Affinage

PSEN1

Presenilin-1 · UniProt P49768

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

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PSEN1 (presenilin-1, PS1) is the catalytic core of the γ-secretase intramembrane protease and functions in both the Notch signaling pathway and the autophagy-lysosomal system (PMID:7566091, PMID:20541250). Genetic studies in C. elegans first placed presenilin within Notch-family receptor signaling in receiving cells (PMID:7566091), and PS1-dependent intramembrane cleavage is required for normal Notch-regulated neurogenesis in human neural stem cells, where pathogenic mutations skew the balance between progenitor maintenance and premature post-mitotic neuron production (PMID:33440141). As the catalytic subunit, PS1 promotes intramembrane proteolysis of membrane-bound C-terminal fragments of APP and related substrates, and its level alone is rate-limiting for assembly and activity of the complex with Nicastrin and Pen-2 (PMID:9856475, PMID:22140537). PS1 catalytic specificity is conformationally controlled: substrate transmembrane substitutions and PKA-mediated phosphorylation at Ser367 drive a 'closed' PS1 conformation that increases the Aβ42/40 ratio (PMID:16086682, PMID:28132667). FAD-linked PSEN1 mutations are mechanistically heterogeneous — they destabilize γ-secretase–APP/Aβ interactions during processive cleavage to favor longer Aβ peptides (PMID:33969176), and the resulting Aβ isoform profile correlates quantitatively with age at disease onset (PMID:35365805); some mutations exert opposite, mutation-specific effects on Notch-driven neurogenesis (PMID:37352850). Independently of its protease activity, PS1 holoprotein acts as a chaperone that binds the unglycosylated V0a1 subunit of v-ATPase and the Sec61α/oligosaccharyltransferase complex to enable V0a1 N-glycosylation and ER-to-lysosome delivery, supporting lysosomal acidification and autophagosome clearance (PMID:20541250). Reciprocally, autophagy impairment elevates PS1 expression through the GCN2–ATF4 axis, increasing γ-secretase activity (PMID:20168091).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1995 High

    Established that presenilin acts within the Notch signaling pathway, defining its first biological context before any enzymatic role was known.

    Evidence Genetic suppressor screen of the sel-12 ortholog in C. elegans showing loss-of-function epistasis with lin-12/glp-1 Notch receptors

    PMID:7566091

    Open questions at the time
    • Did not establish a molecular mechanism (proteolysis vs. trafficking)
    • Used an invertebrate ortholog, not human PSEN1
    • No connection to APP/Aβ at this stage
  2. 1998 High

    Showed PS1 is required for intramembrane processing of APP-family C-terminal fragments and for trafficking of selected membrane proteins, linking presenilin loss to defective substrate metabolism.

    Evidence Biochemical analysis of APP/APLP1 CTF accumulation and TrkB maturation in PS1-deficient primary neurons

    PMID:9856475

    Open questions at the time
    • Did not resolve whether PS1 is itself the protease or a cofactor
    • Mechanism of TrkB trafficking defect undefined
  3. 2002 Medium

    Demonstrated in vivo that FAD mutant PS1 alone is sufficient to drive Aβ42 elevation and amyloid deposition without APP overproduction, and alters PS1 endoproteolysis.

    Evidence Gene-targeted PS1-P264L knock-in mice crossed with APP knock-in mice; western blotting and amyloid histology

    PMID:11959395

    Open questions at the time
    • Single mutation tested
    • Mechanism linking altered endoproteolysis to Aβ42 increase not resolved
  4. 2005 Medium

    Introduced PS1 conformation as a measurable determinant of catalytic output, showing substrate transmembrane mutations change PS1 N-/C-terminal proximity with differential effects on Aβ and AICD.

    Evidence FRET-based conformational imaging of PS1 with APP mutagenesis; in vitro AICD and cell-based Aβ measurement

    PMID:16086682

    Open questions at the time
    • FRET proximity is an indirect conformational readout
    • Single lab
    • No structural model of the conformational states
  5. 2010 High

    Revealed a protease-independent function of PS1 holoprotein as a chaperone for v-ATPase V0a1 glycosylation and lysosomal delivery, explaining autophagy defects in PS1 loss.

