Memory-related Hippocampal Brain-derived Neurotrophic Factor Activation Pathways from Repetitive Transcranial Magnetic Stimulation in the 3xTg-AD Mouse Line

Overview

Journal Exp Gerontol

Specialty Geriatrics

Date 2024 Oct 1

PMID 39351497

Authors

M Windy McNerney

Eric P Kraybill

Sindhu Narayanan

Fatemeh S Mojabi

Vaibhavi Venkataramanan

Alesha Heath

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease is associated with a loss of plasticity and cognitive functioning. Previous research has shown that repetitive transcranial magnetic stimulation (rTMS) boosts cortical neurotrophic factors, potentially addressing this loss. The current study aimed to expand these findings by measuring brain-derived neurotrophic factor (BDNF), its downstream hippocampal signaling molecules, and behavioral effects of rTMS on the 3xTg-AD mouse line. 3xTg-AD (n = 24) and B6 wild-type controls (n = 26), aged 12 months, were given 14 days of consecutive rTMS at 10 Hz for 10 min. Following treatment, mice underwent a battery of behavioral tests and biochemical analysis of BDNF and its downstream cascades were evaluated via Western blot and ELISA. Results showed that brain stimulation did improve performance on the Object Place Task and increased hippocampal TrkB, ERK, and PLCγ in 3xTg-AD mice with minimal effects on wild-type mice. There was no significant difference in the levels of AKT and Truncated TrkB (TrkB.T1) between treatment and sham. Thus, rTMS has the potential to provide an efficacious non-invasive therapy for the treatment of Alzheimer's disease through activation of neurotrophic factor signaling.

Citing Articles

rTMS Modulation of Behavioral and Biological Measures in 3xTg-AD Mice.

Kraybill E, Mojabi F, Heath A, Spikes C, Beard C, McNerney M Brain Sci. 2025; 14(12).

PMID: 39766385 PMC: 11674534. DOI: 10.3390/brainsci14121186.

References

Jin W . Regulation of BDNF-TrkB Signaling and Potential Therapeutic Strategies for Parkinson's Disease. J Clin Med. 2020; 9(1). PMC: 7019526. DOI: 10.3390/jcm9010257. View

Satoh Y, Endo S, Ikeda T, Yamada K, Ito M, Kuroki M . Extracellular signal-regulated kinase 2 (ERK2) knockdown mice show deficits in long-term memory; ERK2 has a specific function in learning and memory. J Neurosci. 2007; 27(40):10765-76. PMC: 6672813. DOI: 10.1523/JNEUROSCI.0117-07.2007. View

McNerney M, Heath A, Narayanan S, Yesavage J . Repetitive Transcranial Magnetic Stimulation Improves Brain-Derived Neurotrophic Factor and Cholinergic Signaling in the 3xTgAD Mouse Model of Alzheimer's Disease. J Alzheimers Dis. 2022; 86(1):499-507. PMC: 9028616. DOI: 10.3233/JAD-215361. View

Danelon V, Montroull L, Unsain N, Barker P, Masco D . Calpain-dependent truncated form of TrkB-FL increases in neurodegenerative processes. Mol Cell Neurosci. 2016; 75:81-92. DOI: 10.1016/j.mcn.2016.07.002. View

Fleury S, Boukhatem I, Le Blanc J, Welman M, Lordkipanidze M . Tissue-Specificity of Antibodies Raised Against TrkB and p75 Receptors; Implications for Platelets as Models of Neurodegenerative Diseases. Front Immunol. 2021; 12:606861. PMC: 7905091. DOI: 10.3389/fimmu.2021.606861. View

Carim-Todd L, Bath K, Fulgenzi G, Yanpallewar S, Jing D, Barrick C . Endogenous truncated TrkB.T1 receptor regulates neuronal complexity and TrkB kinase receptor function in vivo. J Neurosci. 2009; 29(3):678-85. PMC: 2719435. DOI: 10.1523/JNEUROSCI.5060-08.2009. View

