ArticleHuman molecular genetics2019
Candidate-based screening via gene modulation in human neurons and astrocytes implicates FERMT2 in Aβ and TAU proteostasis.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 45 citations in OpenAlex.
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- The Rise of Pluripotent Stem Cell-Derived Glia Models of Neuroinflammation.Neurology international · 2025Review
- The top 100 most cited publications on astrocytes in Alzheimer's disease from 2000 to 2025: a bibliometric analysis.Frontiers in neuroscience · 2025Article
- The Emerging Role of PCSK9 in the Pathogenesis of Alzheimer's Disease: A Possible Target for the Disease Treatment.International journal of molecular sciences · 2024Review
- Diverse signaling mechanisms and heterogeneity of astrocyte reactivity in Alzheimer's disease.Journal of neurochemistry · 2024Review
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- Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease.Acta neuropathologica communications · 2023Article
- A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity.International journal of molecular sciences · 2023Article
- Human-Induced Pluripotent Stem Cell (hiPSC)-Derived Neurons and Glia for the Elucidation of Pathogenic Mechanisms in Alzheimer's Disease.Methods in molecular biology (Clifton, N.J.) · 2023Review
- Relationship BetweenJournal of Alzheimer's disease reports · 2023Article
- Identification of Sex-Specific Genetic Variants Associated With Tau PET.Neurology. Genetics · 2022Article
- Human neural cell type-specific extracellular vesicle proteome defines disease-related molecules associated with activated astrocytes in Alzheimer's disease brain.Journal of extracellular vesicles · 2022Article
- Emerging Methods in Modeling Brain Development and Disease with Human Pluripotent Stem Cells.Methods in molecular biology (Clifton, N.J.) · 2022Article
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- Role of adaptin protein complexes in intracellular trafficking and their impact on diseases.Bioengineered · 2021Article
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Authors and funding
10 authors at 5 institutions in 1 country.
Funding
Abstract
Large-scale 'omic' studies investigating the pathophysiological processes that lead to Alzheimer's disease (AD) dementia have identified an increasing number of susceptibility genes, many of which are poorly characterized and have not previously been implicated in AD. Here, we evaluated the utility of human induced pluripotent stem cell-derived neurons and astrocytes as tools to systematically test AD-relevant cellular phenotypes following perturbation of candidate genes identified by genome-wide studies. Lentiviral-mediated delivery of shRNAs was used to modulate expression of 66 genes in astrocytes and 52 genes in induced neurons. Five genes (CNN2, GBA, GSTP1, MINT2 and FERMT2) in neurons and nine genes (CNN2, ITGB1, MINT2, SORL1, VLDLR, NPC1, NPC2, PSAP and SCARB2) in astrocytes significantly altered extracellular amyloid-β (Aβ) levels. Knockdown of AP3M2, CNN2, GSTP1, NPC1, NPC2, PSAP and SORL1 reduced interleukin-6 levels in astrocytes. Only knockdown of FERMT2 led to a reduction in the proportion of TAU that is phosphorylated. Further, CRISPR-Cas9 targeting of FERMT2 in both familial AD (fAD) and fAD-corrected human neurons validated the findings of reduced extracellular Aβ. Interestingly, FERMT2 reduction had no effect on the Aβ42:40 ratio in corrected neurons and a reduction of phospho-tau, but resulted in an elevation in Aβ42:40 ratio and no reduction in phospho-tau in fAD neurons. Taken together, this study has prioritized 15 genes as being involved in contributing to Aβ accumulation, phosphorylation of tau and/or cytokine secretion, and, as illustrated with FERMT2, it sets the stage for further cell-type-specific dissection of the role of these genes in AD.
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Registered trials
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.