    Evidence PS1-null/hypomorphic/conditional models and FAD fibroblasts; Co-IP with Sec61α/OST, N-glycosylation, cathepsin activity, and autolysosome pH assays

    PMID:20541250

    Open questions at the time
    • Relationship between chaperone and protease functions not fully separated
    • How FAD mutations affect this chaperone role incompletely defined
  6. 2010 Medium

    Established reciprocal regulation in which autophagy-lysosomal failure raises PS1 expression and γ-secretase activity via GCN2/ATF4.

    Evidence Sequential shRNA knockdown of Atg5, GCN2, ATF4 plus chloroquine in HEK293; Aβ ELISA and Notch1 cleavage assays

    PMID:20168091

    Open questions at the time
    • Mechanism of ATF4-driven PSEN1 induction not detailed
    • Performed in non-neuronal cells
  7. 2011 Medium

    Showed PS1 level is rate-limiting for γ-secretase assembly and that FAD mutant complexes are less active overall yet shifted toward Aβ42-site cleavage.

    Evidence Transgenic mouse overexpression of WT/FAD PS1; γ-secretase activity assays, Aβ isoform measurement, component western blots

    PMID:22140537

    Open questions at the time
    • Single lab
    • Overexpression may not reflect endogenous stoichiometry
  8. 2015 Medium

    Reconstituted the core FAD biochemical signature (elevated Aβ42/40) in patient-derived human neural cells, validating disease-relevance of the cleavage shift.

    Evidence Aβ42/40 ELISA in iPSC-derived NPCs and fibroblasts from PSEN1 mutation carriers

    PMID:24416243

    Open questions at the time
    • Correlative biochemistry without mechanistic dissection
    • Single lab
  9. 2017 High

    Identified PKA phosphorylation at Ser367 as a physiological switch driving a pathogenic closed PS1 conformation and higher Aβ42/40, connecting signaling to cleavage specificity.

    Evidence FRET conformational imaging in cells and living mouse brain; PKA manipulation and phospho-site mutagenesis; Aβ42/40 measurement

    PMID:28132667

    Open questions at the time
    • Upstream signals activating PKA toward PS1 in vivo unclear
    • Structural basis of the closed state not resolved
  10. 2021 Medium

    Demonstrated that PSEN1/γ-secretase activity is required for Notch-regulated human neurogenesis, with FAD mutations causing premature neuron generation rescuable by Notch augmentation.

    Evidence iPSC-derived 2D cortical cultures and 3D organoids from FAD carriers; Notch target genes, rescue experiments, postmortem analysis

    PMID:33440141

    Open questions at the time
    • Partial rescue only
    • Single lab
    • Link between neurogenic defect and adult AD pathology indirect
  11. 2021 Medium

    Showed that a specific FAD mutation destabilizes γ-secretase–APP/Aβn interactions during processive cleavage to favor longer Aβ without preventing complex assembly.

    Evidence Biochemical reconstitution of PSEN1 T291P γ-secretase and APP/Aβ interaction stability assays; Aβ profiling

    PMID:33969176

    Open questions at the time
    • Single mutation, single lab
    • Processivity model not generalized across mutations here
  12. 2022 Medium

    Provided a quantitative mechanistic link between γ-secretase processivity (Aβ isoform profile) and clinical age at onset across many FAD variants.

    Evidence Cell-based Aβ profiling of 25 PSEN1 variants with linear regression against age at onset

    PMID:35365805

    Open questions at the time
    • Cell-based profiling may not capture in vivo processivity exactly
    • Spastic-paraparesis variants show distinct unexplained profiles
  13. 2023 Medium

    Demonstrated mutation-specific divergence by showing L435F increases Notch signaling and progenitors, opposite to other PSEN1 mutations, refining the view that PSEN1 mutations are not mechanistically uniform.

