Scientists strengthen new neurons to restore memory and boost mood in Alzheimer’s research model

Dr. Juan Song and his colleagues’ lab at the UNC School of Medicine are using rodent models to develop therapeutic strategies for new neurons generated in adulthood to modulate the pathology and dysfunction associated with Alzheimer’s disease. demonstrated its potential.

Chapel Hill, NC – In the adult brain, the hippocampus generates new neurons (adult-born neurons, or ABNs) throughout life, helping to maintain memory and regulate emotions. Scientists call this process “adult hippocampal neurogenesis (AHN).” In patients with Alzheimer’s disease (AD), this process is impaired, resulting in decreased production of her ABN of poor quality. Given that AD patients often develop both cognitive symptoms (such as memory loss) and non-cognitive symptoms (such as anxiety and depression) in which AHN plays an important role, it is worth noting that Alzheimer’s disease patients may experience symptom relief. One way to help achieve this is to restore AHN.

It was published in the magazine cell stem cell, A study by scientists at the UNC School of Medicine found that stimulating a brain region in the hypothalamus called the SuPramammilary nucleus (SuM) effectively activated adult-born neurons in the brains of mice with impaired Alzheimer’s disease. proven to be enhanced. After Sam’s patterned stimulation, the AD brain developed more ABNs with improved quality. Importantly, activation of these SuM-modified ABNs reversed both cognitive and affective deficits in AD mouse models.

“It has long been a question whether AHN can be sufficiently enhanced in the impaired AD brain to improve brain function,” said lead author Jeffrey Haupt, Associate Professor of Pharmacology and Distinguished Fellow at the UNC School of Medicine. Dr. Juan Song said: “An important consideration when addressing these issues is the low level of hippocampal neurogenesis, which is even lower in patients with AD.

We show that manipulating a small number of ABNs in the AD brain can enhance ABNs even in the presence of AD pathology, and that these enhanced ABNs are important for restoring behavior and hippocampal function. “

To enhance ABNs in AD brains, Song and colleagues first stimulated SuM using a patterned optogenetic paradigm aimed at promoting the generation and developmental properties of ABNs, followed by We employed an elegant two-step ABN-enhancing strategy by stimulating the activity of SuM with ABN enriched using chemical genetics.

Optogenetics uses light to alter the activity of brain cells that express light-sensitive opsin genes. Chemogenetics uses inert molecules to alter the activity of brain cells that express designer receptors.

“Interestingly, ABN activation with or without SuM stimulation failed to reverse behavioral deficits in AD mice,” Song said. “These results suggest that multilevel enhancement of ABNs—increased numbers, improved developmental traits, and enhanced activity—is required for therapeutic benefit in the Alzheimer’s disease brain. ”

Song et al. further analyzed protein changes in response to activation of SuM-enhanced ABN in the hippocampus of AD mice, and the researchers found that several well-known protein pathways were activated intracellularly. These pathways include not only pathways important for phagocytosis of non-neuronal microglia, which enable efficient plaque clearance, but also pathways important for neuronal synaptic plasticity, which enhances interneuronal communication. will be

“It is surprising that such a small number of ABNs can make such a large functional contribution to diseased AD brains through multilevel enhancement of ABNs by combined SuM and ABN stimulation,” Song said. “We hope to find the mechanisms underlying these beneficial effects mediated by activation of SumM-enhanced ABN on AD pathology and hippocampal function. Future efforts will be needed to develop drugs that mimic these beneficial effects of Alzheimer’s disease and related dementias. We hope to develop a cure.”

The National Institutes of Health provided grants R01MH111773, R01MH122692, RF1AG058160, R01NS104530 to Juan Song and R21AG071229, R01GM133107 to Dr. Xian Chen, Professor of Biochemistry and Biophysics, UNC School of Medicine, for this work.

The co-first authors of the Cell Stem Cell paper are Ya-Dong Li and Yan-Jia Luo from Song Lab. Other authors are Ling Xie, Dalton Tart, Ryan N Sheehy, Libo Zhang, and Leon G Coleman Jr, all from the UNC School of Medicine.

Media Contact: Mark Derewitz919-923-0959