summary: Stimulation of the supramammilary nucleus of the hypothalamus enhances adult-born neurons in the hippocampus of Alzheimer’s disease mouse models. These adult-born neurons restored cognitive impairments and mood-related disorders associated with Alzheimer’s disease in mice.
In the brains of adult humans, the hippocampus generates new neurons (adult-born neurons, or ABNs) throughout life, helping us maintain memories and regulate emotions. Scientists call this process “adult hippocampal neurogenesis (AHN).” In people with Alzheimer’s disease (AD), this process is disrupted, resulting in decreased production of ABNs with impaired traits.
Given that Alzheimer’s patients often present with both cognitive symptoms (such as memory loss) and non-cognitive symptoms (such as anxiety and depression) in which AHN plays a critical role, one way to help Alzheimer’s patients relieve symptoms could be to restore AHN.
Published in the journal stem cell cellsResearch from the United Nations University School of Medicine showed that stimulating a brain region called the supramillary nucleus (SuM) located in the hypothalamus effectively boosts adult-born neurons in the brains of mice with Alzheimer’s disease.
After patterned stimulation of SuM, AD brains developed more ABNs with enhanced traits. Importantly, activation of ABNs modulated by SuM restored both cognitive and emotional deficits in rat models of AD.
“It has been a longstanding question whether AHN could be sufficiently improved in the brains of people with Alzheimer’s disease to improve brain function,” said senior author Juan Song, PhD, assistant professor of pharmacology and Jeffrey Haupt Distinguished Investigator at the University of North Carolina School of Medicine.
“An important point to consider when addressing these questions is the low level of neurogenesis in the hippocampus, which becomes lower in Alzheimer’s patients.
By manipulating a small number of ABNs in the AD brain, we demonstrate that ABNs can be improved even in the presence of Alzheimer’s disease, and that these enhanced ABNs are important for restoring behaviors and hippocampal function. “
To enhance ABNs in AD brains, Song and colleagues adopted an elegant two-step strategy to enhance ABN by first stimulating SuM using an optogenetics model with the goal of enhancing the generation and developmental properties of ABNs, followed by stimulating the activity of enhanced SuM-ABNs using chemical genetics.
Optogenetics involves using light to alter the activity of brain cells that express photosensitive opsin genes. Chemogenetics involves using inert molecules to alter the activity of brain cells that express designer receptors.
“Intriguingly, SuM stimulation alone or activation of ABNs without SuM stimulation failed to restore behavioral deficits in AD rats.” Song said. “These results indicate that multilevel enhancement of ABNs—that is, increasing their number, improving their developmental properties, and enhancing their activity—is required to achieve their therapeutic benefits in AD brains.”
When Song and colleagues analyzed protein changes in the hippocampus of Alzheimer’s mice in response to SuM-enhanced activation of ABNs, the researchers found that several known intracellular protein pathways were activated.
These pathways include those important for neuronal synaptic plasticity allowing enhanced communication between them, as well as pathways important for phagocytosis in non-neuronal microglia allowing efficient plaque removal.
“It is surprising that the multilevel enhancement of ABNs through combined SuM and ABN stimulation allows such a small number of ABNs to make a profound functional contribution in diseased AD brains,” Song said.
“We are keen to discover the mechanisms underlying these beneficial effects mediated by activation of SuM-enhanced ABNs on Alzheimer’s pathology and hippocampal function. Future efforts will be required to develop drugs that mimic these beneficial effects mediated by activation of SuM-enhanced ABNs. Ultimately, the hope lies In developing highly targeted first-line therapies for the treatment of Alzheimer’s disease and related dementia.”
Funding: The National Institutes of Health funded this research with grants R01MH111773, R01MH122692, RF1AG058160, R01NS104530 to Juan Song and R21AG071229, R01GM133107 to co-author Xian Chen, Ph.D., Professor of Biochemistry and Biophysics at the United Nations University School of Medicine.
About this search for Alzheimer’s disease news
author: Mark Derwich
communication: Mark Derwich – UNC
picture: Image credits Song Lab, UNC School of Medicine
Original search: open access.
“Activation of enhanced adult-born neurons in the hypothalamus restores cognitive and emotional function in Alzheimer’s disease” by Juan Song et al. stem cell cells
Activation of enhanced adult-born neurons in the hypothalamus restores cognitive and emotional function in Alzheimer’s disease.
- Patterned optogenetic stimulation of SuM enhances neurogenesis in the hippocampus of AD
- SuM-enhanced ABNs activation rescues memory and emotion deficits in AD
- SuM-enhanced ABNs activation enhances hippocampal plasticity and activity in Alzheimer’s disease
- Enhanced activation of ABNs by SuM increases microglia phagocytosis of plaques in AD
Patients with Alzheimer’s disease (AD) show progressive amnesia, depression, and anxiety, accompanied by abnormalities in adult hippocampal neurogenesis (AHN). Whether AHN in AD brain impairment can be improved to restore cognitive and emotional function remains elusive.
Here, we report that patterned optogenetic stimulation of the supramammary nucleus (SuM) enhances AHN in two distinct AD mouse models, 5×FAD and 3×Tg-AD. Remarkably, chemical activation of SuM-enhanced adult-onset neuronal genes (ABNs) rescues memory and disability in these AD mice. In contrast, stimulation of SuM alone or activation of ABNs without modification of SuM fails to restore behavioral deficits.
Furthermore, quantitative analyzes of the phosphoproteome reveal activation of canonical pathways related to synaptic plasticity and microglia phagocytosis of plaques after acute chemoattractive activation of ABNs enhanced with SuM (versus control).
Our study identifies the activity-dependent contribution of SuM-enhanced ABNs in modulating AD-related deficiencies and informs the signaling mechanisms mediated by the activation of SuM-enhanced ABNs.