    Evidence iPSC-derived cortical spheroids from PSEN1 L435F carriers; Notch target genes, progenitor/neuron quantification, activity measurement

    PMID:37352850

    Open questions at the time
    • Single mutation, single system
    • Basis for opposite directionality not mechanistically resolved
  14. 2024 Medium

    Extended FAD mechanism to primates, showing knock-in PSEN1 mutations perturb γ-secretase enzyme-substrate interactions and elevate plasma Aβ early in life.

    Evidence CRISPR/Cas9 knock-in marmosets; longitudinal plasma Aβ, brain γ-secretase enzyme-substrate interaction analysis, multiomics

    PMID:38574388

    Open questions at the time
    • Two mutations only
    • Early biochemical perturbation not yet linked to downstream neuropathology in this model

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PS1's protease-dependent (Aβ/Notch) and protease-independent (v-ATPase chaperone) functions are coordinately disrupted by individual FAD mutations, and what structural transitions underlie the conformational/processivity changes, remain unresolved.
  • No unified structural model linking conformation, phosphorylation, and processivity
  • Non-neuronal roles (inflammatory, tumor immune, MAPT regulation) rest on low-confidence single studies
  • Quantitative relationship between chaperone-loss and protease-shift across mutations undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0016787 hydrolase activity 2 GO:0044183 protein folding chaperone 1
Localization
GO:0005886 plasma membrane 2 GO:0005764 lysosome 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1643685 Disease 3 GO:0140096 catalytic activity, acting on a protein 2 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-9612973 Autophagy 2
Partners
APPATP6V0A1NCSTNNOTCH1PSENENSEC61A1
Complex memberships
γ-secretase complex

