Fight Aging!

Use of ultrasound as a tool is commonplace in medicine these days, with applications ranging from tissue imaging to breaking up dental plaque to destruction of kidney stones. Many of the effects, actual and potential, at the cellular level are still being explored, however, and they range from the merely intriguing to the very promising. For example, ultrasound appears to speed wound healing in aged skin. More relevant to the research presented here, ultrasound applied to the brain makes the blood-brain barrier leak a little, enough to spur the immune system into greater productive activity. In mice this has been shown to improve cognitive function as well as produce some clearance of the metabolic waste known as β-amyloid that is associated with Alzheimer's disease.

There are lengthy and poorly mapped chains of cause and effect spanning the gap between the application of ultrasound and end results such as amyloid clearance. Which mechanisms are relevant, and how exactly the ultrasound produces the end results of interest, is a line of work that remains very open to hypothesis, competing evidence, and debate. If we consider the effects on the blood brain barrier noted above, it is worth bearing in mind that growing age-related dysfunction and leakage in this structure is thought by many in the field to be a part of the problem in the aging brain. The purpose of the barrier, which lines blood vessels in the brain, is to keep the environment of the brain insulated from that of the rest of the body. Leakage encourages greater levels of neural inflammation and contributes to early development of Alzheimer's disease. So how is it that brief disruption can be as beneficial as long-term disruption is harmful? Nothing is simple when it comes to cellular biochemistry and the progression of aging.

The question of mechanisms is particular pronounced in the research linked below, in which researchers examine the fine structures of dendrites in one area of the brain and how those structures change over time. Dendrites are a part of the structure of the synapses that link neurons into networks. They are decorated with spines that some research suggests are the form in which the data of memory is encoded in the brain. Synapses, dendrites, and spines all change over time, and in characteristic ways with aging. With the application of ultrasound, this age-related change appears to be reduced, but there is no shortage of places to start fishing for the reasons why that might be the case. One could build a career simply trying to fill in the gaps in this picture.

Research finds that ultrasound slows brain ageing

Research shows that scanning ultrasound prevented degeneration of cells in the brains of healthy mice. "We found that, far from causing any damage to the healthy brain, ultrasound treatments may in fact have potential beneficial effects for healthy ageing brains. In a normal brain the structure of neuronal cells in the hippocampus, a brain area extremely important for learning and memory, is reduced with age. What we found is that treating mice with scanning ultrasound prevents this reduction in structure, which suggests that by using this approach we can keep the structure of the brain younger as we get older. We are currently conducting experiments to see if this preservation of the brain cell structure will ameliorate reductions in learning and memory that occur with ageing." In the next stage of research, the team will test the effect of ultrasound on the brain structure and function of older mice.

Scanning Ultrasound (SUS) Causes No Changes to Neuronal Excitability and Prevents Age-Related Reductions in Hippocampal CA1 Dendritic Structure in Wild-Type Mice

Recently, our group has reported that repeated scanning ultrasound (SUS) treatments reduced the amyloid plaque pathology in a transgenic mouse model of Alzheimer's disease (AD) and improved hippocampal-dependent spatial memory performance by activating brain-resident microglia. In this approach, ultrasound was combined with microbubbles to disrupt the blood-brain barrier (BBB) which is achieved by mechanical interactions between the microbubbles and the blood vessel wall as pulsed focused ultrasound is applied, resulting in cycles of compression and rarefaction of the microbubbles. This leads to a transient disruption of tight junctions and the uptake of blood-borne factors by the brain, which are likely to have a role in the activation of microglia that were found to take up amyloid into their lysosomes.

However, the short- and long-term effects of SUS treatment on individual neuronal action potential (AP) firing and dendritic morphology have not been investigated. To address this issue, we evaluated the physiological effects of both a single and multiple SUS treatments on short- and long-term neuronal excitability, dendritic morphology and dendritic spine densities in the CA1 region of the hippocampus of wild-type mice. This allowed us to determine the effect of different SUS treatments in a non-disease state system before eventually moving to a more complicated disease model, where alterations in neuronal function are already present at an early age. For example, reductions in dendritic spine density, AP firing, synaptic activity and long-term potentiation (LTP) have all been reported to occur in amyloid-depositing mouse models of AD.

In our study using wild-type mice, we found that the different SUS treatment regimes had no deleterious effect on neuronal function or morphology. In addition to this we made the interesting observation that repeated SUS treatments prevented reductions in the dendritic complexity and length of CA1 pyramidal neurons that occur in age-matched sham-treated wild-type mice over the course of three months, while a reduction in dendritic spine density was not halted. Taken together, these findings suggest that multiple SUS treatments ameliorate a reduction in the total number of dendritic spines per neuron. A more extensive follow-up study will determine, whether SUS treatments improves cognition in aging mice and what the underlying mechanism is of such an effect.

Age-associated reductions in the structure of neuronal dendritic trees have previously been reported in a range of brain areas and species. However, our understanding of changes in dendritic tree arborization in the hippocampus is less advanced, where both increases and decreases in CA1 pyramidal dendritic length and complexity have previously been reported. While a number of differences exist between these reports and the current work, perhaps the most important is the duration of ageing over which changes in dendritic tree structure was quantified (approximately 1.5 years versus 3 months in the current study). This is a limitation of the current study when evaluating changes in dendritic structure associated with ageing. Further experimentation will be required to assess changes in dendritic tree structure over longer time periods. Despite this, it is evident that multiple SUS treatments are able to prevent reductions in dendritic structure.

Also, the question of how SUS preserves dendritic structure remains to be determined. One possibility is that microglia may play a role, because SUS treatment has previously been reported to activate this cell-type in mouse models as well as in wild-type mice. Microglia constantly probe their local environment and secrete factors that alter neuronal signalling. During activation they can also modify synaptic connections, the key mediators of learning and memory, by increasing the expression of neurotrophins such as brain-derived neurotrophic factor (BDNF). In fact, a recent study has reported that microglia mediate synapse loss at an early time-point in Alzheimer's disease mouse models. One possible mechanism for the neurotrophic effect of SUS may therefore be the delivery of endogenously circulating neurotrophic factors from the blood to the brain. Furthermore, ultrasound waves by themselves, without the need for BBB opening, may also contribute to the observed preservation of dendritic structure, as increased BDNF expression has been reported following ultrasound application. Other neurotrophic factors such as glial cell-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) have also been linked to improve memory performance in rats following ultrasound treatment.