Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 May 27;22(11):5719.
doi: 10.3390/ijms22115719.

Brain-Derived Neurotrophic Factor Signaling in the Pathophysiology of Alzheimer's Disease: Beneficial Effects of Flavonoids for Neuroprotection

Tadahiro Numakawa  1 , Haruki Odaka  2
Affiliations
Review

Brain-Derived Neurotrophic Factor Signaling in the Pathophysiology of Alzheimer's Disease: Beneficial Effects of Flavonoids for Neuroprotection

Tadahiro Numakawa et al. Int J Mol Sci. .

Abstract

The function of the brain-derived neurotrophic factor (BDNF) via activation through its high-affinity receptor Tropomyosin receptor kinase B (TrkB) has a pivotal role in cell differentiation, cell survival, synaptic plasticity, and both embryonic and adult neurogenesis in central nervous system neurons. A number of studies have demonstrated the possible involvement of altered expression and action of the BDNF/TrkB signaling in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). In this review, we introduce an essential role of the BDNF and its downstream signaling in neural function. We also review the current evidence on the deregulated the BDNF signaling in the pathophysiology of AD at gene, mRNA, and protein levels. Further, we discuss a potential usefulness of small compounds, including flavonoids, which can stimulate BDNF-related signaling as a BDNF-targeting therapy.

Keywords: Alzheimer’s disease; brain-derived neurotrophic factor; flavonoids; intracellular signaling.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic illustration of the BDNF signaling. The BDNF is initially translated as a precursor (proBDNF). proBDNF preferably binds with the p75-sortilin receptor complex and activates the JNK/caspase3 pathways which cause neural apoptosis and synaptic depression. proBDNF is proteolytically processed to a mature form (mBDNF). Binding of TrkB with mBDNF leads to activation of ERK1/2 and PI3K/Akt pathways to maintain cell survival and synaptic plasticity. mBDNF/TrkB also regulates Ca2+ homeostasis and neurotransmission via the PLCγ/IP3 pathway.
Figure 2
Figure 2
Schematic illustration of dysregulation of the BDNF in Alzheimer’s disease (AD). In the AD brain, mature BDNF (mBDNF) expression is affected by at least three distinct mechanisms, including gene polymorphism (rs6265, BDNF val66met), mRNA translation, and BDNF processing. Through these mechanisms, a reduction of functional mBDNF, impairment of synaptic plasticity/neurogenesis, and then significant decline in memory and learning functions are caused. Black arrow: downregulation.
See this image and copyright information in PMC

References

    1. Numakawa T., Odaka H. Brain-derived neurotrophic factor and neurogenesis. In: Martin C., Preedy V., Rajendram R., editors. Factors Affecting Neurodevelopment: Genetics, Neurology, Behavior, and Diet. Elsevier; Amsterdam, The Netherlands: 2021.
    1. Moreno-Jiménez E.P., Flor-García M., Terreros-Roncal J., Rábano A., Cafini F., Pallas-Bazarra N., Ávila J., Llorens-Martín M. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat. Med. 2019;25:554–560. doi: 10.1038/s41591-019-0375-9. - DOI - PubMed
    1. Garzon D., Yu G., Fahnestock M. A new brain-derived neurotrophic factor transcript and decrease in brain-derived neurotrophic factor transcripts 1, 2 and 3 in Alzheimer’s disease parietal cortex. J. Neurochem. 2002;82:1058–1064. doi: 10.1046/j.1471-4159.2002.01030.x. - DOI - PubMed
    1. Phillips H.S., Hains J.M., Armanini M., Laramee G.R., Johnson S.A., Winslow J.W. BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron. 1991;7:695–702. doi: 10.1016/0896-6273(91)90273-3. - DOI - PubMed
    1. Hock C., Heese K., Hulette C., Rosenberg C., Otten U. Region-specific neurotrophin imbalances in Alzheimer disease: Decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch. Neurol. 2000;57:846–851. doi: 10.1001/archneur.57.6.846. - DOI - PubMed

MeSH terms