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 The C. elegans gene sel-12, a homolog of human S182/PSEN1, facilitates signaling mediated by the Notch-family receptors lin-12 and glp-1 in receiving cells, establishing that presenilin functions in the Notch signaling pathway. This was demonstrated by a suppressor screen identifying sel-12 as a suppressor of a lin-12 gain-of-function mutation. Genetic suppressor screen in C. elegans; loss-of-function epistasis Nature High 7566091
1998 PS1-deficient neurons fail to secrete Aβ and accumulate C-terminal fragments (CTFs) from APP and APLP1, indicating PS1 promotes intramembrane cleavage and/or degradation of membrane-bound CTFs. Additionally, maturation and BDNF-inducible autophosphorylation of TrkB is severely compromised in PS1-null neurons, showing PS1 modulates trafficking and metabolism of a selected set of membrane proteins. Genetic knockout (PS1-deficient neurons); biochemical analysis of APP processing and TrkB trafficking in primary neurons Neuron High 9856475
2010 PS1 is required for lysosomal acidification and autophagosome clearance during macroautophagy. PS1 holoprotein selectively binds the unglycosylated V0a1 subunit of v-ATPase and the Sec61α/oligosaccharyltransferase complex, enabling N-glycosylation of V0a1 and its efficient ER-to-lysosome delivery. Loss of PS1 prevents v-ATPase targeting to lysosomes, impairing lysosomal acidification, cathepsin activation, and substrate proteolysis. PS1 null blastocysts, PS1 hypomorphic and conditional knockout neurons, fibroblasts from FAD patients; biochemical fractionation, co-immunoprecipitation with Sec61α/OST complex, N-glycosylation assays, cathepsin activity assays, autolysosome pH measurements Cell High 20541250
2005 APP transmembrane domain substitutions V715F and L720P both significantly increase the distance between the N- and C-termini of PS1 (measured by FRET), indicating they alter PS1 conformation, with differential effects on Aβ and AICD production by γ-secretase. FRET-based conformational imaging of PS1; in vitro generation of AICD; cell-based Aβ peptide measurement Journal of neurochemistry Medium 16086682
2011 Overexpression of PS1 alone in vivo is sufficient to increase levels of other γ-secretase components (Nicastrin, Pen-2) and elevate the level of active γ-secretase complex and its enzymatic activity, leading to increased Aβ deposition. FAD mutant PS1-containing γ-secretase is less catalytically active overall than wild-type PS1 γ-secretase but cleaves APP-CTFs more efficiently at the Aβ42 site than the Aβ40 site. Transgenic mouse overexpression of wild-type or FAD mutant PS1; γ-secretase activity assays; Aβ isoform measurement; western blotting of γ-secretase components PloS one Medium 22140537
2017 PS1 phosphorylation at Ser367 (domain 3: S365, S366, S367) by Protein Kinase A drives a pathogenic 'closed' PS1 conformation (measured by FRET-based imaging) and increases the Aβ42/40 ratio. Activity-driven and PKA-mediated phosphorylation at three domains of PS1 (T74; S310/S313; S365/S366/S367) modulate γ-secretase cleavage specificity, with S367 being the critical residue. FRET-based conformational imaging of PS1 in cells and living mouse brain; PKA pharmacological manipulation; site-directed mutagenesis at phosphorylation sites; Aβ42/40 ratio measurement eLife High 28132667
2010 Autophagy impairment (via Atg5 knockdown or chloroquine treatment) increases PS1 expression through the eIF2α kinase GCN2 and its downstream target ATF4, which in turn elevates γ-secretase activity (Aβ production and Notch1 cleavage). This establishes that the autophagy-lysosomal system regulates γ-secretase/PS1 activity through GCN2. shRNA knockdown of Atg5, GCN2, or ATF4 in HEK293 cells; chloroquine treatment; Aβ ELISA; Notch1 cleavage assay; western blotting Autophagy Medium 20168091
2021 PSEN1 mutations reduce Notch signaling and cause premature neurogenesis in human iPSC-derived cortical cultures (2D) and cerebral organoids (3D). This was confirmed by observing increased progenitor depletion and premature post-mitotic neuron generation, partially rescued by augmenting Notch signaling, establishing that PSEN1/γ-secretase activity is required for normal Notch-regulated neurogenesis in human neural stem cells. iPSC-derived cortical differentiation in 2D and 3D organoids from FAD PSEN1 mutation carriers; Notch target gene expression; Notch signaling rescue experiments; postmortem tissue analysis of adult hippocampal neurogenesis Cell reports Medium 33440141
