Researchers led by a BBRF grantee have made important discoveries in mice that have the potential to lead to completely new ways of attempting to treat and even reverse the symptoms of Alzheimer’s disease.

Alzheimer’s is associated with the formation in the brain of what scientists call amyloid-beta plaques as well as neurofibrillary tangles—abnormal accumulations of a protein called tau that collect inside neurons. Inflammation of brain tissue as well as neurodegeneration are also linked with Alzheimer’s.

Drugs designed to prevent or reduce disease-related plaques and tangles have so far yielded less-then-robust results in Alzheimer’s patients, meaning the intense search continues for related or alternative strategies for fighting back the disease’s devastating impacts on memory and mood. It is thought that about 7 million U.S. adults 65 and over currently suffer from Alzheimer’s.

In the journal Cell Stem Cell, Juan Song, Ph.D., a 2013 BBRF Young Investigator at the University of North Carolina, Chapel Hill, and colleagues including first author Ya-Dong Li, Ph.D., a 2020 BBRF Young Investigator, published results of research using two strains of genetically modified mice that model the progression of Alzheimer’s disease in humans. Like people, the mice develop plaques and tangles in the brain, and display behavioral impacts including memory impairment and depression- and anxiety-like behaviors.

The team was focused, as it had been in prior studies, on processes involving the brain’s hippocampus—a center for memory and learning. Specifically, they were interested in a process called adult hippocampal neurogenesis (AHN). In a part of the hippocampus called the dentate gyrus, neural stem cells give rise to new neurons—not only early in life, but throughout adulthood and into old age, as extensive research has revealed. This is true in both mice and people.

Prior research in rodents has established that AHN declines markedly as Alzheimer’s disease progresses, and that this is correlated with both memory performance and emotional states. Knowing, this, Drs. Song, Li and colleagues asked “whether AHN can be enhanced in otherwise impaired Alzheimer’s disease brains, and exploited for therapeutic purposes”—in effect, restoring hippocampal function lost due to declines in new neuron birth.

Recently, the team reported research on the brain’s hypothalamus, which helps regulate the body via the autonomic nervous system and hormone management. The subregion of the hypothalamus the team studied, called the supramammillary nucleus (SuM), sends many neuronal projections to the dentate gyrus area of the hippocampus, where adult neuron generation occurs. The team demonstrated that the SuM is highly responsive to stimuli that promote neurogenesis. Indeed, they showed that activation of neurons in the SuM is required in order for certain kinds of environmental stimulation to promote the birth of new adult neurons in the hippocampus.

The new study asked the exciting and previously untested question: could artificial stimulation of the SuM stimulate the birth of new adult neurons in the hippocampus; and would that help therapeutically modify known Alzheimer’s pathologies?

Their new paper reports that this strategy works in two mouse models of Alzheimer’s. The experiment involved two distinct steps. First, the team used optogenetics to stimulate the SuM in the mice. Optogenetics enables researchers to activate specific neurons or sets of them by shining color-specific laser light into the mouse brain, via threadlike fibers that don’t impair the movement or activities of the mouse-subjects.

Sophisticated labeling enabled the team to identify new adult-born neurons in the hippocampus of the same mice that had received SuM stimulation. Then, they used a technology called chemogenetics to activate a small number of these “SuM-enhanced” new neurons in the hippocampus. This second step resulted in the reversal of memory deficits and reduction of anxiety- and depression-like behaviors in the mice modeling human Alzheimer’s.

Chemogenetics is an important technology pioneered by a colleague of Drs. Song and Li at the University of North Carolina, Bryan L. Roth, M.D., Ph.D., a three-time BBRF grantee and member of the BBRF Scientific Council. Like optogenetics, chemogenetics enables researchers to activate specific neurons, but instead of using light to do so, it uses chemically engineered receptors and molecules that engage with these receptors.

Additional analysis revealed to the team that their two-step experiment resulted in the activation of pathways in the hippocampus known to be involved in synaptic plasticity—the ability of connections between neurons to change in strength. The experiments were also shown to affect processes involving immune cells called microglia that help to reduce plaques in the brain.

“It was striking that the multi-step enhancement of such a small number of adult-born new neurons made such a profound functional impact in the animals’ diseased brains,” Dr. Song commented. “We were also surprised to find that activation of SuM-enhanced neurons promoted the process that can potentially remove plaques” like those seen in human Alzheimer’s.

Now the team will work on developing potential therapeutics that mimic the actions generated by optogenetics and chemogenetics in their rodent experiments. They hope to develop drugs “that could exert therapeutic effects in patients with low or no hippocampal neurogenesis,” Dr. Song said. “Ultimately, the hope is to develop first-in-class, highly targeted therapies to treat Alzheimer’s and related dementia.”