Hippocampal neurogenesis in cognitive function and dysfunction in Alzheimer's disease.

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Abstract In contrast to rodents, little is known about neurogenesis in the human brain. The few studies that examined neurogenesis in the human hippocampus have come to vastly different conclusions. Determining the existence and course of hippocampal neurogenesis in the human brain is critical for the understanding of brain function, cognition, putative preventative and therapeutic approaches for the treatment of cognitive decline, Alzheimer’s disease (AD) and related dementia (ADRD). Our previous studies showed that hippocampal neurogenesis persists throughout the 10th decade of life. New neurons were observed in the brains of participants with no cognitive impairments (NCI), as well as in patients exhibiting mild cognitive impairments (MCI) or AD. Interestingly, the number of new neurons was significantly lower in MCI and AD compared to NCI. On the other hand, the number of early differentiating and mature astrocytes was increased in the AD brain. Importantly, higher numbers of neuroblasts were associated with better cognitive performance in the brains of aging, MCI and AD patients. Intriguingly, levels of neurogenesis in the brains of SuperAgers, individuals in their 80ies who exhibit memory performance comparable to people in their 50ies, were significantly greater, compared to age-matched individuals with age-appropriate cognitive function. Nevertheless, the observations above were made using the same neurogenic proxies used in the rodent brain and the nature of cells in the human brain recognized by these proxies is not clear. Evidently, studies that could not detect neurogenesis in the human brain used the same proxies. Thus, the goal of this project is to test the hypothesis that hippocampal neurogenesis persists in the aged and AD human brain and its level is associated with cognitive function. By providing new evidence for the presence of hippocampal neurogenesis using novel tools that would validate previously used proxies. Experiments in Aim 1 will examine the hypothesis that neural progenitor cells have a lower level of proliferation and preferable differentiation into astrocytes leading to fewer new neurons in MCI and AD, using multiplex RNA scope and neurogenic proxies. Experiments in Aim 2 will determine the spatial organization of hippocampal neurogenesis in NCI, MCI and AD, and examine the hypothesis that autonomous and non-autonomous factors in the DG determine the level of human neurogenesis in the aging and AD brain, using a combination of spatial transcriptomics (pciSeq) and RNAseq. Aim 3 will address whether new neurons play a role in cognitive reserve and resilience to AD. Experiments will examine the association between cognitive performance , hippocampal neurogenesis and AD hallmarks in SuperAgers, age-appropriate cognitive performance, MCI and AD patients. In summary, this project will provide novel crucial information about the presence of neurogenesis and its role in hippocampal function in the human aging and AD brain.