Alzheimer′s disease (AD) is the most common age-related neurodegenerative disorder in which learning, memory and cognitive functions decline progressively. Familial forms of AD (FAD) are caused by mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes. Presenilin 1 (PS1) and its homologue, presenilin 2 (PS2), represent, alternatively, the catalytic core of the γ-secretase complex that, by cleaving APP, produces neurotoxic amyloid beta (Aβ) peptides responsible for one of the histopathological hallmarks in AD brains, the amyloid plaques. Recently, PSEN1 FAD mutations have been associated with a loss-of-function phenotype. To investigate whether this finding can also be extended to PSEN2 FAD mutations, we studied two processes known to be modulated by PS2 and altered by FAD mutations: Ca²⁺ signaling and mitochondrial function. By exploiting neurons derived from a PSEN2 knock-out (PS2–/–) mouse model, we found that, upon IP₃-generating stimulation, cytosolic Ca²⁺ handling is not altered, compared to wild-type cells, while mitochondrial Ca²⁺ uptake is strongly compromised. Accordingly, PS2–/– neurons show a marked reduction in endoplasmic reticulum–mitochondria apposition and a slight alteration in mitochondrial respiration, whereas mitochondrial membrane potential, and organelle morphology and number appear unchanged. Thus, although some alterations in mitochondrial function appear to be shared between PS2–/– and FAD-PS2-expressing neurons, the mechanisms leading to these defects are quite distinct between the two models. Taken together, our data appear to be difficult to reconcile with the proposal that FAD-PS2 mutants are loss-of-function, whereas the concept that PS2 plays a key role in sustaining mitochondrial function is here confirmed.

中文翻译：

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早老素 2 基因敲除小鼠的钙信号传导和线粒体功能：寻找与阿尔茨海默病相关的任何功能丧失表型

阿尔茨海默病 (AD) 是最常见的与年龄相关的神经退行性疾病，其中学习、记忆和认知功能进行性下降。家族性 AD (FAD) 是由淀粉样前体蛋白 ( APP )、早老素 1 ( PSEN1 ) 和早老素 2 ( PSEN2 ) 基因突变引起的。早老素 1 (PS1) 及其同系物早老素 2 (PS2) 代表了 γ-分泌酶复合物的催化核心，该复合物通过裂解 APP，产生神经毒性淀粉样蛋白 β (Aβ) 肽，负责以下组织病理学标志之一： AD大脑，淀粉样斑块。最近，PSEN1 FAD 突变与功能丧失表型有关。调查这一发现是否也可以扩展到PSEN2 FAD 突变，我们研究了两个已知受 PS2 调节并受 FAD 突变改变的过程：Ca ²⁺信号传导和线粒体功能。通过利用源自PSEN2敲除 (PS2–/–) 小鼠模型的神经元，我们发现，在产生IP _{3 的}刺激下，与野生型细胞相比，细胞溶质 Ca ^{2+ 的}处理没有改变，而线粒体 Ca ^{2 +}吸收受到严重损害。因此，PS2-/- 神经元的内质网-线粒体并列显着减少，线粒体呼吸略有改变，而线粒体膜电位、细胞器形态和数量似乎没有变化。因此，尽管线粒体功能的一些改变似乎在 PS2–/– 和 FAD-PS2 表达神经元之间共享，但导致这些缺陷的机制在两种模型之间是截然不同的。总之，我们的数据似乎难以与 FAD-PS2 突变体功能丧失的提议相协调，而 PS2 在维持线粒体功能中起关键作用的概念在这里得到证实。