ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2024
Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer's disease in mice.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 15 citations in OpenAlex.
- Endothelial C/EBPβ/AEP pathway drives vascular deterioration and systemic aging.Science advances · 2026Article
- Protease-Mediated TAR DNA-Binding Protein 43 (TDP-43) Pathogenesis: From Molecular Mechanisms to Therapeutic Opportunities.ACS pharmacology & translational science · 2026Review
- Neuroinflammation and Secretase Regulation in Alzheimer's Disease: From Molecular Cross-Talk to Multi-Target Therapeutics.International journal of molecular sciences · 2026Review
- C/EBPβ dictates postmenopausal FSHβ transcription and blockade of AEP/C/EBPβ pathway alleviates osteoporosis.Bone research · 2026Article
- Asparagine endopeptidase (AEP) inhibitor formulation via zein-based nanoparticle improves the therapeutic efficacy toward Alzheimer's disease.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- Review
- Immunotherapy against tau fragment diminishes AD pathology, improving synaptic function and cognition.Molecular neurodegeneration · 2025Article
- Targeting Active Microglia Alleviates Distal Edge of Proton Radiation-induced Neural Damage.Advances in radiation oncology · 2025Article
- Intranasal delivery of AEP inhibitor-loaded neuron-targeted liposome ameliorates radiation-induced brain injury.Materials today. Bio · 2025Article
- Intraneuronal Aβ accumulation causes tau hyperphosphorylation via endolysosomal leakage.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Asparagine Endopeptidase Inhibition Attenuates Tissue Plasminogen Activator-Induced Brain Hemorrhagic Transformation After Ischemic Stroke.CNS neuroscience & therapeutics · 2025Article
- Nanotechnology for Neurodegenerative Diseases: Recent Progress in Brain-Targeted Delivery, Stimuli-Responsive Platforms, and Organelle-Specific Therapeutics.International journal of nanomedicine · 2025Review
- Roles of C/EBPβ/AEP in Neurodegenerative Diseases.Current topics in medicinal chemistry · 2025Review
- Thy1-ApoE4/C/EBPβ double transgenic mice act as a sporadic model with Alzheimer's disease.Molecular psychiatry · 2024Article
- Norepinephrine Drives Sleep Fragmentation Activation of Asparagine Endopeptidase, Locus Ceruleus Degeneration, and Hippocampal Amyloid-βThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease with cognitive dysfunction as its major clinical symptom. However, there is no disease-modifying small molecular medicine to effectively slow down progression of the disease. Here, we show an optimized asparagine endopeptidase (AEP, also known as δ-secretase) inhibitor, #11 A, that displays an orderly in vivo pharmacokinetics/pharmacodynamics (PK/PD) relationship and robustly attenuates AD pathologies in a sporadic AD mouse model. #11 A is brain permeable with great oral bioavailability. It blocks AEP cleavage of APP and Tau dose-dependently, and significantly decreases Aβ40 and Aβ42 and p-Tau levels in APP/PS1 and Tau P301S mice after oral administration. Notably, #11 A strongly inhibits AEP and prevents mouse APP and Tau fragmentation by AEP, leading to reduction of mouse Aβ42 (mAβ42), mAβ40 and mouse p-Tau181 levels in Thy1-ApoE4/C/EBPβ transgenic mice in a dose-dependent manner. Repeated oral administration of #11 A substantially decreases mAβ aggregation as validated by Aβ PET assay, Tau pathology, neurodegeneration and brain volume reduction, resulting in alleviation of cognitive impairment. Therefore, our results support that #11 A is a disease-modifying preclinical candidate for pharmacologically treating 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.