ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2000
Presenilin-1 P264L knock-in mutation: differential effects on abeta production, amyloid deposition, and neuronal vulnerability.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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Who cites it
67 citing papers in PubMed, 134 citations in OpenAlex.
- Traumatic brain injury exacerbates mitochondrial dysfunction in APP/PS1 knock-in mice through time-dependent pathways.Experimental neurology · 2026Article
- Traumatic brain injury exacerbates mitochondrial dysfunction in APP/PS1 knock-in mice through time-dependent pathways.bioRxiv : the preprint server for biology · 2025Article
- Mutations in PSEN1 predispose inflammation in an astrocyte model of familial Alzheimer's disease through disrupted regulated intramembrane proteolysis.Molecular neurodegeneration · 2025Article
- Rodent Models of Alzheimer's Disease: Past Misconceptions and Future Prospects.International journal of molecular sciences · 2024Review
- Presenilin mutations and their impact on neuronal differentiation in Alzheimer's disease.Neural regeneration research · 2022Article
- Patient-Derived Fibroblasts With Presenilin-1 Mutations, That Model Aspects of Alzheimer's Disease Pathology, Constitute a Potential Object for Early Diagnosis.Frontiers in aging neuroscience · 2022Article
- Implications of Phosphoinositide 3-Kinase-Akt (PI3K-Akt) Pathway in the Pathogenesis of Alzheimer's Disease.Molecular neurobiology · 2022Review
- Relevance of transgenic mouse models for Alzheimer's disease.Progress in molecular biology and translational science · 2021Article
- Accelerated brain aging towards transcriptional inversion in a zebrafish model of the K115fs mutation of human PSEN2.PloS one · 2020Article
- Brain transcriptome analysis of a familial Alzheimer's disease-like mutation in the zebrafish presenilin 1 gene implies effects on energy production.Molecular brain · 2019Article
- Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer's disease.BMC neuroscience · 2019Article
- A method of predicting the in vitro fibril formation propensity of Aβ40 mutants based on their inclusion body levels in E. coli.Scientific reports · 2019Article
- Introduction of pathogenic mutations into the mouse Psen1 gene by Base Editor and Target-AID.Nature communications · 2018Article
- Integration of Drosophila and Human Genetics to Understand Notch Signaling Related Diseases.Advances in experimental medicine and biology · 2018Review
- Practical considerations for choosing a mouse model of Alzheimer's disease.Molecular neurodegeneration · 2017Review
- Genetic variants associated with neurodegenerative Alzheimer disease in natural models.Biological research · 2016Review
- Gene Therapy Models of Alzheimer's Disease and Other Dementias.Methods in molecular biology (Clifton, N.J.) · 2016Article
- Closed head injury in an age-related Alzheimer mouse model leads to an altered neuroinflammatory response and persistent cognitive impairment.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2015Article
- Cortical iron regulation and inflammatory response in Alzheimer's disease and APPSWE/PS1ΔE9 mice: a histological perspective.Frontiers in neuroscience · 2015Article
- Obesity and diabetes cause cognitive dysfunction in the absence of accelerated β-amyloid deposition in a novel murine model of mixed or vascular dementia.Acta neuropathologica communications · 2014Article
7 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The pathogenic mechanism linking presenilin-1 (PS-1) gene mutations to familial Alzheimer's disease (FAD) is uncertain, but has been proposed to include increased neuronal sensitivity to degeneration and enhanced amyloidogenic processing of the beta-amyloid precursor protein (APP). We investigated this issue by using gene targeting with the Cre-lox system to introduce an FAD-linked P264L mutation into the endogenous mouse PS-1 gene, an approach that maintains normal regulatory controls over expression. Primary cortical neurons derived from PS-1 homozygous mutant knock-in mice exhibit basal neurodegeneration similar to their PS-1 wild-type counterparts. Staurosporine and Abeta1-42 induce apoptosis, and neither the dose dependence nor maximal extent of cell death is altered by the PS-1 knock-in mutation. Similarly, glutamate-induced neuronal necrosis is unaffected by the PS-1P264L mutation. The lack of effect of the PS-1P264L mutation is confirmed by measures of basal- and toxin-induced caspase and calpain activation, biochemical indices of apoptotic and necrotic signaling, respectively. To analyze the influence of the PS-1P264L knock-in mutation on APP processing and the development of AD-type neuropathology, we created mouse lines carrying mutations in both PS-1 and APP. In contrast to the lack of effect on neuronal vulnerability, cortical neurons cultured from PS-1P264L homozygous mutant mice secrete Abeta42 at an increased rate, whereas secretion of Abeta40 is reduced. Moreover, the PS-1 knock-in mutation selectively increases Abeta42 levels in the mouse brain and accelerates the onset of amyloid deposition and its attendant reactive gliosis, even as a single mutant allele. We conclude that expression of an FAD-linked mutant PS-1 at normal levels does not generally increase cortical neuronal sensitivity to degeneration. Instead, enhanced amyloidogenic processing of APP likely is critical to the pathogenesis of PS-1-linked FAD.
Indexed as
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11102478PMC6773081W1651448739What OpenQuestion holds
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.