PSEN2, short for presenilin-2, is one of the proteins that, when mutated, can cause autosomal-dominant forms of early-onset Alzheimer disease (AD-EOAD). It is a component of the γ-secretase complex, responsible for the intramembranous cleavage of the beta-amyloid precursor protein, leading to the production of amyloid-β (Aβ) peptides. Additionally, it has γ-secretase-independent functions, such as modulating intracellular Ca²⁺ homeostasis, which is involved in various cell signaling pathways [4,6].

Mutations in PSEN2 are less common compared to those in APP and PSEN1. In a study screening AD-EOAD families and sporadic cases, a novel PSEN2 mutation was identified, and among 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 87% had abnormal levels of total tau protein (Tau), phospho-tau protein (P-Tau), and Aβ42 [1]. Functional analysis of PSEN2 variants in HEK293 cells showed that some variants like N141S, M239T, I368F led to higher Aβ42 and Aβ42/Aβ40 levels, while others did not alter Aβ production [3]. A case report described a patient with PSEN2 and ABCA7 variants showing early-onset preclinical pathological changes in AD [2]. Another study found alternative splicing patterns of PSEN2 specific to sporadic Alzheimer's disease, with some spliced products predicted to generate a prematurely truncated PSEN2 protein. Functional analysis of PSEN2 mutants linked to familial Alzheimer disease showed impaired autophagy and altered Ca²⁺ homeostasis [6]. iPSC-derived astrocytes and microglia with a PSEN2 (N141I) mutation exhibited a primed inflammatory phenotype, characterized by reduced morphological complexity, exaggerated pro-inflammatory cytokine secretion, and altered Aβ42 production and phagocytosis [7].

In conclusion, PSEN2 plays a crucial role in the pathogenesis of Alzheimer's disease, mainly through its functions in Aβ production, Ca²⁺ homeostasis regulation, and potential impact on autophagy and inflammation. Studies on PSEN2, especially those focused on its mutations and variant functions, contribute significantly to understanding the molecular mechanisms of Alzheimer's disease, which may provide insights for developing targeted therapeutic strategies [1-3].

References:

1. Lanoiselée, Hélène-Marie, Nicolas, Gaël, Wallon, David, Hannequin, Didier, Campion, Dominique. 2017. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. In PLoS medicine, 14, e1002270. doi:10.1371/journal.pmed.1002270. https://pubmed.ncbi.nlm.nih.gov/28350801/

2. Gan, Jiale, Zhou, Hui, Liu, Chao, Fang, Liangjuan. 2023. PSEN2 and ABCA7 variants causing early-onset preclinical pathological changes in Alzheimer's disease: a case report and literature review. In Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 44, 1987-2001. doi:10.1007/s10072-023-06602-5. https://pubmed.ncbi.nlm.nih.gov/36701017/

3. Dong, Liling, Liu, Caiyan, Sha, Longze, Xu, Qi, Gao, Jing. . PSEN2 Mutation Spectrum and Novel Functionally Validated Mutations in Alzheimer's Disease: Data from PUMCH Dementia Cohort. In Journal of Alzheimer's disease : JAD, 87, 1549-1556. doi:10.3233/JAD-220194. https://pubmed.ncbi.nlm.nih.gov/35491795/

4. Selkoe, D J. . Alzheimer's disease: genes, proteins, and therapy. In Physiological reviews, 81, 741-66. doi:. https://pubmed.ncbi.nlm.nih.gov/11274343/

5. Course, Meredith M, Gudsnuk, Kathryn, Keene, C Dirk, Jayadev, Suman, Valdmanis, Paul N. . Aberrant splicing of PSEN2, but not PSEN1, in individuals with sporadic Alzheimer's disease. In Brain : a journal of neurology, 146, 507-518. doi:10.1093/brain/awac294. https://pubmed.ncbi.nlm.nih.gov/35949106/

6. Fedeli, Chiara, Filadi, Riccardo, Rossi, Alice, Mammucari, Cristina, Pizzo, Paola. 2019. PSEN2 (presenilin 2) mutants linked to familial Alzheimer disease impair autophagy by altering Ca2+ homeostasis. In Autophagy, 15, 2044-2062. doi:10.1080/15548627.2019.1596489. https://pubmed.ncbi.nlm.nih.gov/30892128/

7. Sullivan, Michael A, Lane, Samuel D, McKenzie, André D J, Werry, Eryn L, Kassiou, Michael. 2024. iPSC-derived PSEN2 (N141I) astrocytes and microglia exhibit a primed inflammatory phenotype. In Journal of neuroinflammation, 21, 7. doi:10.1186/s12974-023-02951-2. https://pubmed.ncbi.nlm.nih.gov/38178159/