Ohno Lab

Head of Lab

Masuo Ohno, PhD

Molecular and Cellular Cognition for Alzheimer's Disease Therapy

The Ohno lab studies molecular and cellular mechanisms of Alzheimer’s disease (AD) and related cognitive disorders by applying multidisciplinary approaches to transgenic mouse models. We focus on the β-secretase enzyme called BACE1, which initiates the production of amyloid-β (Aβ) peptides from their parent molecule APP, since the genetics indicates that Aβ is the key driver of disease progression.



By evaluating gene knockout andsmall-molecule inhibitors in AD mouse models (e.g., 5XFAD), we have demonstrated that successful therapeutic BACE1 inhibition for cognitive benefits needs to start during very early or asymptomatic disease stages. Importantly, recent failure of BACE1 inhibitor clinical trials (especially, cognitive worsening in early or prodromal AD cases including MCI) brings up the issue of critical physiological function of BACE1 (most likely through regulating signaling pathways via substrates other than APP). Our research goal is to develop therapeutic interventions for AD that can increase BACE1 inhibition efficacy in ameliorating cognitive symptoms, while avoiding potential adverse effects associated with direct over-inhibition. Our work will have important implications for designing safe and practical BACE1 inhibitor trials ranging from combination or multi-targeted therapy for symptomatic AD to preventive BACE1 inhibitor monotherapy in a preclinical stage of AD.

Selected Publications

Ohno M. Accelerated long-term forgetting is a BACE1 inhibitor-reversible incipient cognitive phenotype in Alzheimer's disease model mice. Neuropsychopharmacol Rep.2021 Jun;41(2):255-259. doi: 10.1002/npr2.12174. Epub 2021 Mar 22. PMID: 33749160; PMCID: PMC8340838
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Devi L, Tang J, Ohno M. Beneficial effects of the β-secretase inhibitor GRL-8234 in 5XFAD Alzheimer's transgenic mice lessen during disease progression. Curr Alzheimer Res. 2015;12(1):13-21. doi: 10.2174/1567205012666141218125042. PMID: 25523425; PMCID: PMC4414026
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Devi L, Ohno M. PERK mediates eIF2α phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer's disease. Neurobiol Aging. 2014 Oct;35(10):2272-81. doi: 10.1016/j.neurobiolaging.2014.04.031. Epub 2014 May 2. PMID: 24889041; PMCID: PMC4127890
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Publications

All publications