Affinage

PSEN2

Presenilin-2 · UniProt P49810

Length
448 aa
Mass
50.1 kDa
Annotated
2026-06-10
100 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PSEN2 is the catalytic subunit of a spatially distinct γ-secretase complex whose activity governs amyloid-β generation and intersects with autophagy, calcium signaling, and innate immunity (PMID:27293189, PMID:32032730). A motif unique to PSEN2 directs the complex to late endosomes/lysosomes through a phosphorylation-dependent interaction with the AP-1 adaptor, restricting substrate access to acidic compartments and generating an intracellular pool of longer Aβ peptides that is further increased by FAD-linked mutations (PMID:27293189). Presenilin activity is required for Aβ production and for normal Pen-2 expression and Nicastrin glycosylation, confirming PSEN2's role within the γ-secretase complex (PMID:32032730). Across large mutation panels assayed in presenilin-null cells, FAD-associated PSEN2 variants shift γ-secretase processivity toward higher Aβ42/40 and Aβ37/42 ratios, and the magnitude of this shift correlates linearly with age at symptom onset; the comparatively small contribution of PSEN2 to brain APP processing accounts for its substantially later onset relative to PSEN1 (PMID:40281586, PMID:39559858). In patient-derived basal forebrain cholinergic neurons, the N141I mutation raises the Aβ42/40 ratio and produces electrophysiological and calcium-handling deficits that are abolished by isogenic CRISPR correction (PMID:29078805, PMID:29945658). Beyond proteolysis, FAD-PSEN2 mutants impair autophagosome-lysosome fusion independently of γ-secretase activity by depleting ER Ca2+, dampening cytosolic Ca2+ responses, and reducing RAB7 recruitment (PMID:30892128), and the N141I allele dysregulates microglial innate immunity, driving exaggerated cytokine release and NFκB activation (PMID:32741831). In a non-neural context, PSEN2 acts downstream of a UBC9/NEDD4/RUNX2 axis as a required effector of mitophagy in cardiomyocytes (PMID:40210187).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1996 Low

    Established where PSEN2 is expressed and that its expression is altered in disease, framing it as a brain-relevant gene before its enzymatic role was known.

    Evidence in situ hybridization and quantitative mRNA measurement across human brain regions, plus genomic structure and Northern analysis

    PMID:8661049 PMID:8918895

    Open questions at the time
    • Single descriptive expression studies with no functional mechanism
    • Conflicting tissue-distribution emphasis (neuronal vs. skeletal muscle/pancreas) unresolved
    • Functional consequence of the exon 10 splice variant not tested
  2. 2002 Low

    Addressed how PSEN2 transcription might be regulated in disease, linking a promoter polymorphism to inflammatory inducibility.

    Evidence EMSA with human brain nuclear extracts and luciferase reporter assays in neural progenitor cells under IL-1β/Aβ42 stimulation

    PMID:12232783

    Open questions at the time
    • No chromatin or in vivo validation of the IRF2/C/EBPβ switch
    • Effect of altered promoter activity on protein-level function untested
  3. 2009 Medium

    Tested whether PSEN2 has developmental functions through Notch signaling and how it relates to PSEN1, revealing both cooperative and independent roles.

    Evidence morpholino knockdown and genetic epistasis in zebrafish with neurodevelopmental phenotypic readouts

    PMID:19563801

    Open questions at the time
    • Notch substrate cleavage not directly measured
    • Relevance of developmental role to adult/AD biology unclear
    • Morpholino off-target effects not fully excluded
  4. 2016 High

    Resolved why PSEN2 differs functionally from PSEN1 by identifying a localization motif that targets its γ-secretase complex to acidic compartments, defining its distinct substrate pool.

    Evidence motif identification, phosphorylation-dependent AP-1 interaction assay, subcellular fractionation, live imaging, and compartment-specific Aβ profiling

    PMID:27293189

    Open questions at the time
    • Kinase responsible for the phosphorylation-dependent AP-1 interaction not identified
    • Full repertoire of late-endosomal/lysosomal substrates not enumerated
  5. 2017 Medium

    Directly attributed neuronal Aβ and excitability phenotypes to a single PSEN2 mutation using isogenic correction, establishing causality in a human neuronal model.

