People with Alzheimer’s disease (AD) develop defects in cognitive functions including memory, as well as problems with noncognitive functions that can lead to anxiety and depression. Studying a process called adult hippocampus neurogenesis (AHN), through which new neurons are generated in adulthood, researchers at the University of North Carolina at Chapel Hill have now demonstrated that deep brain stimulation of new neurons can help to restore both cognitive and noncognitive functions in different mouse models of Alzheimer’s disease.
The neurons were modified by deep brain stimulation of the suprammamillary nucleus (SuM), which is located in the hypothalamus. “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,” said associate professor Juan Song, PhD. “We are eager to find out the mechanisms that underlie these beneficial effects.” The team hopes that the findings could ultimately lead to targeted treatments for Alzheimer’s disease and other forms of dementia.
Song is senior author of the team’s published paper in Cell Stem Cell, which is titled “Activation of hypothalamic-enhanced adult-born neurons restores cognitive and affective function in Alzheimer’s disease,” in which the investigators concluded, “In summary, our findings present the evidence that boosting the activity of a small population of ABNs with enhanced properties is sufficient to restore cognitive and affective deficits associated with AD.”
Spatial memory decline, depression, and anxiety are known to be early clinical signs of Alzheimer’s disease, in which the hippocampus has a crucial role, the authors wrote. An area called the dentate gyrus (DG) within the hippocampus contains neural stem cells that continue to generate adult-born neurons (ABNs), throughout life, and this process is known as adult hippocampal neurogenesis. “Substantial evidence has supported the existence of AHN in human brains and the level of AHN declines significantly during AD progression,” the scientists commented. However, they continued, while many studies in rodent models have established the causal role of ABNs in regulating memory performance and emotional states, “two key functions of the adult hippocampus that are impaired in AD patients,” the function and therapeutic potential of ABNs in AD brains remains largely unknown. So while “a long-standing question has centered on whether modulating AHN alone is sufficient to rescue cognitive and affective deficits in AD … whether AHN can be enhanced in impaired AD brain to restore cognitive and affective function remains elusive.”
Focusing on a subcortical region of the hypothalamus called the supramammillary nucleus (SuM), and using two distinct mouse models of Alzheimer’s, the investigators applied optogenetics technology to stimulate the SuM and enhance AHN. Their earlier research 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 Alzheimer’s mice, leading to the generation of new neurons that made better connections with other parts of the brain. “Here, we report that patterned optogenetic stimulation of the hypothalamic SuM enhances AHN in two distinct AD mouse models …,” they wrote.
However, they also found that having greater numbers of these new neurons was not enough to benefit memory and mood. Behavioral improvements in the Alzheimer’s mice were in fact seen only when AHN was enhanced in the SuM, and the new neurons were activated by chemogenetics.
The researchers used memory tests and established assessments to look for anxiety-like and depression-like behavior, and confirm these improvements in the treated Alzheimer’s model mice. The results suggested that multi-level enhancement of new neurons—enhancement in number, properties, and activity—is required for behavioral restoration in Alzheimer’s brains. “Strikingly, the chemogenetic activation of SuM-enhanced adult-born neurons (ABNs) rescues memory and emotion deficits in these AD mice,” they pointed out. In contrast, “SuM stimulation alone or activation of ABNs without SuM modification fails to restore behavioral deficits.”
To further understand the underlying mechanism for their observations, the researchers also carried out quantitative phosphoproteomics of the hippocampus to analyze the protein changes in the hippocampus of Alzheimer’s mice in response to activation of SuM-modified adult-born new neurons. They found several well-known protein pathways activated inside cells, including those known to be important for improved memory performance, as well as those that allow clearance of the plaques related to Alzheimer’s. “Our analyses revealed activation of the canonical pathways related to synaptic plasticity and microglia phagocytosis of plaques in response to acute activation of SuM-enhanced ABNs,” they commented.
“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,” Song said. “We were also surprised to find that activation of SuM-enhanced neurons promoted the process that can potentially remove plaques.”
In summary, the authors concluded, “Our findings present the evidence that boosting the activity of a small population of ABNs with enhanced properties is sufficient to restore cognitive and affective deficits associated with AD. Importantly, our studies provide novel ABN-activity-dependent signaling mechanisms underlying the functional improvement in AD brains mediated by the activation of SuM-enhanced ABNs.”
The team’s future research will focus on developing potential therapeutics that mimic the beneficial effects mediated by activation of SuM-modified new neurons. “We are hoping these drugs could exert therapeutic effects in patients with low or no hippocampal neurogenesis,” Song said. “Ultimately, the hope is to develop first-in-class, highly targeted therapies to treat Alzheimer’s and related dementia.”