2023 The PSEN1 L435F heterozygous mutation increases Notch target gene expression during early cortical spheroid (hCS) development, leading to increased hCS size, increased neural progenitors, and decreased post-mitotic neurons—effects opposite to those reported for other PSEN1 mutations—demonstrating mutation-specific differential effects on Notch-regulated neurogenesis. Human iPSC-derived cortical spheroids from PSEN1 L435F heterozygous carriers; Notch target gene expression; progenitor and neuron quantification; neuronal activity measurement Stem cell reports Medium 37352850
2022 Comprehensive analysis of 25 FAD-linked PSEN1 variants showed that the Aβ(37+38+40)/(42+43) ratio produced by γ-secretase (the 'Aβ profile') linearly correlates with age at disease onset, providing a quantitative mechanistic link between γ-secretase processivity and clinical AAO. PSEN1 mutations causing spastic paraparesis show a distinct Aβ profile, suggesting a different mechanistic basis. Cell-based γ-secretase Aβ isoform profiling of 25 PSEN1 FAD variants; linear regression analysis against age at onset; hypothesis-driven and data-driven approaches Molecular psychiatry Medium 35365805
2002 Gene-targeted mice expressing only FAD mutant PS1-P264L (without wild-type PS1) show elevated Aβ42 production sufficient to cause amyloid deposition when crossed with knock-in APP mice, without APP overproduction. Notably, levels of PS1 N- and C-terminal protein fragments are reduced while holoprotein is increased in PS1(P264L/P264L) mice, demonstrating that FAD mutations alter PS1 endoproteolysis. Gene-targeted knock-in mouse model; western blotting; Aβ ELISA; histological amyloid quantification over time Neurobiology of aging Medium 11959395
2015 PSEN1 mutations in early-onset AD lead to increased production of Aβ42 relative to Aβ40, reconstituting a core biochemical feature of FAD. This was demonstrated in iPSC-derived neural progenitor cells (NPCs) from affected PSEN1 mutation carriers, where the elevated Aβ42/40 ratio was more pronounced than in fibroblasts from the same donors. iPSC-derived neural progenitor cells from FAD PSEN1 mutation carriers; Aβ42/40 ELISA; molecular profiling PloS one Medium 24416243
2019 The HS-linked PSEN1-P242LfsX11 frameshift mutation mediates cytokine and chemokine expression in macrophages and prolongs TNFα production in response to LPS stimulation, revealing a role for PS1 in inflammatory signaling in non-neuronal cells. This mutation is located on the opposite face of TM5 from AD-linked PSEN1 mutations. THP-1 cells and PMA-differentiated macrophages with PSEN1-P242LfsX11 expression; cytokine/chemokine measurement by ELISA; LPS stimulation assay Human molecular genetics Low 30544224
2015 Overexpression of wild-type PSEN1 reduces MAPT (tau) promoter activity in a luciferase reporter assay and increases methylation of the endogenous MAPT promoter. A PSEN1 Δexon9 FAD mutation shows a smaller reduction in MAPT promoter activity compared to wild-type PSEN1, consistent with decreased ability to modulate MAPT gene methylation. In vitro PSEN1 overexpression; luciferase MAPT promoter reporter assay; endogenous MAPT promoter methylation measurement; brain tissue MAPT methylation analysis Current Alzheimer research Low 26159201
2021 PS1 is highly expressed in cancer-associated fibroblasts (CAFs) and its silencing promotes CD8+ CTL proliferation and penetration in ovarian tumor models. PS1 silencing reduces IL-1β (a major immune inhibitor) in the tumor microenvironment via the WNT/β-catenin pathway, establishing PS1 as a regulator of tumor immune suppression through this pathway. PS1 knockdown in CAFs; in vivo ovarian tumor models; CTL penetration assays; IL-1β measurement; WNT/β-catenin pathway analysis Frontiers in immunology Low 32587587
2024 Marmosets carrying PSEN1 C410Y or A426P knock-in mutations show alterations in gamma-secretase enzyme-substrate interactions in brain prior to adulthood and elevated plasma amyloid beta, demonstrating that FAD PSEN1 mutations perturb γ-secretase catalytic interactions early in life. CRISPR/Cas9 knock-in marmosets; longitudinal plasma Aβ measurement; brain gamma-secretase enzyme-substrate interaction analysis; multiomics Alzheimer's & dementia Medium 38574388
2021 The PSEN1 T291Pro mutation destabilizes γ-secretase-APP/Aβn interactions during proteolysis, enhancing production of longer Aβ peptides, even though it does not alter active γ-secretase reconstitution. This was established by biochemical analysis of the mutant γ-secretase complex. Biochemical analysis of mutant PSEN1 T291Pro γ-secretase reconstitution and APP/Aβ interaction stability; Aβ peptide profiling Alzheimer's & dementia (Amsterdam, Netherlands) Medium 33969176

