Alzheimer’s experts have given a cautious welcome to an innovative study that showed an easing of cognitive impairment in rodents through the use of deep brain stimulation.
An estimated 32 million people globally suffer from Alzheimer’s disease, for which there is currently no cure.
The most common form of dementia, it is a progressive, life-limiting illness caused by a build-up of proteins in the brain that slowly destroys the memory, thinking, behaviour, and social skills, eventually leaving the sufferer unable to carry out even the simplest of tasks.
But researchers from the University of North Carolina at Chapel Hill have demonstrated that deep brain stimulation of new neurons can help to restore both cognitive and noncognitive functions in mouse models of Alzheimer’s disease.
However, leading Alzheimer’s specialists, whilst welcoming any new study that helps to “unravel the complexities” of such a devastating disease, have pointed to the results being in mice rather than humans.
Dr Sara Imarisio, Head of Strategic Initiatives at Alzheimer’s Research UK, said: “It’s important to note that these results are in mice, and there are differences between mouse and human brains. And while these findings provide a promising lead for investigating potential new approaches for treating Alzheimer’s in humans, it’s a very long way from practical application.
“Nevertheless, studies like these are essential to unravel the complexities of Alzheimer’s, and bring us closer to ways to effectively treat, and even cure, the disease,” she added.
Prof Malcolm Macleod, Professor of Neurology and Translational Neuroscience at the University of Edinburgh, said the study was potentially of interest, but pointed to some problems with the methods used.
“Specifically, on the presentation, the title says that the intervention ‘restores cognitive and affective function in Alzheimer’s disease’, but this is to overstate things.
“Mice do not get Alzheimer’s, although scientists can model some of the features in certain animal models, as presented here. But these do not capture the whole story of what Alzheimer’s does to humans, and we know of many interventions which appear to improve outcome in these (imperfect) animal models, but which have no effect in humans.”
Reporting in the journal Cell Stem Cell, the team detailed how they utilised the mice to demonstrate a process called adult hippocampus neurogenesis (AHN), through which neurons are made in adulthood.
The neurons were modified by deep brain stimulation of the supramammillary nucleus (SuM), which is located in the hypothalamus, a gland which controls many bodily functions such as heart rate, hunger, body temperature, sleep and emotions.
A neurological process, deep brain stimulation involves planting electrodes into certain parts of the brain and connecting them by wires to a pacemaker-like device placed under the skin in the chest area.
The electrodes create electrical impulses that override abnormal signals that could cause neurological problems. It is a type of surgery that is already used to treat Parkinson’s disease to help improve tremors, stiffness, and movement issues, as well as epilepsy, dystonia and obsessive compulsive disorder.
Senior report author, Juan Yong, as associate professor at the University of North Carolina at Chapel Hill, said: “We were surprised to find that activating only a small population of adult-born new neurons was enough to make a significant contribution to these brain functions.
“We are eager to find out the mechanisms that underlie these beneficial effects.”
The study used two distinct mouse models of Alzheimer’s disease. The investigators used optogenetics to stimulate the SuM and enhance AHN in Alzheimer’s mice.
Earlier research conducted by the team had shown that stimulation of the SuM could increase the production of new neurons and improve their qualities in normal adult mice.
In the new study, the investigators showed that this strategy was also effective in the Alzheimer’s mice, leading to the generation of new neurons that made better connections with other areas of the brain.
However, having more improved new neurons is not enough to enhance memory and mood. Behavioural improvement in Alzheimer’s mice was seen only when these improved new neurons were activated by chemogenetics, a method of using synthetic designer drugs to control and investigate intracellular signalling pathways.
The researchers used memory tests as well as established assessments to look for anxiety and depression-like behaviour to verify these improvements. The findings suggested that multi-level enhancement of new neurons – including increased numbers, properties, and activity – is needed for behavioural restoration in Alzheimer’s brains.
Juan Yong said: “It was striking that multilevel enhancement of such a small number of adult-born new neurons made such a profound functional contribution to the animals’ diseased brains.”
But Prof Macleod pointed out the number of animals used was “fairly low, which again brings the conclusions into question. They say they based the numbers of animals used on previous experiments, but we know that experiments in the neurosciences are substantially under-powered (ie too small reliably to detect the effects they report), and so doing it this way because that’s how we have always done it is problematic.”