ArticleJournal of Alzheimer's disease : JAD2020
Early-Onset Familial Alzheimer Disease Variant PSEN2 N141I Heterozygosity is Associated with Altered Microglia Phenotype.
Article in Journal of Alzheimer's disease : JAD, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 38 citations in OpenAlex.
- Loss of presenilin 2 function age-dependently increases susceptibility to kainate-induced acute seizures and blunts hippocampal kainate-type glutamate receptor expression.Experimental neurology · 2026Article
- Alzheimer's disease PSEN-2 N141I mutation reveals altered and shear-sensitive brain endothelial cell-like phenotype in human iPSC-derived models.Acta neuropathologica communications · 2025Article
- Loss of presenilin 2 function age-dependently increases susceptibility to kainate-induced acute seizures and blunts hippocampal kainate-type glutamate receptor expression.bioRxiv : the preprint server for biology · 2025Article
- Down syndrome and a presenilin 2 variant: dual genetic risk of Alzheimer's disease.Acta neuropathologica · 2025Article
- Biomarkers and therapeutic strategies targeting microglia in neurodegenerative diseases: current status and future directions.Molecular neurodegeneration · 2025Review
- Inferring cell-type-specific gene regulatory network from cellular transcriptomics data with GeneLink.Briefings in bioinformatics · 2025Article
- Alzheimer's disease-associated genotypes differentially influence chronic evoked seizure outcomes and antiseizure medicine efficacy in aged mice.Journal of Alzheimer's disease : JAD · 2025Article
- Non-transgenic rodent models of Alzheimer's disease for preclinical research: a review.Molecular biology reports · 2025Review
- Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer's disease.Alzheimer's research & therapy · 2025Article
- Altered expression of Presenilin2 impacts endolysosomal homeostasis and synapse function in Alzheimer's disease-relevant brain circuits.Nature communications · 2024Article
- Comprehensive Overview of Alzheimer's Disease: Etiological Insights and Degradation Strategies.International journal of molecular sciences · 2024Review
- Dynamic neuroinflammatory profiles predict Alzheimer's disease pathology in microglia-containing cerebral organoids.bioRxiv : the preprint server for biology · 2024Article
- Chronic evoked seizures in young pre-symptomatic APP/PS1 mice induce serotonin changes and accelerate onset of Alzheimer's disease-related neuropathology.Progress in neurobiology · 2024Article
- iPSC-derived PSEN2 (N141I) astrocytes and microglia exhibit a primed inflammatory phenotype.Journal of neuroinflammation · 2024Article
- Innate neuroimmunity across aging and neurodegeneration: a perspective from amyloidogenic evolvability.Frontiers in cell and developmental biology · 2024Review
- Development of a three-dimensional organoid model to explore early retinal phenotypes associated with Alzheimer's disease.Scientific reports · 2023Article
- Lysosomal acidification dysfunction in microglia: an emerging pathogenic mechanism of neuroinflammation and neurodegeneration.Journal of neuroinflammation · 2023Review
- Genetic Phenotypes of Alzheimer's Disease: Mechanisms and Potential Therapy.Phenomics (Cham, Switzerland) · 2023Review
- Aberrant splicing of PSEN2, but not PSEN1, in individuals with sporadic Alzheimer's disease.Brain : a journal of neurology · 2023Article
- The neuroimmune axis of Alzheimer's disease.Genome medicine · 2023Review
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundEarly-onset familial Alzheimer disease (EOFAD) is caused by heterozygous variants in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and APP genes. Decades after their discovery, the mechanisms by which these genes cause Alzheimer's disease (AD) or promote AD progression are not fully understood. While it is established that presenilin (PS) enzymatic activity produces amyloid-β (Aβ), PSs also regulate numerous other cellular functions, some of which intersect with known pathogenic drivers of neurodegeneration. Accumulating evidence suggests that microglia, resident innate immune cells in the central nervous system, play a key role in AD neurodegeneration.
objectivePrevious work has identified a regulatory role for PS2 in microglia. We hypothesized that PSEN2 variants lead to dysregulated microglia, which could further contribute to disease acceleration. To mimic the genotype of EOFAD patients, we created a transgenic mouse expressing PSEN2 N141I on a mouse background expressing one wildtype PS2 and two PS1 alleles.
resultsMicroglial expression of PSEN2 N141I resulted in impaired γ-secretase activity as well as exaggerated inflammatory cytokine release, NFκB activity, and Aβ internalization. In vivo, PS2 N141I mice showed enhanced IL-6 and TREM2 expression in brain as well as reduced branch number and length, an indication of "activated" morphology, in the absence of inflammatory stimuli. LPS intraperitoneal injection resulted in higher inflammatory gene expression in PS2 N141I mouse brain relative to controls.
conclusionOur findings demonstrate that PSEN2 N141I heterozygosity is associated with disrupted innate immune homeostasis, suggesting EOFAD variants may promote disease progression through non-neuronal cells beyond canonical dysregulated Aβ production.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.