    Evidence iPSC-derived basal forebrain cholinergic neurons with CRISPR correction of N141I, Aβ42/40 ELISA, and patch-clamp electrophysiology

    PMID:29078805

    Open questions at the time
    • Mechanistic link between Aβ shift and electrophysiological deficit not dissected
    • Single mutation in a single cell type
  6. 2018 Medium

    Defined a calcium-handling defect downstream of PSEN2 N141I and showed it is pharmacologically rescuable, while excluding cell-autonomous insulin resistance.

    Evidence isogenic CRISPR-corrected iPSC-BFCNs with Ca2+ flux measurement, insulin signaling phosphorylation assays, and chronic insulin rescue

    PMID:29945658

    Open questions at the time
    • Molecular basis of the calcium defect not pinned to a specific channel/store
    • Insulin rescue mechanism on Aβ42/40 unexplained
  7. 2019 High

    Separated PSEN2's autophagy role from its protease activity, showing FAD mutants block autophagosome-lysosome fusion via ER Ca2+ depletion and reduced RAB7 recruitment.

    Evidence FAD-PSEN2 cell models with autophagy flux assays, RAB7 recruitment, FRET-based Ca2+ imaging, and γ-secretase inhibitor controls

    PMID:30892128

    Open questions at the time
    • How PSEN2 controls ER Ca2+ store content mechanistically unresolved
    • In vivo relevance to neurodegeneration not established
  8. 2020 Medium

    Extended PSEN2 function beyond neurons by demonstrating its role in microglial innate immune homeostasis, and validated reconstitution systems for variant testing.

    Evidence PSEN2 N141I transgenic mice and microglial assays (cytokine ELISA, NFκB reporter, Aβ internalization, morphometry); PSEN1/PSEN2 double-knockout N2A cells with variant reintroduction; zebrafish CRISPR models with transcriptomics

    PMID:31978074 PMID:32032730 PMID:32658922 PMID:32741831

    Open questions at the time
    • Whether microglial inflammatory phenotype depends on γ-secretase substrate cleavage unclear
    • Functional consequence of N-terminally truncated zebrafish Psen2 not directly demonstrated
    • Transcriptomic changes not linked to a defined molecular lesion
  9. 2024 Medium

    Quantified across large variant panels how PSEN2-driven γ-secretase processivity predicts clinical onset and explains PSEN2's late onset relative to PSEN1.

    Evidence expression of 74 and 28 PSEN2 variants in presenilin-null HEK293/cells, Aβ isoform ELISA, and correlation with age-at-onset data

    PMID:39559858 PMID:40281586

    Open questions at the time
    • Correlation (R²~0.52) leaves substantial variance unexplained
    • Mechanism by which longer Aβ ratios set onset timing not established
    • Single-lab assay systems
  10. 2025 Medium

    Placed PSEN2 as a required downstream effector in a cardiac mitophagy pathway, broadening its physiological context beyond amyloid biology.

    Evidence cardiomyocyte-specific UBC9 knockout/overexpression mice, NEDD4 Co-IP, RUNX2 ubiquitination assay, and PSEN2 knockdown rescue of mitophagy

    PMID:40210187

    Open questions at the time
    • Molecular mechanism by which PSEN2 promotes mitophagy not defined
    • Whether γ-secretase activity is involved in the cardiac role unknown
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PSEN2's compartment-specific proteolysis, calcium/autophagy regulation, microglial immune signaling, and cardiac mitophagy roles are mechanistically integrated remains unresolved.
  • No structural model of the late-endosomal PSEN2/γ-secretase complex
  • The kinase and full signaling network controlling its AP-1-dependent targeting unknown
  • Causal chain from Aβ ratio shifts to neuronal dysfunction undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016787 hydrolase activity 2
Localization
GO:0005764 lysosome 1 GO:0005768 endosome 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-9612973 Autophagy 2 GO:0140096 catalytic activity, acting on a protein 1 R-HSA-168256 Immune System 1
Partners
AP-1NEDD4RAB7RUNX2UBC9
Complex memberships
γ-secretase complex

