Mckean Natasha E, Liu Jun, Rudiger Skye R, Kelly Jennifer M, McLaughlan Clive, Verma Paul J, Hardy John, Gusella James F, Zetterberg Henrik, Reid Suzanne J, Handley Renee H, Lehnert Klaus, Sutherland Greg T, Heslegrave Amanda, Veleva Elena, Laban Rhiannon, Pearson John F, Bawden Simon C, Snell Russell G
Applied Translational Genetics Group, School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand.
Stem Cell and Genetic Engineering Group, Monash Institute of Medical Engineering, Faculty of Engineering, Monash University, Victoria 3800, Australia; TIGRR Lab, The School of BioSciences, University of Melbourne, Victoria 3010, Australia.
Neurobiol Aging. 2025 Aug;152:25-33. doi: 10.1016/j.neurobiolaging.2025.04.006. Epub 2025 Apr 25.
Alzheimer's disease (AD) is a neurodegenerative condition and one of the most significant medical challenges today. Dominant mutations causing early-onset AD have been identified in the presenilin 1 and 2 (PSEN1 and PSEN2), and the amyloid precursor protein (APP) genes. Either PSEN1 or PSEN2 is required by γ-secretase, a functional complex that cleaves APP to produce amyloid-beta (Aβ) peptides of varying lengths. These mutations result in relative or absolute increases in the longer Aβ peptides (Aβ, Aβ ), which accumulate as plaques, characteristic of both early and late-onset AD. To investigate the effects of modulating PSEN1 expression, we have produced PSEN1 hemizygous sheep. Sheep PSEN and APP genes are highly conserved relative to humans, including the APP proteolytic cleavage sites, and like humans, sheep naturally develop plaques and TAU tangles with age. At five years of age, the PSEN1 hemizygous animals are phenotypically and biochemically normal. Interestingly, the characteristic Aβ peptide levels in their cerebrospinal fluid and plasma remain at wildtype levels, indicating that a 50 % reduction in PSEN1 abundance does not materially affect γ-secretase's APP cleavage activity. These results suggest that generalized regulation of PSEN1 expression is unlikely to be an effective therapeutic approach for AD on its own. However, it does suggest that loss of one PSEN1 allele may be tolerated in higher organisms, with no deleterious side-effects. It is therefore possible that knocking-out or knocking-down one copy of PSEN1 via genetic modification will be tolerated in humans, especially as functional hemizygous humans are present in the population (gnomad). These kinds of therapies could potentially prevent AD caused by dominant gain-of-function mutations in PSEN1.
阿尔茨海默病（AD）是一种神经退行性疾病，也是当今最重大的医学挑战之一。已在早老素1和2（PSEN1和PSEN2）以及淀粉样前体蛋白（APP）基因中鉴定出导致早发性AD的显性突变。γ-分泌酶需要PSEN1或PSEN2，γ-分泌酶是一种功能性复合物，可切割APP以产生不同长度的淀粉样β（Aβ）肽。这些突变导致较长的Aβ肽（Aβ、Aβ）相对或绝对增加，这些肽会积聚形成斑块，这是早发性和晚发性AD的特征。为了研究调节PSEN1表达的影响，我们培育了PSEN1半合子绵羊。绵羊的PSEN和APP基因与人类高度保守，包括APP蛋白水解切割位点，并且与人类一样，绵羊会随着年龄增长自然形成斑块和TAU缠结。5岁时，PSEN1半合子动物在表型和生化方面均正常。有趣的是，它们脑脊液和血浆中的特征性Aβ肽水平保持在野生型水平，这表明PSEN1丰度降低50%不会实质性影响γ-分泌酶对APP的切割活性。这些结果表明，仅对PSEN1表达进行一般性调节不太可能成为治疗AD的有效方法。然而，这确实表明在高等生物中一个PSEN1等位基因的缺失可能是可耐受的，且没有有害的副作用。因此，通过基因改造敲除或敲低一个PSEN1拷贝在人类中可能是可耐受的，特别是因为人群中存在功能性半合子人类（gnomad）。这类疗法可能潜在地预防由PSEN1中显性功能获得性突变引起的AD。
