Repetitive Transcranial Magnetic Stimulation Improves Brain-Derived Neurotrophic Factor and Cholinergic Signaling in the 3xTgAD Mouse Model of Alzheimer’s Disease

Abstract

Background: Alzheimer’s disease (AD) is a debilitating disorder involving the loss of plasticity and cholinergic neurons in the cortex. Pharmaceutical treatments are limited in their efficacy, but brain stimulation is emerging as a treatment for diseases of cognition. More research is needed to determine the biochemical mechanisms and treatment efficacy of this technique. Objective: We aimed to determine if forebrain repetitive transcranial magnetic stimulation can improve cortical BDNF gene expression and cholinergic signaling in the 3xTgAD mouse model of AD. Methods: Both B6 wild type mice and 3xTgAD mice aged 12 months were given daily treatment sessions for 14 days or twice weekly for 6 weeks. Following treatment, brain tissue was extracted for immunological stains for plaque load, as well as biochemical analysis for BDNF gene expression and cholinergic signaling via acetylcholinesterase and choline acetyltransferase ELISA assays. Results: For the 3xTgAD mice, both 14 days and 6 weeks treatment regimens resulted in an increase in BDNF gene expression relative to sham treatment, with a larger increase in the 6-week group. Acetylcholinesterase activity also increased for both treatments in 3xTgAD mice. The B6 mice only had an increase in BDNF gene expression for the 6-week group. Conclusion: Brain stimulation is a possible non-invasive and nonpharmaceutical treatment option for AD as it improves both plasticity markers and cholinergic signaling in an AD mouse model.

The Rehabilitation Potential of Neurostimulation for Mild Traumatic Brain Injury in Animal and Human Studies

“…Newly developed methods demonstrate how to provide consistent rTMS to mice without restraint or anesthesia [119], and this method improved post-encoding memory in mice [120]. Indeed, rTMS in unrestrained triple transgenic Alzheimer's mice (3×TgAD) mice improved cholinergic and neurotrophic factor signaling, both of which are important for cognition and mTBI recovery [121].…”

Enhanced prefrontal nicotinic signaling as evidence of active compensation in Alzheimer’s disease models

“…While the remodelling of the cholinergic system in AD has been extensively probed, key clinical [32][33][34] and preclinical studies [35][36][37] focus on cholinergic neurodegeneration and synapse loss. There has been relatively little functional investigation in early to mid-disease synaptic changes, except in the most swiftly-progressing genetic models of AD that preclude the use of littermate controls [38][39][40][41][42][43][44][45][46][47]. To detect and systematically investigate mechanisms of compensatory plasticity, it is essential to use a well-charted model with appropriately-matched non-transgenic controls.…”