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 PSEN2 contains a unique motif that directs the PSEN2/γ-secretase complex to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex, restricting its subcellular localization and thereby determining substrate specificity. PSEN2/γ-secretase selectively cleaves late endosomal/lysosomal-localized substrates and generates the prominent intracellular pool of longer Aβ peptides. FAD-associated mutations in PSEN2 further increase levels of longer Aβ in these acidic compartments. Identification of PSEN2 localization motif, phosphorylation-dependent AP-1 interaction assay, subcellular fractionation, live-cell imaging, Aβ isoform measurement in compartment-specific assays Cell High 27293189
2019 FAD-linked PSEN2 mutants impair autophagy by blocking autophagosome-lysosome fusion, not by altering lysosomal function per se, but by reducing RAB7 recruitment to autophagosomes. This effect is independent of PSEN2's γ-secretase activity and depends instead on PSEN2's ability to partially deplete ER Ca2+ content, thereby reducing cytosolic Ca2+ responses upon IP3-linked stimulation. FAD-PSEN2 cell models (knockdown and overexpression), autophagy flux assays (LC3-II, SQSTM1/p62), live-cell imaging of autophagosome-lysosome fusion, RAB7 recruitment assay, Ca2+ measurements (FRET-based), γ-secretase inhibitor controls Autophagy High 30892128
2009 In zebrafish embryos, reduced Psen2 activity decreases Notch signaling, perturbs spinal neurogenin1 expression, and affects trunk neural crest development and melanocyte number. Reduced Psen2 also increases Dorsal Longitudinal Ascending (DoLA) interneuron number, an effect that can be suppressed by simultaneous reduction of Psen1, demonstrating cooperative and independent genetic interactions between Psen1 and Psen2 in Notch-dependent developmental processes. Morpholino antisense oligonucleotide knockdown in zebrafish embryos; phenotypic readouts of melanocyte number, DoLA interneuron count, and neurogenin1 expression; genetic epistasis (psen1 + psen2 double knockdown) Experimental cell research Medium 19563801
2020 PSEN2 N141I heterozygosity in microglia impairs γ-secretase activity and causes exaggerated inflammatory cytokine release, enhanced NFκB activity, and increased Aβ internalization in vitro. In vivo, PS2 N141I mice show enhanced IL-6 and TREM2 expression in brain and reduced microglial branch number/length indicative of an activated morphology, demonstrating a role for PSEN2 in regulating innate immune homeostasis in microglia. Transgenic mouse expressing PSEN2 N141I; in vitro microglial assays (γ-secretase activity, cytokine ELISA, NFκB reporter, Aβ internalization); in vivo brain gene expression; LPS challenge; microglial morphometry Journal of Alzheimer's disease : JAD Medium 32741831
2020 A premature termination codon near the translation start of zebrafish psen2 (psen2S4Ter) does not cause nonsense-mediated decay of the transcript; instead, the mutant mRNA permits utilization of cryptic downstream translation start codons, likely generating N-terminally truncated Psen2 proteins lacking late endosomal/lysosomal localization sequences. Transcriptome analysis of brains from homozygous psen2S4Ter fish reveals dominant effects on ribosomal and mitochondrial gene expression. CRISPR/Cas9 mutagenesis of zebrafish psen2; RT-PCR and northern analysis for NMD; EGFP fusion reporter to test cryptic start codon usage; brain transcriptome (RNA-seq) PloS one Medium 32658922
2023 In sporadic Alzheimer's disease prefrontal cortex, PSEN2 shows disease-specific alternative splicing including a human-specific cryptic exon in intron 9 and a 77 bp intron retention before exon 6, both predicted to generate prematurely truncated PSEN2 protein. The proportion of canonical full-length PSEN2 transcripts is significantly reduced in sporadic AD relative to familial AD and controls. Additionally, pathogenic alleles in PSEN2 variant carriers are represented by far fewer full-length transcripts than wild-type alleles, and frequent RNA editing at Alu elements occurs in the extended 3' UTR of PSEN2. Targeted long-read isoform sequencing (Iso-Seq) of PSEN1 and PSEN2 transcripts in postmortem prefrontal cortex; validation in independent cerebellum RNA-seq dataset; bioinformatic prediction of truncated protein products Brain : a journal of neurology Medium 35949106
2020 In a zebrafish model of the PSEN2 K115fs mutation (which mimics the PS2V alternative isoform), young heterozygous fish show transcriptional changes consistent with accelerated brain aging and increased glucocorticoid signaling; aged heterozygous fish show a transcriptional inversion including glucocorticoid resistance, altered microglia-associated ETS transcription factor immune responses, and changes in ribosomal/mitochondrial gene networks, occurring without obvious histopathology and possibly without Aβ accumulation. CRISPR/Cas9 genome editing of zebrafish psen2 to model K115fs; brain transcriptome (RNA-seq) and proteome at 6 and 24 months; WGCNA co-expression network analysis; comparison to human AD datasets PloS one Medium 31978074
2020 In a PSEN1/PSEN2 double knockout N2A cell line generated by CRISPR/Cas9, complete ablation of both presenilins eliminates Aβ production, decreases Pen-2 expression, and reduces Nicastrin glycosylation, confirming that presenilin activity is required for these γ-secretase complex properties. Reintroduction of known PSEN2 mutants (e.g., N141I) increases the Aβ42/Aβ40 ratio, validating the cell line for functional testing of PSEN2 variants. CRISPR/Cas9 double knockout of PSEN1 and PSEN2 in N2A cells; Aβ ELISA; western blot for Pen-2 and Nicastrin glycosylation; reintroduction of PSEN2 variants Neurobiology of disease Medium 32032730