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 984 20541250
1995 Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature 629 7566091
2017 APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS medicine 468 28350801
1995 The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nature genetics 411 7550356
1998 Effects of PS1 deficiency on membrane protein trafficking in neurons. Neuron 325 9856475
1996 Expression of presenilin 1 and 2 (PS1 and PS2) in human and murine tissues. The Journal of neuroscience : the official journal of the Society for Neuroscience 250 8922407
2019 Urolithin A attenuates memory impairment and neuroinflammation in APP/PS1 mice. Journal of neuroinflammation 211 30871577
2017 Inflammatory microglia are glycolytic and iron retentive and typify the microglia in APP/PS1 mice. Brain, behavior, and immunity 171 29061364
2013 CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in AβPP/PS1 mice. Journal of Alzheimer's disease : JAD 168 23515018
2014 Characterization and molecular profiling of PSEN1 familial Alzheimer's disease iPSC-derived neural progenitors. PloS one 138 24416243
2010 Increased cortical thickness and caudate volume precede atrophy in PSEN1 mutation carriers. Journal of Alzheimer's disease : JAD 128 20858974
2002 FAD mutant PS-1 gene-targeted mice: increased A beta 42 and A beta deposition without APP overproduction. Neurobiology of aging 116 11959395
2019 Fructooligosaccharides Ameliorating Cognitive Deficits and Neurodegeneration in APP/PS1 Transgenic Mice through Modulating Gut Microbiota. Journal of agricultural and food chemistry 113 30816709
2005 Receptor-operated Ca2+ entry mediated by TRPC3/TRPC6 proteins in rat prostate smooth muscle (PS1) cell line. Journal of cellular physiology 92 15672411
1996 Identification and neuron specific expression of the S182/presenilin I protein in human and rodent brains. Journal of neuroscience research 91 8841992
2022 Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Molecular psychiatry 86 35365805
2021 Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis. Cell reports 86 33440141
2019 The Pseudogene Olfr29-ps1 Promotes the Suppressive Function and Differentiation of Monocytic MDSCs. Cancer immunology research 82 30914411
2022 Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene. International journal of molecular sciences 79 36142879
1997 E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles. Human mutation 79 9298817
2013 Puerarin alleviates cognitive impairment and oxidative stress in APP/PS1 transgenic mice. The international journal of neuropsychopharmacology 75 24345484
2004 Clinical, pathological, and biochemical spectrum of Alzheimer disease associated with PS-1 mutations. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 75 15010344
1994 Drosophila PS1 integrin is a laminin receptor and differs in ligand specificity from PS2. Proceedings of the National Academy of Sciences of the United States of America 75 7972082
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
2010 Autophagy impairment stimulates PS1 expression and gamma-secretase activity. Autophagy 63 20168091
2020 Epigallocatechin-3-gallate Alleviates Cognitive Deficits in APP/PS1 Mice. Current medical science 58 32166661
2017 miR-124 downregulates BACE 1 and alters autophagy in APP/PS1 transgenic mice. Toxicology letters 56 28867212
1995 High levels of amyloid-beta protein from S182 (Glu246) familial Alzheimer's cells. Neuroreport 51 8742455
2013 Origin of the PSEN1 E280A mutation causing early-onset Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association 50 24239249
1993 Cloning and characterization of alpha PS1, a novel Drosophila melanogaster integrin. Mechanisms of development 50 8240969
2019 APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease. International journal of molecular sciences 49 31557888
2014 The miR-193a-3p regulated PSEN1 gene suppresses the multi-chemoresistance of bladder cancer. Biochimica et biophysica acta 49 25542424
2016 Chronic Stress Aggravates Cognitive Impairment and Suppresses Insulin Associated Signaling Pathway in APP/PS1 Mice. Journal of Alzheimer's disease : JAD 48 27392857
2020 Suvorexant ameliorates cognitive impairments and pathology in APP/PS1 transgenic mice. Neurobiology of aging 47 32224066
2020 Codonopsis pilosula polysaccharide attenuates Aβ toxicity and cognitive defects in APP/PS1 mice. Aging 47 32652518
