Laboratory for Membrane Trafficking, VIB Center for Brain and Disease Research, Leuven, Belgium.
Department of Neurosciences, KU Leuven, Herestraat 49box 602, Leuven, Belgium.
Nat Commun. 2024 Nov 29;15(1):10412. doi: 10.1038/s41467-024-54777-y.
Rare mutations in the gene encoding presenilin2 (PSEN2) are known to cause familial Alzheimer's disease (FAD). Here, we explored how altered PSEN2 expression impacts on the amyloidosis, endolysosomal abnormalities, and synaptic dysfunction observed in female APP knock-in mice. We demonstrate that PSEN2 knockout (KO) as well as the FAD-associated N141IKI mutant accelerate AD-related pathologies in female mice. Both models showed significant deficits in working memory that linked to elevated PSEN2 expression in the hippocampal CA3 region. The mossy fiber circuit of APPxPSEN2KO and APPxFADPSEN2 mice had smaller pre-synaptic compartments, distinct changes in synaptic vesicle populations and significantly impaired long term potentiation compared to APPKI mice. At the cellular level, altered PSEN2 expression resulted in endolysosomal defects and lowered surface expression of synaptic proteins. As PSEN2/γ-secretase is restricted to late endosomes/lysosomes, we propose PSEN2 impacts endolysosomal homeostasis, affecting synaptic signaling in AD-relevant vulnerable brain circuits; which could explain how mutant PSEN2 accelerates AD pathogenesis.
编码早老素 2（PSEN2）的基因罕见突变已知会导致家族性阿尔茨海默病（FAD）。在这里，我们探讨了 PSEN2 表达的改变如何影响在雌性 APP 基因敲入小鼠中观察到的淀粉样变性、内溶酶体异常和突触功能障碍。我们证明 PSEN2 敲除（KO）以及与 FAD 相关的 N141IKI 突变加速了雌性小鼠的 AD 相关病变。这两种模型均显示出工作记忆的明显缺陷，这与海马 CA3 区 PSEN2 表达升高有关。与 APPKI 小鼠相比，APPxPSEN2KO 和 APPxFADPSEN2 小鼠的苔藓纤维电路的突触前小泡体积明显减小，突触小泡群体发生明显变化，长时程增强明显受损。在细胞水平上，改变的 PSEN2 表达导致内溶酶体缺陷和突触蛋白表面表达降低。由于 PSEN2/γ-分泌酶仅限于晚期内体/溶酶体，我们提出 PSEN2 影响内溶酶体平衡，影响 AD 相关易损脑回路中的突触信号；这可以解释为什么突变 PSEN2 会加速 AD 的发病机制。