Barker G, Warburton E . When is the hippocampus involved in recognition memory?. J Neurosci. 2011; 31(29):10721-31. PMC: 6622630. DOI: 10.1523/JNEUROSCI.6413-10.2011. View

Kemppainen S, Rantamaki T, Jeronimo-Santos A, Lavasseur G, Autio H, Karpova N . Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice. Neurobiol Aging. 2012; 33(6):1122.e23-39. DOI: 10.1016/j.neurobiolaging.2011.11.006. View

Peng S, Zhang Y, Zhang J, Wang H, Ren B . ERK in learning and memory: a review of recent research. Int J Mol Sci. 2010; 11(1):222-232. PMC: 2821000. DOI: 10.3390/ijms11010222. View

10.

Heath A, Brewer M, Yesavage J, McNerney M . Improved object recognition memory using post-encoding repetitive transcranial magnetic stimulation. Brain Stimul. 2021; 15(1):78-86. PMC: 10612530. DOI: 10.1016/j.brs.2021.11.009. View

11.

Esang M, Gupta M . Aducanumab as a Novel Treatment for Alzheimer's Disease: A Decade of Hope, Controversies, and the Future. Cureus. 2021; 13(8):e17591. PMC: 8483432. DOI: 10.7759/cureus.17591. View

12.

Belfiore R, Rodin A, Ferreira E, Velazquez R, Branca C, Caccamo A . Temporal and regional progression of Alzheimer's disease-like pathology in 3xTg-AD mice. Aging Cell. 2018; 18(1):e12873. PMC: 6351836. DOI: 10.1111/acel.12873. View

13.

Li W, Wu M, Zhang Y, Wei X, Zang J, Liu Y . Intermittent fasting promotes adult hippocampal neuronal differentiation by activating GSK-3β in 3xTg-AD mice. J Neurochem. 2020; 155(6):697-713. DOI: 10.1111/jnc.15105. View

14.

Otani K, Okada M, Yamawaki H . Diverse distribution of tyrosine receptor kinase B isoforms in rat multiple tissues. J Vet Med Sci. 2017; 79(9):1516-1523. PMC: 5627321. DOI: 10.1292/jvms.17-0257. View

15.

Banerjee J, Sorrell M, Celnik P, Pelled G . Immediate Effects of Repetitive Magnetic Stimulation on Single Cortical Pyramidal Neurons. PLoS One. 2017; 12(1):e0170528. PMC: 5256952. DOI: 10.1371/journal.pone.0170528. View

16.

Lin T, Shih Y, Chen S, Lien C, Chang C, Huang T . Running exercise delays neurodegeneration in amygdala and hippocampus of Alzheimer's disease (APP/PS1) transgenic mice. Neurobiol Learn Mem. 2014; 118:189-97. DOI: 10.1016/j.nlm.2014.12.005. View

17.

Ehret M, Chamberlin K . Current Practices in the Treatment of Alzheimer Disease: Where is the Evidence After the Phase III Trials?. Clin Ther. 2015; 37(8):1604-16. DOI: 10.1016/j.clinthera.2015.05.510. View

18.

Fenner B . Truncated TrkB: beyond a dominant negative receptor. Cytokine Growth Factor Rev. 2012; 23(1-2):15-24. DOI: 10.1016/j.cytogfr.2012.01.002. View

19.

Styr B, Slutsky I . Imbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer's disease. Nat Neurosci. 2018; 21(4):463-473. PMC: 6533171. DOI: 10.1038/s41593-018-0080-x. View

20.

Cortese G, Barrientos R, Maier S, Patterson S . Aging and a peripheral immune challenge interact to reduce mature brain-derived neurotrophic factor and activation of TrkB, PLCgamma1, and ERK in hippocampal synaptoneurosomes. J Neurosci. 2011; 31(11):4274-9. PMC: 3086395. DOI: 10.1523/JNEUROSCI.5818-10.2011. View