Boosting the production of new neurons in a mouse model of Alzheimer’s disease (AD) leads to the rescue of memory formation, according to a new study led by researchers from the University of Illinois at Chicago. The researchers’ results indicated that enhancing neurogenesis in patients with AD could be a viable treatment strategy.
A report of the work appears in the Journal of Experimental Medicine “Augmenting neurogenesis rescues memory impairments in Alzheimer’s disease by restoring the memory-storing neurons”.
Previous studies have shown that neurogenesis is impaired in both AD patients and laboratory mice carrying genetic mutations linked to AD, particularly in a region of the brain called the hippocampus that is crucial for memory acquisition and retrieval.
“However, the role of newly formed neurons in memory formation, and whether defects in neurogenesis contribute to the cognitive impairments associated with AD, [was] unclear,” explained Professor Orly Lazarov, PhD, who led the new study.
Lazarov’s team set out to investigate whether deficits in hippocampal neurogenesis, such as those seen in AD, cause impaired engram formation. An engram is the physical manifestation of a memory.
“Using a virus-mediated engram-labeling strategy, we show that the number of new neurons recruited into the memory engram in the [mouse model of AD] was significantly reduced compared to wild-type mice, their transcriptomic profile differed, and the density of dendritic spines of new neurons in the engram was impaired,” the team wrote in their report of the work. Dendritic spines are structures in synapses known to be critical for memory formation.
However, when the team boosted neurogenesis in the AD mice, these abnormalities were reversed and ultimately restored the animals’ performance in two different tests measuring spatial and contextual memory. The researchers boosted neurogenesis by deleting Bax, a gene that plays a major role in neuronal stem cell death.
Lazarov’s team then confirmed the importance of newly formed neurons for memory formation by specifically inactivating them in the brains of AD mice. “Importantly, the chemogenetic inactivation of immature neurons in [these mice] caused memory deficits, suggesting that immature neurons are required for proper engram function, and their deficiency leads to engram malformation in AD, manifested by memory impairments,” the authors wrote.
In other words, reversing the benefits of boosting neurogenesis prevented improvements in the animals’ memory.
Furthermore, the researchers showed that the genes App, ApoE, and Adam10, which are linked to AD, were some of the top differentially expressed genes in engram cells between the experimental groups. Future work will evaluate the functional roles of these and other differentially expressed genes identified in the study.
“Most importantly, our results show that augmenting neurogenesis modulates the transcription profile of engram neurons in the [AD mice] to resemble one of the engram neurons in [the] wild-type mice,” the researchers wrote. “This suggests that augmenting neurogenesis rescues memory deficits in [the AD mice] by affecting the molecular profile of the engram.”
Overall, the finding that defects in neurogenesis contribute to the memory deficits associated with AD has important implications. “Taken together, our results suggest that augmenting neurogenesis may be of therapeutic value in AD patients,” Lazarov said.