2017 iPSC-derived basal forebrain cholinergic neurons (BFCNs) harboring the PSEN2 N141I mutation show an increased Aβ42/40 ratio and electrophysiological deficits (reduced maximal spike number and decreased first action potential height at rheobase). CRISPR/Cas9 correction of the N141I point mutation abolishes both the electrophysiological deficit and the elevated Aβ42/40 ratio, directly linking the PSEN2 mutation to these cellular phenotypes. iPSC differentiation to BFCNs; CRISPR/Cas9 correction of PSEN2 N141I; Aβ42/40 ELISA; patch-clamp electrophysiology Acta neuropathologica communications Medium 29078805
2018 iPSC-derived BFCNs with PSEN2 N141I show a CRISPR/Cas9-correctable defect in calcium flux that can be prevented by chronic insulin exposure. Chronic insulin treatment reduces the Aβ42/40 ratio in BFCNs of all genotypes. PSEN2 N141I does not induce neuronal insulin resistance in a cell-autonomous fashion (insulin signaling pathway phosphorylation is indistinguishable from controls). iPSC-derived BFCNs; CRISPR/Cas9 isogenic correction; Ca2+ flux measurements; phosphorylation assays for insulin signaling pathway; Aβ42/40 ELISA with chronic insulin treatment Molecular neurodegeneration Medium 29945658
2025 UBC9 protects against diabetic cardiomyopathy by binding directly to NEDD4, enhancing RUNX2 ubiquitination and degradation, which in turn increases PSEN2 expression. PSEN2 knockdown reverses the protective effect of UBC9 overexpression on cardiomyocyte mitophagy, placing PSEN2 downstream of the NEDD4/RUNX2 axis as a required effector of UBC9-mediated mitophagy regulation in cardiomyocytes. Cardiomyocyte-specific UBC9 knockout and overexpression mice; NEDD4 co-immunoprecipitation; RUNX2 ubiquitination assay; PSEN2 knockdown rescue experiment; mitophagy assays Metabolism: clinical and experimental Medium 40210187
2025 Biochemical assessment of 28 PSEN2 mutations shows that Aβ profile composition (Aβ42/40 and Aβ37/42 ratios, reflecting γ-secretase processivity) correlates linearly with age at symptom onset (R²=0.52). Compared to PSEN1, PSEN2 variants cause an average ~27-year delay in onset, consistent with PSEN2 making a smaller contribution to brain APP processing. Extremely inactivating PSEN1 variants similarly delay onset, supporting the model that reduced γ-secretase contribution underlies PSEN2's later onset. Cell-based γ-secretase activity assay for 28 PSEN2 and 19 APP mutations expressed in presenilin-null cells; Aβ isoform ELISA; correlation with clinical age-at-onset data Molecular neurodegeneration Medium 40281586
2024 Expression of 74 PSEN2 missense variants in HEK293 cells lacking presenilin 1/2 shows that Aβ42/40 and Aβ37/42 ratios correlate with age at symptom onset across PSEN2 variants. PSEN2 variants with homologous pathogenic PSEN1 variants show highly correlated Aβ production patterns and age-at-onset values (PSEN2 AAO averaging 18.3 years later than PSEN1 homologs). Most non-homologous PSEN2 variants had Aβ42/40 ratios near wild-type, arguing against their pathogenicity. Expression of 74 PSEN2 variants in presenilin 1/2-null HEK293 cells; Aβ isoform ELISA; correlation with clinical age-at-onset Alzheimer's & dementia : the journal of the Alzheimer's Association Medium 39559858
1996 STM2 (PSEN2) mRNA is expressed broadly in human brain and is primarily neuronal, as determined by in situ hybridization. Quantification shows significantly decreased STM2 mRNA levels in the basal forebrain, frontal cortex, and hippocampus of AD-affected subjects compared to normal age-matched controls. In situ hybridization histochemistry; quantitative mRNA measurement in human brain regions The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society Low 8918895
1996 The STM2 (PSEN2) gene spans 23,737 bp, contains 12 exons (10 coding), and produces two transcripts (2.4 and 2.8 kb). An alternative splice variant of the 2.4-kb transcript lacking a single glutamate codon (in exon 10) was identified. Expression is highest in skeletal muscle and pancreas, with comparatively low levels in brain. Genomic sequencing; exon mapping; Northern blot expression analysis; RT-PCR identification of splice variant Genomics Low 8661049
2022 Transfection of HEK293 cells with PSEN2 variants N141S, M239T, and I368F resulted in higher Aβ42 levels and elevated Aβ42/Aβ40 ratios relative to wild-type PSEN2, functionally validating these as pathogenic mutations. PSEN2 variants L396I, G117X, S147N, H220Y, and R62C did not alter Aβ42, Aβ40 levels, or Aβ42/Aβ40 ratio. Transfection of HEK293 cells with PSEN2 variant plasmids; Aβ42 and Aβ40 ELISA Journal of Alzheimer's disease : JAD Low 35491795
2002 A single adenine deletion polymorphism in the PSEN2 5' upstream promoter region negates binding of the putative repressor transcription factor IRF2 (in nuclear extracts from aged human brain neocortex) and creates a C/EBPβ binding site responsive to pro-inflammatory induction. Luciferase reporter assays in human neural progenitor cells show the mutant PSEN2 regulatory region has 1.8-fold higher basal expression and is synergistically induced 3.2-fold over wild-type by combined IL-1β + Aβ42. DNA-protein binding analysis (EMSA) with human brain nuclear extracts; luciferase reporter assay in neural progenitor cells; IL-1β and Aβ42 stimulation Molecular psychiatry Low 12232783

