7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease
Open accessAbstract
Increasing evidence suggests that reductions in brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) may have a role in the pathogenesis of Alzheimer's disease (AD). However, the efficacy and safety profile of BDNF therapy (eg, gene delivery) remains to be established toward clinical trials. Here, we evaluated the effects of 7,8-dihydroxyflavone (7,8-DHF), a recently identified small-molecule TrkB agonist that can pass the blood-brain barrier, in the 5XFAD transgenic mouse model of AD. 5XFAD mice at 12-15 months of age and non-transgenic littermate controls received systemic administration of 7,8-DHF (5 mg/kg, i.p.) once daily for 10 consecutive days. We found that 7,8-DHF rescued memory deficits of 5XFAD mice in the spontaneous alternation Y-maze task. 5XFAD mice showed impairments in the hippocampal BDNF-TrkB pathway, as evidenced by significant reductions in BDNF, TrkB receptors, and phosphorylated TrkB. 7,8-DHF restored deficient TrkB signaling in 5XFAD mice without affecting endogenous BDNF levels. Meanwhile, 5XFAD mice exhibited elevations in the β-secretase enzyme (BACE1) that initiates amyloid-β (Aβ) generation, as observed in sporadic AD. Interestingly, 7,8-DHF blocked BACE1 elevations and lowered levels of the β-secretase-cleaved C-terminal fragment of amyloid precursor protein (C99), Aβ40, and Aβ42 in 5XFAD mouse brains. Furthermore, BACE1 expression was decreased by 7,8-DHF in wild-type mice, suggesting that BDNF-TrkB signaling is also important for downregulating baseline levels of BACE1. Together, our findings indicate that TrkB activation with systemic 7,8-DHF can ameliorate AD-associated memory deficits, which may be, at least in part, attributable to reductions in BACE1 expression and β-amyloidogenesis.
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DHF restores memory deficits in 5XFAD and APP/PS1 mouse models of Alzheimer's disease after acute and chronic administration.
“Indeed, restoration of memory deficits in 5XFAD and APP/PS1 mouse models of Alzheimer’s disease (AD) have been shown after both acute and chronic administration of DHF (Bollen et al. 2013; Devi and Ohno 2012; Zhang et al. 2014c)”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Devi and Ohno 2012
The Drug Treatments section and the results under “Systemic 7,8-DHF Ameliorates Memory Deficits in 5XFAD Mice” report that ten daily doses restored spatial working-memory performance in 5XFAD mice. This paper does not report memory restoration after acute administration or test a separate APP/PS1 model; the citation therefore supports only the repeated-treatment 5XFAD part of the sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDelivery of the BDNF mimetic 7,8-dihydroxyflavone reverts cognitive deficits in an Alzheimer's disease animal model.
“Delivery of the BDNF mimetic 7-8-dihydroxiflavone is able to revert cognitive deficits in an AD animal model [202].”
From Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation (2019) · cites this paper as [202]
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- Authors
- Devi, L., & Ohno, M.
- Affiliations
- Nathan Kline Institute for Psychiatric Research (US)
- Corresponding author
- Ohno, Masuo
- ORCID
- Ohno, Masuo
- Venue
- Neuropsychopharmacology
- Published
- 2011-09-07
- Volume
- 37
- Issue
- 2
- Pages
- 434-444
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3242305
- OpenAlex
- W1979702721
- Cited by
- 282
- References
- 56
- Citations by year
- 2026: 14 · 2025: 7 · 2024: 18 · 2023: 15 · 2022: 14 · 2021: 27 · 2020: 18 · 2019: 23 · 2018: 18 · 2017: 15 · 2016: 22 · 2015: 21 · 2014: 25 · 2013: 34 · 2012: 11
- FWCI
- 15.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association (IIRG-08-91231)
- American Health Assistance Foundation (A2011311)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Keywords
- 7,8-dihydroxyflavone, TrkB agonist, Alzheimer's disease, BDNF/TrkB signaling, BACE1, beta-secretase, amyloid-beta, memory impairment, 5xFAD mice, hippocampus, blood-brain barrier
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Female, Humans, Male, Memory Disorders, Mice, Inbred Strains, Mice, Transgenic, Peptide Fragments, Phosphorylation, Signal Transduction, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Maze Learning, Brain-Derived Neurotrophic Factor, Receptor, trkB, Flavones, Mice, Amyloid Precursor Protein Secretases
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