ArticleEMBO molecular medicine2016
Generation and deposition of Aβ43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease.
Article in EMBO molecular medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 75 citations in OpenAlex.
- The relationship between amyloid-β peptide spectrum and the spastic paraparesis phenotype in autosomal dominant Alzheimer's disease.Alzheimer's research & therapy · 2025Article
- Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes.Molecular neurodegeneration · 2025Article
- γ-Secretase modulator resistance of an aggressive Alzheimer-causing presenilin mutant can be overcome in the heterozygous patient state by a set of advanced compounds.Alzheimer's research & therapy · 2025Article
- Article
- The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated Aβ43 and atypical clinical manifestations.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Alzheimer's disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling.bioRxiv : the preprint server for biology · 2024Article
- New precision medicine avenues to the prevention of Alzheimer's disease from insights into the structure and function of γ-secretases.The EMBO journal · 2024Review
- APP substrate ectodomain defines amyloid-β peptide length by restraining γ-secretase processivity and facilitating product release.The EMBO journal · 2023Article
- Aβ43 levels determine the onset of pathological amyloid deposition.The Journal of biological chemistry · 2023Article
- Different transmembrane domains determine the specificity and efficiency of the cleavage activity of the γ-secretase subunit presenilin.The Journal of biological chemistry · 2023Article
- Cooperation of N- and C-terminal substrate transmembrane domain segments in intramembrane proteolysis by γ-secretase.Communications biology · 2023Article
- Effects of presenilin-1 familial Alzheimer's disease mutations on γ-secretase activation for cleavage of amyloid precursor protein.Communications biology · 2023Article
- Intracellular Amyloid-β in the Normal Rat Brain and Human Subjects and Its relevance for Alzheimer's Disease.Journal of Alzheimer's disease : JAD · 2023Article
- Enzyme-substrate interface targeting by imidazole-based γ-secretase modulators activates γ-secretase and stabilizes its interaction with APP.The EMBO journal · 2022Article
- Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset.Molecular psychiatry · 2022Article
- Alzheimer's disease - the journey of a healthy brain into organ failure.Molecular neurodegeneration · 2022Review
- Disease-Modifying Therapies for Alzheimer's Disease: More Questions than Answers.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022Review
- Aβ43 aggregates exhibit enhanced prion-like seeding activity in mice.Acta neuropathologica communications · 2021Article
- Amyloid-βAlzheimer's research & therapy · 2020Article
- Unraveling the complexity of γ-secretase.Seminars in cell & developmental biology · 2020Review
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
As stated by the prevailing amyloid cascade hypothesis, Alzheimer's disease (AD) is caused by the aggregation and cerebral deposition of long amyloid-β peptide (Aβ) species, which are released from a C-terminal amyloid precursor protein fragment by γ-secretase. Mutations in its catalytic subunit presenilin-1 (PS1) increase the Aβ42 to Aβ40 ratio and are the major cause of familial AD (FAD). An opposing hypothesis states that loss of essential presenilin functions underlies the disease. A major argument for this hypothesis is the observation that the nearly inactive PS1 L435F mutant, paradoxically, causes FAD We now show that the very little Aβ generated by PS1 L435F consists primarily of Aβ43, a highly amyloidogenic species which was overlooked in previous studies of this mutant. We further demonstrate that the generation of Aβ43 is not due to a trans-dominant effect of this mutant on WT presenilin. Furthermore, we found Aβ43-containing plaques in brains of patients with this mutation. The aberrant generation of Aβ43 by this particular mutant provides a direct objection against the presenilin hypothesis.
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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.