2008 Novel PSEN1 and PGRN mutations in early-onset familial frontotemporal dementia. Neurobiology of aging 47 18314228
2024 Exercise-Induced Reduction of IGF1R Sumoylation Attenuates Neuroinflammation in APP/PS1 Transgenic Mice. Journal of advanced research 46 38565402
2019 Intermittent hypoxia improves cognition and reduces anxiety-related behavior in APP/PS1 mice. Brain and behavior 45 31877583
2023 Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer's Disease. International journal of molecular sciences 41 37176125
2015 Apolipoprotein D modulates amyloid pathology in APP/PS1 Alzheimer's disease mice. Neurobiology of aging 41 25784209
2015 CART treatment improves memory and synaptic structure in APP/PS1 mice. Scientific reports 41 25959573
2021 Downregulating expression of OPTN elevates neuroinflammation via AIM2 inflammasome- and RIPK1-activating mechanisms in APP/PS1 transgenic mice. Journal of neuroinflammation 40 34861878
2019 Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice. Acta neuropathologica communications 40 30885273
2012 Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiology of aging 39 22503161
2020 Bilberry anthocyanins improve neuroinflammation and cognitive dysfunction in APP/PSEN1 mice via the CD33/TREM2/TYROBP signaling pathway in microglia. Food & function 38 32003387
2018 Characterization of Impaired Cerebrovascular Structure in APP/PS1 Mouse Brains. Neuroscience 38 29777753
2010 Worldwide distribution of PSEN1 Met146Leu mutation: a large variability for a founder mutation. Neurology 37 20164095
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
2020 Zerumbone ameliorates behavioral impairments and neuropathology in transgenic APP/PS1 mice by suppressing MAPK signaling. Journal of neuroinflammation 35 32066466
2020 Riluzole attenuates glutamatergic tone and cognitive decline in AβPP/PS1 mice. Journal of neurochemistry 34 33107040
2019 Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiology of aging 34 30822634
2020 A Three-Dimensional Alzheimer's Disease Cell Culture Model Using iPSC-Derived Neurons Carrying A246E Mutation in PSEN1. Frontiers in cellular neuroscience 33 32655369
2014 Clinical and neuroimaging characterization of Chinese dementia patients with PSEN1 and PSEN2 mutations. Dementia and geriatric cognitive disorders 32 25323700
2019 Analysis of hidradenitis suppurativa-linked mutations in four genes and the effects of PSEN1-P242LfsX11 on cytokine and chemokine expression in macrophages. Human molecular genetics 29 30544224
2005 APP substitutions V715F and L720P alter PS1 conformation and differentially affect Abeta and AICD generation. Journal of neurochemistry 29 16086682
2024 Tirzepatide shows neuroprotective effects via regulating brain glucose metabolism in APP/PS1 mice. Peptides 27 39002758
2023 Aerobic exercise attenuates autophagy-lysosomal flux deficits by ADRB2/β2-adrenergic receptor-mediated V-ATPase assembly factor VMA21 signaling in APP-PSEN1/PS1 mice. Autophagy 27 37964627
2023 Familial Alzheimer's disease-associated PSEN1 mutations affect neurodevelopment through increased Notch signaling. Stem cell reports 26 37352850
2020 Knockdown of lncRNA BLACAT1 enhances radiosensitivity of head and neck squamous cell carcinoma cells by regulating PSEN1. The British journal of radiology 26 31944856
2023 Aberrant splicing of PSEN2, but not PSEN1, in individuals with sporadic Alzheimer's disease. Brain : a journal of neurology 25 35949106
2018 Protein levels of ADAM10, BACE1, and PSEN1 in platelets and leukocytes of Alzheimer's disease patients. European archives of psychiatry and clinical neuroscience 25 29845446
1996 Molecular analysis of the presenilin 1 (S182) gene in "sporadic" cases of Alzheimer's disease: identification and characterisation of unusual splice variants. Journal of neurochemistry 25 8627338
2021 Spastic paraplegia preceding PSEN1-related familial Alzheimer's disease. Alzheimer's & dementia (Amsterdam, Netherlands) 24 33969176
2020 Muscone Ameliorates Synaptic Dysfunction and Cognitive Deficits in APP/PS1 Mice. Journal of Alzheimer's disease : JAD 24 32538849
2020 Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimer's research & therapy 24 32917274
2021 Andrographolide ameliorates neuroinflammation in APP/PS1 transgenic mice. International immunopharmacology 23 34162168
2019 miR-124 regulates cerebromicrovascular function in APP/PS1 transgenic mice via C1ql3. Brain research bulletin 23 31499089
1996 Association between a PS-1 intronic polymorphism and late onset Alzheimer's disease. Neuroreport 23 8930979