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS medicine 468 28350801
1992 A common trans-acting factor, Ad4-binding protein, to the promoters of steroidogenic P-450s. The Journal of biological chemistry 432 1517227
2006 Foxl2 up-regulates aromatase gene transcription in a female-specific manner by binding to the promoter as well as interacting with ad4 binding protein/steroidogenic factor 1. Molecular endocrinology (Baltimore, Md.) 370 17192407
2012 Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PloS one 262 22312439
2016 Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool. Cell 249 27293189
2008 Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 142 18520802
2020 CheckMate 171: A phase 2 trial of nivolumab in patients with previously treated advanced squamous non-small cell lung cancer, including ECOG PS 2 and elderly populations. European journal of cancer (Oxford, England : 1990) 135 32028209
2017 CRISPR/Cas9-Correctable mutation-related molecular and physiological phenotypes in iPSC-derived Alzheimer's PSEN2 N141I neurons. Acta neuropathologica communications 119 29078805
2006 (PS)2: protein structure prediction server. Nucleic acids research 107 16844981
2019 PSEN2 (presenilin 2) mutants linked to familial Alzheimer disease impair autophagy by altering Ca2+ homeostasis. Autophagy 102 30892128
2004 Small ubiquitin-like modifier 1 (SUMO-1) modification of the synergy control motif of Ad4 binding protein/steroidogenic factor 1 (Ad4BP/SF-1) regulates synergistic transcription between Ad4BP/SF-1 and Sox9. Molecular endocrinology (Baltimore, Md.) 97 15192080
2009 (PS)2-v2: template-based protein structure prediction server. BMC bioinformatics 92 19878598
2008 Randomized phase III trial comparing single-agent paclitaxel Poliglumex (CT-2103, PPX) with single-agent gemcitabine or vinorelbine for the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 92 18594318
1995 Immunohistochemical localization of Ad4-binding protein with correlation to steroidogenic enzyme expression in cycling human ovaries and sex cord stromal tumors. The Journal of clinical endocrinology and metabolism 83 7673429
1996 Expression of Ad4-BP/cytochrome P450 side chain cleavage enzyme and induction of cell death in long-term cultures of human granulosa cells. Molecular human reproduction 79 9238709
2020 PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association 70 31914229
2007 N-acetylcysteine amide (AD4) attenuates oxidative stress in beta-thalassemia blood cells. Biochimica et biophysica acta 68 18082636
2022 Efficacy and safety of baricitinib in combination with topical corticosteroids in patients with moderate-to-severe atopic dermatitis with inadequate response, intolerance or contraindication to ciclosporin: results from a randomized, placebo-controlled, phase III clinical trial (BREEZE-AD4). The British journal of dermatology 65 35484697
1996 Genomic structure and expression of STM2, the chromosome 1 familial Alzheimer disease gene. Genomics 50 8661049
2019 APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease. International journal of molecular sciences 49 31557888
2008 A novel PSEN2 mutation associated with a peculiar phenotype. Neurology 48 18427071
2012 The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease. Journal of Alzheimer's disease : JAD 46 22027014
2009 ps-2, the gene responsible for functional sterility in tomato, due to non-dehiscent anthers, is the result of a mutation in a novel polygalacturonase gene. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 42 19219598
2015 (PS)2: protein structure prediction server version 3.0. Nucleic acids research 39 25943546
2015 Pilot whole-exome sequencing of a German early-onset Alzheimer's disease cohort reveals a substantial frequency of PSEN2 variants. Neurobiology of aging 39 26522186
2012 Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiology of aging 39 22503161
2009 Independent and cooperative action of Psen2 with Psen1 in zebrafish embryos. Experimental cell research 38 19563801
