported major differences in the aggregation kinetics between E22G and E22Δ Aβ are likely reflected in different disease pathomechanisms.

家族形式的阿尔茨海默氏病（AD）是由早老素基因或编码淀粉样前体蛋白（APP）的基因中的突变引起的。APP的蛋白水解切割产生β-淀粉样肽（Aβ），其聚集成淀粉样斑块，这是AD的主要标志之一。Aβ序列内的APP突变（所谓的Aβ内突变）聚集在APP的E693位置周围，该位置对应于Aβ序列中的E22位置。这些突变之一是大阪突变E693Δ，它具有独特的聚集特性，患者在淀粉样蛋白PET扫描中显示出异常低的脑淀粉样蛋白水平。尽管对不同的Aβ内突变体的致病机理进行了深入研究，但由于各种研究中的争议性研究，我们的知识仍然有限。在这里，我们进行了离体调查实验系统对两个具有不同内在聚集倾向的Aβ内Aβ突变体（大阪突变E22Δ和北极突变E22G）的神经和突触毒性进行了比较，并将它们与野生型（wt）Aβ进行了比较。对转基因小鼠海马切片培养物中的实验进行了补充，方法是用重组产生的含有各自内部Aβ突变的Aβ40或Aβ42处理野生型切片。我们的分析显示，重组和转基因的wtAβ和E22GAβ引起树突棘的丧失，以及tau磷酸化和tau依赖性神经变性的增加。在所有实验中，wt和E22GAβ的42个残基变异体均比各自的Aβ40亚型表现出更强的作用。相反，离体系统。我们的发现表明，先前报道的E22G和E22ΔAβ之间聚集动力学的主要差异可能反映在不同的疾病发病机制中。