Alzheimer's disease (AD) is a debilitating neurodegenerative condition that affects a significant proportion of older people worldwide. Synapses are points of communication between neural cells that are malleable to change based on our experiences. By adding, removing, strengthening, or weakening synaptic contacts, our brain encodes new events or forgets previous ones. In AD, synaptic plasticity, the brain's ability to regulate the strength of synaptic connections between neurons, is significantly disrupted. This worsens over time, reducing cognitive and memory functions leading to reduced quality of life. To date, there is no effective cure for AD, and only limited treatments for managing the symptoms.
Studies have shown that repetitive transcranial magnetic stimulation (rTMS), a noninvasive brain stimulation technique that uses electromagnetic pulses to target specific brain regions, has therapeutic potential to manage dementia and related diseases. From previous studies, we know that rTMS can promote synaptic plasticity in healthy nervous systems. Moreover, it is already used to treat certain neurodegenerative and neuropsychiatric conditions. However, individual responses to rTMS for AD management are variable, and the underlying mechanisms are not clearly understood.
Recently, researchers from the University of Queensland (Australia) and the Wicking Dementia Research and Education Centre at the University of Tasmania investigated the effects of rTMS on synapses in the brain cortex of mice with Alzheimer's type dementia. Their report is published in Neurophotonics . "Since synaptic dysfunction is a key mechanism in AD, in this study, we quantified the changes in synaptic axonal boutons in AD mouse model in response to rTMS, comparing them to those in healthy mice," explains corresponding author Dr. Barbora Fulopova, a professor at University of Queensland.
Axonal boutons are specialized endings of an axon, which is the long slender part of a neuron that connects neurons by transmitting neural signals. These are sites where synapses form, allowing neurons to communicate. Therefore, any change in the number or function of these boutons can have profound effects on brain connectivity. In this study, the researchers observed structural changes of two types of excitatory boutons, namely "terminaux boutons" (TBs) (short protrusions from the axon shaft typically connecting neurons in a local area) and "en passant boutons" (EPBs) (small bead-like structures along axons typically connecting distal regions). They used two-photon imaging to visualize individual axons and synapses in the brain of a live animal.
The study was conducted on the APP/PS1 xThy-1GFP-M strain of mice, which is a cross between the APP/PS1 strain (genetically modified to show AD-like symptoms seen in humans) and the Thy1-GFP-M strain, which expresses a fluorescent protein in certain neurons. This combination causes axons to glow during imaging, enabling precise tracking of synaptic bouton changes over time. The team monitored the dynamics of the axonal boutons in these mice at 48-hour intervals for eight days, both before and after a single rTMS session. They then compared these findings to healthy wild-type (WT) mice.
They found that both TBs and EPBs in the AD mouse model had comparable density to those in healthy WT mice. However, the turnover of both bouton types was significantly lower in the AD mouse model before rTMS, likely due to the amyloid plaque buildup, a key marker of dementia, and potentially causing diseases like AD. After a single session of low-intensity rTMS, the turnover of TBs in both strains increased significantly, while there was no change in the EPB turnover. Notably, the largest changes were observed two days after stimulation with an 88 percent increase in TB turnover for the WT strain and a 213 percent increase in the APP-GFP strain. However, this increase returned to pre-stimulation levels by the eighth day.
Furthermore, in the AD mouse model, this increased turnover was comparable to the turnover levels in the WT mice seen before stimulation. This indicates that low-intensity rTMS can potentially restore the synaptic plasticity of TBs to those seen in healthy mice. Moreover, the fact that only TBs, and not EPBs, responded to rTMS points to the possibility that the mechanisms of rTMS might be cell-type specific.
"This is the first study to provide evidence of pre-synaptic boutons responding to rTMS in a healthy nervous system as well as a nervous system marked by the presence of dementia," remarks Fulopova. "Given the established link between synaptic dysfunction and cognitive decline in dementia and the use of rTMS for the treatment of other neurodegenerative conditions, our findings highlight its potential as a powerful addition to currently used AD management strategies."
This study marks a significant step forward in understanding AD. While further research is required, the findings of this study pave the way for targeted rTMS treatments that could improve the quality of life of patients with Alzheimer's disease.
For details, see the original Gold Open Access article by B. Fulopova, W. Bennett, and A. Canty, " Repetitive transcranial magnetic stimulation increases synaptic plasticity of cortical axons in the APP/PS1 amyloidosis mouse model ," Neurophotonics 12(S1), S14613 (2025), doi 10.1117/1.NPh.12.S1.S14613 .