2002 Regulatory region variability in the human presenilin-2 (PSEN2) gene: potential contribution to the gene activity and risk for AD. Molecular psychiatry 38 12232783
2003 A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset Alzheimer disease. Archives of neurology 37 12925374
2021 Presence of a mutation in PSEN1 or PSEN2 gene is associated with an impaired brain endothelial cell phenotype in vitro. Fluids and barriers of the CNS 36 33413468
2020 Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiology of disease 36 32087291
2018 iPSC-derived familial Alzheimer's PSEN2 N141I cholinergic neurons exhibit mutation-dependent molecular pathology corrected by insulin signaling. Molecular neurodegeneration 36 29945658
2019 Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiology of aging 34 30822634
2014 Clinical and neuroimaging characterization of Chinese dementia patients with PSEN1 and PSEN2 mutations. Dementia and geriatric cognitive disorders 32 25323700
2020 Early-Onset Familial Alzheimer Disease Variant PSEN2 N141I Heterozygosity is Associated with Altered Microglia Phenotype. Journal of Alzheimer's disease : JAD 31 32741831
2021 Emerging therapeutic opportunities of novel thiol-amides, NAC-amide (AD4/NACA) and thioredoxin mimetics (TXM-Peptides) for neurodegenerative-related disorders. Free radical biology & medicine 28 34481041
2020 Accelerated brain aging towards transcriptional inversion in a zebrafish model of the K115fs mutation of human PSEN2. PloS one 28 31978074
2023 Aberrant splicing of PSEN2, but not PSEN1, in individuals with sporadic Alzheimer's disease. Brain : a journal of neurology 25 35949106
2014 Probable novel PSEN2 Val214Leu mutation in Alzheimer's disease supported by structural prediction. BMC neurology 25 24885952
2021 Pembrolizumab as First-Line Palliative Therapy in PD-L1 Overexpressing (≥ 50%) NSCLC: Real-world Results with Special Focus on PS ≥ 2, Brain Metastases, and Steroids. Clinical lung cancer 24 33648877
2020 Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimer's research & therapy 24 32917274
2020 Novel presenilin 1 and 2 double knock-out cell line for in vitro validation of PSEN1 and PSEN2 mutations. Neurobiology of disease 21 32032730
2010 Evidence for three loci modifying age-at-onset of Alzheimer's disease in early-onset PSEN2 families. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 21 20333730
2024 iPSC-derived PSEN2 (N141I) astrocytes and microglia exhibit a primed inflammatory phenotype. Journal of neuroinflammation 18 38178159
2014 Novel mutation in the PSEN2 gene (N141Y) associated with early-onset autosomal dominant Alzheimer's disease in a Chinese Han family. Neurobiology of aging 18 24838186
1997 Replication and immunogenicity of Ad7-, Ad4-, and Ad5-hepatitis B virus surface antigen recombinants, with or without a portion of E3 region, in chimpanzees. Vaccine 18 9139496
2021 Current state of knowledge on immunotherapy in ECOG PS 2 patients. A systematic review. Advances in medical sciences 16 34315013
2018 A pathogenic PSEN2 p.His169Asn mutation associated with early-onset Alzheimer's disease. Clinical interventions in aging 16 30104866
2009 Novel MAPT Val75Ala mutation and PSEN2 Arg62Hys in two siblings with frontotemporal dementia. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 16 19768372
2005 A novel brain-targeted antioxidant (AD4) attenuates haloperidol-induced abnormal movement in rats: implications for tardive dyskinesia. Clinical neuropharmacology 16 16340385
2012 Molecular genetic analysis of the APP, PSEN1, and PSEN2 genes in Finnish patients with early-onset Alzheimer disease and frontotemporal lobar degeneration. Alzheimer disease and associated disorders 14 21959359
2010 A novel mutation in the predicted TMIII domain of the PSEN2 gene in an Italian pedigree with atypical Alzheimer's disease. Journal of Alzheimer's disease : JAD 14 20164579
2015 Probable novel PSEN2 Pro123Leu mutation in a Chinese Han family of Alzheimer's disease. Neurobiology of aging 13 26422362