2020 Ascorbate deficiency decreases dopamine release in gulo-/- and APP/PSEN1 mice. Journal of neurochemistry 22 32797675
2017 Pathogenic PS1 phosphorylation at Ser367. eLife 22 28132667
2011 Increased expression of PS1 is sufficient to elevate the level and activity of γ-secretase in vivo. PloS one 22 22140537
2023 Differential methylation of circRNA m6A in an APP/PS1 Alzheimer's disease mouse model. Molecular medicine reports 21 36660942
2023 Inhibition of NLRP1 inflammasome improves autophagy dysfunction and Aβ disposition in APP/PS1 mice. Behavioral and brain functions : BBF 21 37055801
2016 The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice. Neurobiology of aging 21 26973101
2016 Widespread white matter and conduction defects in PSEN1-related spastic paraparesis. Neurobiology of aging 21 27614114
2023 Omaveloxolone ameliorates cognitive dysfunction in APP/PS1 mice by stabilizing the STAT3 pathway. Life sciences 20 37951537
2021 Fluoxetine Promotes Hippocampal Oligodendrocyte Maturation and Delays Learning and Memory Decline in APP/PS1 Mice. Frontiers in aging neuroscience 20 33519426
2020 Cell stemness is maintained upon concurrent expression of RB and the mitochondrial ribosomal protein S18-2. Proceedings of the National Academy of Sciences of the United States of America 20 32571933
2023 Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred. Alzheimer's & dementia : the journal of the Alzheimer's Association 19 36951251
2018 Novel peptide dermaseptin-PS1 exhibits anticancer activity via induction of intrinsic apoptosis signalling. Journal of cellular and molecular medicine 19 30461197
2022 Targeting PSEN1 by lnc-CYP3A43-2/miR-29b-2-5p to Reduce β Amyloid Plaque Formation and Improve Cognition Function. International journal of molecular sciences 18 36142465
2020 CTL Attenuation Regulated by PS1 in Cancer-Associated Fibroblast. Frontiers in immunology 18 32587587
2024 Early molecular events of autosomal-dominant Alzheimer's disease in marmosets with PSEN1 mutations. Alzheimer's & dementia : the journal of the Alzheimer's Association 17 38574388
2024 Encapsulated lactiplantibacillus plantarum improves Alzheimer's symptoms in APP/PS1 mice. Journal of nanobiotechnology 16 39304919
2023 Moxibustion improves hypothalamus Aqp4 polarization in APP/PS1 mice: Evidence from spatial transcriptomics. Frontiers in aging neuroscience 16 36819717
2022 Catalpol Ameliorates Neurotoxicity in N2a/APP695swe Cells and APP/PS1 Transgenic Mice. Neurotoxicity research 16 35699892
2022 Berberine Ameliorates Cognitive Disorder via GSK3β/PGC-1α Signaling in APP/PS1 Mice. Journal of nutritional science and vitaminology 15 35768254
2020 Angiopoietin-1 accelerates Alzheimer's disease via FOXA2/PEN2/APP pathway in APP/PS1 mice. Life sciences 15 32061671
2017 A Preliminary Study: PS1 Increases U1 snRNA Expression Associated with AD. Journal of molecular neuroscience : MN 15 28577205
2018 PSEN1 p.Met233Val in a Complex Neurodegenerative Movement and Neuropsychiatric Disorder. Journal of movement disorders 14 29316780
2017 Estrogen Modulates ubc9 Expression and Synaptic Redistribution in the Brain of APP/PS1 Mice and Cortical Neurons. Journal of molecular neuroscience : MN 14 28150190
2015 BACE-1, PS-1 and sAPPβ Levels Are Increased in Plasma from Sporadic Inclusion Body Myositis Patients: Surrogate Biomarkers among Inflammatory Myopathies. Molecular medicine (Cambridge, Mass.) 14 26552061
2011 A novel pathogenic PSEN1 mutation in a family with Alzheimer's disease: phenotypical and neuropathological features. Journal of Alzheimer's disease : JAD 14 21422519
2023 Hydralazine inhibits neuroinflammation and oxidative stress in APP/PS1 mice via TLR4/NF-κB and Nrf2 pathways. Neuropharmacology 13 37661037
2022 Agomelatine Prevents Amyloid Plaque Deposition, Tau Phosphorylation, and Neuroinflammation in APP/PS1 Mice. Frontiers in aging neuroscience 13 35153715
2021 Inflammatory Chemokines Expression Variations and Their Receptors in APP/PS1 Mice. Journal of Alzheimer's disease : JAD 13 34397415
2020 Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice. Molecular and cellular biology 13 31964754
2019 Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer's Disease. Aging and disease 13 31440394
2015 Effect of PSEN1 mutations on MAPT methylation in early-onset Alzheimer's disease. Current Alzheimer research 13 26159201

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