INTRODUCTIONThough recognized as a potential cause of autosomal dominant Alzheimer's disease, the pathogenicity of many PSEN2 variants remains uncertain. We compared amyloid beta (Aβ) production across all missense PSEN2 variants in the AlzForum database and, when possible, to corresponding PSEN1 variants.METHODSWe expressed 74 PSEN2 variants, 21 of which had known, homologous PSEN1 pathogenic variants with the same amino acid substitution, in HEK293 cells lacking presenilin 1/2. Aβ production was compared to age at symptom onset (AAO) and between PSEN1/2 homologs.RESULTSAβ42/40 and Aβ37/42 ratios correlated with AAO across all PSEN2 variants, strongly driven by the subset of PSEN2 variants with PSEN1 homologs. Aβ production across PSEN1/2 homologs was highly correlated. PSEN2 AAO correlated with AAO in PSEN1 homologs but was an average of 18.3 years later.DISCUSSIONThe existence of a PSEN1 homolog and patterns of Aβ production are important considerations in assessing the pathogenicity of previously reported and new PSEN2 variants.Highlights There were associations between the patterns of amyloid beta (Aβ) production across presenilin 2 (PSEN2) variants and age at symptom onset (AAO). PSEN2 variants for which there is a known, corresponding variant in presenilin 1 (PSEN1) are more likely to have abnormal Aβ production patterns that strongly correlate with AAO, compared to those that lack a known PSEN1 counterpart (“non‐homologous PSEN2 variants”). Most PSEN2 variants lacking PSEN1 counterparts had Aβ42/40 ratios close to those of wild‐type PSN2, arguing against their pathogenicity. Homologous PSEN1 and PSEN2 variants had correlated Aβ42/40 and Aβ37/42 ratios, indicating that the corresponding amino acid substitution in each presenilin may have largely similar biochemical effects on γ‐secretase processivity.

中文翻译：

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PSEN2 变体的致病性与 Aβ 的产生和与 PSEN1 的同源性有关


引言虽然被认为是常染色体显性遗传性阿尔茨海默病的潜在原因，但许多 PSEN2 变体的致病性仍不确定。我们比较了 AlzForum 数据库中所有错义 PSEN2 变体的淀粉样蛋白 β （Aβ） 产生，并在可能的情况下与相应的 PSEN1 变体进行了比较。方法在缺乏早老素 1/2 的 HEK293 细胞中表达了 74 个 PSEN2 变体，其中 21 个具有已知的具有相同氨基酸取代的同源 PSEN1 致病性变体。将 Aβ 产生与症状发作年龄 （AAO） 和 PSEN1/2 同源物之间进行比较。结果在所有 PSEN2 变体中，Aβ42/40 和 Aβ37/42 比率与 AAO 相关，这在很大程度上是由具有 PSEN1 同源物的 PSEN2 变体子集驱动的。PSEN1/2 同源物的 Aβ 产生高度相关。PSEN2 AAO 与 PSEN1 同源物中的 AAO 相关，但平均在 18.3 年后。讨论PSEN1 同源物的存在和 Aβ 产生的模式是评估先前报道的和新的 PSEN2 变体的致病性的重要考虑因素。亮点早老素 2 （PSEN2） 变体的 β 淀粉样蛋白 （Aβ） 产生模式与症状发作年龄 （AAO） 之间存在关联。与缺乏已知 PSEN1 对应物的 PSEN2 变体（“非同源 PSEN2 变体”）相比，早老素 1 （PSEN1） 中存在已知相应变体的 PSEN2 变体更有可能具有与 AAO 密切相关的异常 Aβ 产生模式。大多数缺乏 PSEN1 对应物的 PSEN2 变体的 Aβ42/40 比率接近野生型 PSN2，反对它们的致病性。 同源 PSEN1 和 PSEN2 变体具有相关的 Aβ42/40 和 Aβ37/42 比率，表明每个早老素中相应的氨基酸取代可能对 γ-分泌酶持续合成能力具有大致相似的生化影响。