1996 Neuronal expression of STM2 mRNA in human brain is reduced in Alzheimer's disease. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 13 8918895
2017 Role of Ad4-binding protein/steroidogenic factor 1 in regulating NADPH production in adrenocortical Y-1 cells. Endocrine journal 12 28202838
2006 High-resolution fine mapping of ps-2, a mutated gene conferring functional male sterility in tomato due to non-dehiscent anthers. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 12 16932878
2004 Dilemmas in management: the controversial role of chemotherapy in PS 2 advanced NSCLC and the potential role of CT-2103 (Xyotax). The oncologist 12 15266093
2010 The N141I mutation in PSEN2: implications for the quintessential case of Alzheimer disease. Archives of neurology 11 20457965
1982 A single step separation of PS 1, PS 2 and chlorophyll-antenna particles from spinach chloroplasts. Photosynthesis research 11 24458286
2025 Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer's disease. Alzheimer's research & therapy 9 39754192
2017 MicroRNA Profiling in Aging Brain of PSEN1/PSEN2 Double Knockout Mice. Molecular neurobiology 9 28879407
2022 PSEN2 Mutation Spectrum and Novel Functionally Validated Mutations in Alzheimer's Disease: Data from PUMCH Dementia Cohort. Journal of Alzheimer's disease : JAD 8 35491795
2021 Immunotherapy in patients with non-small cell lung cancer with ECOG PS 2. Contemporary oncology (Poznan, Poland) 8 33911982
2020 Transcriptome analysis indicates dominant effects on ribosome and mitochondrial function of a premature termination codon mutation in the zebrafish gene psen2. PloS one 8 32658922
2024 Lipid-polymer hybrid nanoparticles loaded with N-acetylcysteine for the modulation of neuroinflammatory biomarkers in human iPSC-derived PSEN2 (N141I) astrocytes as a model of Alzheimer's disease. Journal of materials chemistry. B 7 38713059
2021 Novel PSEN1 and PSEN2 Mutations Identified in Sporadic Early-onset Alzheimer Disease and Posterior Cortical Atrophy. Alzheimer disease and associated disorders 7 33973882
2005 Sequential therapy with Vinorelbine followed by Gemcitabine in patients with metastatic non small cell lung cancer (NSCLC), performance status (PS) 2, or elderly with comorbidities--a multicenter phase II trial. Lung cancer (Amsterdam, Netherlands) 7 15949597
2025 UBC9 ameliorates diabetic cardiomyopathy by modulating cardiomyocyte mitophagy through NEDD4/RUNX2/PSEN2 axis. Metabolism: clinical and experimental 6 40210187
2024 The pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1. Alzheimer's & dementia : the journal of the Alzheimer's Association 6 39559858
2022 The associations of APP, PSEN1, and PSEN2 genes with Alzheimer's disease: A large case-control study in Chinese population. CNS neuroscience & therapeutics 6 36217304
2020 A phase II study of daily carboplatin plus irradiation followed by durvalumab for stage III non-small cell lung cancer patients with PS 2 up to 74 years old and patients with PS 0 or 1 from 75 years: NEJ039A (trial in progress). BMC cancer 6 33023530
2018 Involvement of Acidic Polysaccharide Ph-PS-2 and Protein in Initiation of Coccolith Mineralization, as Demonstrated by In Vitro Calcification on the Base Plate. Marine biotechnology (New York, N.Y.) 6 29619589
2015 Identification of PSEN2 mutation p.N141I in Argentine pedigrees with early-onset familial Alzheimer's disease. Neurobiology of aging 6 26166204
2011 Randomised phase II trial of 4 dose levels of single agent docetaxel in performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC): DOC PS2 trial. Manchester lung cancer group. Lung cancer (Amsterdam, Netherlands) 6 21296449
1996 The effect of tetraethylammonium on intracellular calcium concentration in Alzheimer's disease fibroblasts with APP, S182 and E5-1 missense mutations. Neuroscience letters 6 8733308
2025 Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes. Molecular neurodegeneration 5 40281586
