ArticleMolecular neurodegeneration2012
Inhibition of γ-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia.
Article in Molecular neurodegeneration, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 80 citations in OpenAlex.
- The γ-Secretase Modulator, BMS-932481, Modulates Aβ Peptides in the Plasma and Cerebrospinal Fluid of Healthy Volunteers.The Journal of pharmacology and experimental therapeutics · 2016Trial
- Pathological mechanisms of motor dysfunction in familial Danish dementia: insights from a knock-in rat model.Journal of neuroinflammation · 2025Article
- Functional BRI2-TREM2 interactions in microglia: implications for Alzheimer's and related dementias.EMBO reports · 2024Article
- Novel Vaccine against Pathological Pyroglutamate-Modified Amyloid Beta for Prevention of Alzheimer's Disease.International journal of molecular sciences · 2023Article
- The Binding of Different Substrate Molecules at the Docking Site and the Active Site of γ-Secretase Can Trigger Toxic Events in Sporadic and Familial Alzheimer's Disease.International journal of molecular sciences · 2023Article
- Late-long-term potentiation magnitude, but not Aβ levels and amyloid pathology, is associated with behavioral performance in a rat knock-in model of Alzheimer disease.Frontiers in aging neuroscience · 2022Article
- Article
- Structural Analysis of the Simultaneous Activation and Inhibition of γ-Secretase Activity in the Development of Drugs for Alzheimer's Disease.Pharmaceutics · 2021Article
- Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer's disease models and human brains.Acta neuropathologica · 2021Article
- Tau is not necessary for amyloid-β-induced synaptic and memory impairments.The Journal of clinical investigation · 2020Article
- Extracellular vesicles: where the amyloid precursor protein carboxyl-terminal fragments accumulate and amyloid-β oligomerizes.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Knock-in rats with homozygousThe Journal of biological chemistry · 2020Article
- Trem2 Splicing and Expression are Preserved in a Human Aβ-producing, Rat Knock-in Model of Trem2-R47H Alzheimer's Risk Variant.Scientific reports · 2020Article
- Pharmacokinetic and Pharmacodynamic Effects of a γ-Secretase Modulator, PF-06648671, on CSF Amyloid-β Peptides in Randomized Phase I Studies.Clinical pharmacology and therapeutics · 2020Article
- Facilitation of glutamate, but not GABA, release in Familial Alzheimer's APP mutant Knock-in rats with increased β-cleavage of APP.Aging cell · 2019Article
- Tuning of Glutamate, But Not GABA, Release by an Intrasynaptic Vesicle APP Domain Whose Function Can Be Modulated by β- or α-Secretase Cleavage.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
- NGP 555, a γ-secretase modulator, shows a beneficial shift in the ratio of amyloid biomarkers in human cerebrospinal fluid at safe doses.Alzheimer's & dementia (New York, N. Y.) · 2019Article
- Exosome Production Is Key to Neuronal Endosomal Pathway Integrity in Neurodegenerative Diseases.Frontiers in neuroscience · 2019Review
- A role for tau in learning, memory and synaptic plasticity.Scientific reports · 2018Article
- Abolishing Tau cleavage by caspases at AspartateTranslational psychiatry · 2017Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
backgroundA mutation in the BRI2/ITM2b gene causes familial Danish dementia (FDD). BRI2 is an inhibitor of amyloid-β precursor protein (APP) processing, which is genetically linked to Alzheimer's disease (AD) pathogenesis. The FDD mutation leads to a loss of BRI2 protein and to increased APP processing. APP haplodeficiency and inhibition of APP cleavage by β-secretase rescue synaptic/memory deficits of a genetically congruous mouse model of FDD (FDDKI). β-cleavage of APP yields the β-carboxyl-terminal (β-CTF) and the amino-terminal-soluble APPβ (sAPPβ) fragments. γ-secretase processing of β-CTF generates Aβ, which is considered the main cause of AD. However, inhibiting Aβ production did not rescue the deficits of FDDKI mice, suggesting that sAPPβ/β-CTF, and not Aβ, are the toxic species causing memory loss.
resultsHere, we have further analyzed the effect of γ-secretase inhibition. We show that treatment with a γ-secretase inhibitor (GSI) results in a worsening of the memory deficits of FDDKI mice. This deleterious effect on memory correlates with increased levels of the β/α-CTFs APP fragments in synaptic fractions isolated from hippocampi of FDDKI mice, which is consistent with inhibition of γ-secretase activity.
conclusionThis harmful effect of the GSI is in sharp contrast with a pathogenic role for Aβ, and suggests that the worsening of memory deficits may be due to accumulation of synaptic-toxic β/α-CTFs caused by GSI treatment. However, γ-secretase cleaves more than 40 proteins; thus, the noxious effect of GSI on memory may be dependent on inhibition of cleavage of one or more of these other γ-secretase substrates. These two possibilities do not need to be mutually exclusive. Our results are consistent with the outcome of a clinical trial with the GSI Semagacestat, which caused a worsening of cognition, and advise against targeting γ-secretase in the therapy of AD. Overall, the data also indicate that FDDKI is a valuable mouse model to study AD pathogenesis and predict the clinical outcome of therapeutic agents for AD.
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