Loss of Hippocampal Neurogenesis in Alzheimer's Disease

Neurogenesis is the process by which new neurons are produced from neural stem cells and then integrated into existing neural circuits in the brain. Adult neurogenesis is important to memory function, as well as to the resilience of the brain to injury and degeneration. Neurogenesis declines with age, and is noted to be one of the many aspects of neural biology that is negatively impacted by the onset of Alzheimer's disease. Is this loss of neurogenesis secondary to the better known disease mechanisms associated with Alzheimer's? Is it important enough to be pursued as a basis for therapy? Researchers here discuss the topic.

The hippocampus, a critical hub for cognition and memory, is one of the first brain regions to be affected in Alzheimer's disease (AD) patients. The dentate gyrus (DG), a hippocampal subfield implicated in learning and memory, particularly in pattern separation, shows substantial age-related functional decline in humans, non-human primates, and rodents. The DG is further unique as it contains the so-called "neurogenic niche," wherein stem cells continue to generate new neurons in the adult brain, in a special form of cellular plasticity referred to as "adult hippocampal neurogenesis" (AHN). Adult-born dentate granule cells (aDGCs) functionally incorporate into the granule cell layer of the DG as part of the hippocampal circuitry, where they, via their unique physiological properties, play key roles in neural plasticity and cognition. AHN has been shown to be impacted by (several aspects of) AD pathology in both rodents and humans.

Despite a substantial focus on amyloid and tau pathologies over the past decades, disease-modifying therapies for AD are still lacking. Hence, "mapping" the full mechanistic heterogeneity of AD, i.e. beyond amyloid and tau, is an important critical step to developing novel therapeutic targets. Key mechanistic questions as to what renders an individual vulnerable or resilient to developing AD remain unanswered, but may be "hidden" in the brains of a unique group of elderly individuals with preserved cognition, despite the presence of substantial AD pathology. This "cognitive reserve" that is apparent in these subjects may likely increase resilience toward developing dementia. Notably, AHN levels in postmortem brains were recently correlated with ante-mortem cognition in mild cognitive impaired (MCI) and AD patients, pointing toward a potential active role of AHN in the buildup of cognitive reserve, which can later on confer resilience to AD-related dementia.

Here, we critically discuss current knowledge on the putative role of AHN in AD pathophysiology and resilience, focusing primarily on the human brain. We emphasize the importance of the multicellular complexity of the neurogenic niche where AHN resides, and hence the relevance of integrating both intrinsic and extrinsic signals from distinct cellular populations, into any future therapeutic strategies aimed to "rejuvenate" the AD brain.

Link: https://doi.org/10.1016/j.stem.2023.01.002