2014 Previously unrecognized missense mutation E126K of PSEN2 segregates with early onset Alzheimer's disease in a family. Journal of Alzheimer's disease : JAD 5 24844686
2007 Two polymorphisms of presenilin-2 gene (PSEN2) 5' regulatory region are not associated with Alzheimer's disease (AD) in the Polish population. Journal of neural transmission (Vienna, Austria : 1996) 5 18087668
2025 Evaluating pathogenicity of variants of unknown significance in APP, PSEN1, and PSEN2. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 4 39875235
2023 PSEN2 and ABCA7 variants causing early-onset preclinical pathological changes in Alzheimer's disease: a case report and literature review. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 4 36701017
1997 Assignment of Alzheimer's presenilin-2 (PS-2) gene to 1q42.1 by fluorescence in situ hybridization. Neuroscience letters 4 9121700
2025 Benchmarking AlphaMissense pathogenicity predictions against APP, PSEN1, and PSEN2 variants of unknown significance. Biochemistry and biophysics reports 3 40486492
2020 Lack of APOE Christchurch variant in five age of onset outliers with PSEN1, PSEN2 Alzheimer's disease and MAPT frontotemporal dementia. Journal of the neurological sciences 3 32977230
2017 A case of possibly pathogenic PSEN2 R62C mutation in a patient with probable early-onset Alzheimer's dementia supported by structure prediction. Clinical interventions in aging 3 28243073
2013 Results of platinum-based chemotherapy in unselected performance status (PS) 2 patients with advanced non-small cell lung cancer: a cohort study. Medical oncology (Northwood, London, England) 3 23535999
2007 The 800-lb gorilla we all ignore: treatment of NSCLC in elderly and PS 2 patients. Clinical advances in hematology & oncology : H&O 3 17519883
2002 [Role of the pS(2) in gastric mucosa adaptative cytoprotection from stress]. Zhonghua yi xue za zhi 3 11953153
2024 Case report: Double mutations in a patient with early-onset Alzheimer's disease in China, PSEN2 and IDE variants. Frontiers in neuroscience 2 39539495
2022 A Possible Pathogenic PSEN2 Gly56Ser Mutation in a Korean Patient with Early-Onset Alzheimer's Disease. International journal of molecular sciences 2 35328387
2022 PSEN2 Thr421Met Mutation in a Patient with Early Onset Alzheimer's Disease. International journal of molecular sciences 2 36362122
2007 [What treatment for a patient of PS 2-3 with stage IV non-small cell lung cancer?]. Revue des maladies respiratoires 2 18235404
2023 Double Mutations in a Patient with Early-Onset Alzheimer's Disease in Korea: An APP Val551Met and a PSEN2 His169Asn. International journal of molecular sciences 1 37108607
2021 A novel PSEN2 p.Ser175Phe variant in a family with Alzheimer's disease. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 1 33855622
2021 A Novel Probable Pathogenic PSEN2 Mutation p.Phe369Ser Associated With Early-Onset Alzheimer's Disease in a Chinese Han Family: A Case Report. Frontiers in aging neuroscience 1 34366829
2006 [Expressions of Her-2, EGFR, PS-2 and ER in breast cancer and their clinical implications]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 1 16503540
2025 Presence of Alzheimer's disease variants in circular RNA of PSEN1 and PSEN2. Journal of Alzheimer's disease : JAD 0 40518825
2024 Orchestration of Genetic Alterations in PSEN1 and PSEN2 Genes in Development of Alzheimer's Disease through Computational Analysis. Global medical genetics 0 38213663
2024 Generation and characterization of an iPS cell line (PUMCi006-A) from skin fibroblasts of a patient with an M239T mutation in PSEN2 gene. Stem cell research 0 38531230
2024 PSEN2 Mutations May Mimic Frontotemporal Dementia: Two New Case Reports and a Review. Biomedicines 0 39200345
2024 A Novel Rare PSEN2 Val226Ala in PSEN2 in a Korean Patient with Atypical Alzheimer's Disease, and the Importance of PSEN2 5th Transmembrane Domain (TM5) in AD Pathogenesis. International journal of molecular sciences 0 39273625

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