ArticleProceedings of the National Academy of Sciences of the United States of America2022
Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer's disease mice.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 28 citations in OpenAlex.
- KARIs, Ghrelin Receptor Agonists With Excellent Brain Permeability, Increase Food Intake and Attenuate the Muscle Loss in Mice.Journal of cachexia, sarcopenia and muscle · 2026Article
- Gut Microbiome-Sphingolipid Metabolism-Brain Axis Interactions: Neuroprotective Effects of Amitriptyline as Functional Inhibitor of Acid Sphingomyelinase in a Mouse Model of Tauopathy.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2026Article
- Acid sphingomyelinase activity suggests a new antipsychotic pharmaco-treatment strategy for schizophrenia.Molecular psychiatry · 2025Article
- HDL-bound S1P affects the subventricular niche and early neuropathological features of Alzheimer's disease.Nature communications · 2025Article
- Metformin carbon dots enhance neurogenesis and neuroprotection in Alzheimer's disease: A potential nanomedicine approach.Materials today. Bio · 2024Article
- Acid sphingomyelinase as a pathological and therapeutic target in neurological disorders: focus on Alzheimer's disease.Experimental & molecular medicine · 2024Review
- Simple model systems reveal conserved mechanisms of Alzheimer's disease and related tauopathies.Molecular neurodegeneration · 2023Review
- Multi-faceted small molecule for Alzheimer's disease.Neural regeneration research · 2023Article
- Ghrelin inhibits NLRP3 inflammasome activation by upregulating autophagy to improve Alzheimer's disease.In vitro cellular & developmental biology. Animal · 2023Article
- Immunotherapy targeting plasma ASM is protective in a mouse model of Alzheimer's disease.Nature communications · 2023Article
- Ghrelin system in Alzheimer's disease.Current opinion in neurobiology · 2023Review
- Acid sphingomyelinase inhibition improves motor behavioral deficits and neuronal loss in an amyotrophic lateral sclerosis mouse model.BMB reports · 2022Article
- Myelin repair in Alzheimer's disease: a review of biological pathways and potential therapeutics.Translational neurodegeneration · 2022Review
- Diverse Roles of Ceramide in the Progression and Pathogenesis of Alzheimer's Disease.Biomedicines · 2022Review
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Authors and funding
19 authors at 7 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Alzheimer's disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.
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