Adult Hippocampal Neurogenesis in Cognitive Function and Dysfunction

Alzheimer’s disease (AD) is characterized by cognitive impairments and memory loss. The hippocampus, which plays an important role in memory acquisition, consolidation, and retrieval, is one of the earliest brain regions to be affected by AD pathology [2]. The hippocampus encompasses a neurogenic niche where new neurons are born and incorporated in the dentate gyrus (DG) throughout life by a process called hippocampal neurogenesis [73]. Adult Hippocampal neurogenesis (AHN) is important for spatial and contextual memories; Nakashiba et al. have shown that mice with impaired neurogenesis show impairment in the pattern separation task [12]. Further, Sahay et al. have shown that increasing neurogenesis improves the animal’s performance in pattern separation [74]. Previously, we and others have reported impairments in AHN in Alzheimer’s disease rodent models [73]. Moreover, recent data from our lab shows that increasing neurogenesis in FAD mice rescues deficits in the novel object location and contextual fear conditioning tasks [76]. This clearly establishes the role of AHN in learning and memory in rodents. However, whether AHN neurogenesis is correlated with cognition in humans is poorly understood. Preliminary data from our recently published paper from n=6 per group [65], have shown proof for the existence of AHN up to the 10th decade of life not only in healthy individuals but also in patients with mild cognitive impairment (MCI) and AD. In addition, we have shown that the number of neuroblasts (DCX+PCNA+) is lower in MCI and AD patients, which implied a possible association between the extent of neurogenesis and cognitive function. Although these data are promising, it is preliminary. We are yet to fully understand which stage of neurogenesis is defective in humans and whether these defective stages are linked to cognitive decline in MCI and AD patients. SuperAgers are defined as individuals who are 80 years old or older with an inclusion criterion of having episodic memory capacity similar to, or even better than, cognitively average individuals in their 50s or 60s. Interestingly, their hippocampus and entorhinal cortex have high plaque load and neurofibrillary tangles mostly in the Braak IIIII stages [75]. The mechanism underlying their superior cognition remains elusive. Thus, we sought to investigate whether the extent of neurogenesis in the hippocampi of these individuals correlates with their superior cognitive function. Taken together, we posit our global hypothesis as adult hippocampal neurogenesis is impaired in MCI and AD patients and correlates with their cognitive deficits. In turn, the level of neurogenesis is greater in SuperAgers compared to healthy aging. To address this hypothesis, we propose the following: Specific aim 1: To determine the extent of neurogenesis and its state in aging with no cognitive impairments, MCI, and AD. To address this specific aim, we will test two hypotheses: (1A) Adult hippocampal neurogenesis is impaired in MCI and AD in a stage-specific manner and the severity of impairment (in AHN) is correlated with their cognitive performance. To test this hypothesis, we quantified the number of neural stem cells, progenitors, and immature neurons in each of the diagnostic groups (normal aging, MCI, and AD). Logistic regression analysis between the numbers of neural stem cells, neural progenitor cells, neuroblast, Immature or mature neurons in the dentate gyrus of the postmortem hippocampal slides of these patients and their cognitive score. This result will lend evidence to support the hypothesis of a link between AHN and cognitive diagnosis in humans. (1B) Expression of genes regulating cell proliferation and survival is altered in AD and MCI patients compared to NCI. To test this hypothesis, a multi-omic approach, including single nucleus deep sequencing, spatial transcriptomics lipidomics, and proteomics, was performed on fresh frozen hippocampal tissue from Healthy, MCI, and AD patients. Following the sequencing, single-cell resolution gene expression level data from newly formed immature neurons, neuroblasts, neural stem, and progenitor cells were acquired and levels of expression and pathway analysis were performed. Overall, this aim will identify putative defective stages of neurogenesis in MCI and AD patients and its correlation with cognitive function. Moreover, this aim will provide candidate genes that could regulate human neurogenesis. Specific Aim 2: To determine the extent of neurogenesis in SuperAgers and its association with patients’ superior cognition. We will test two hypothesizes; (2A) The extent of neurogenesis in SuperAgers is higher than that of their normal aging and cognitively impaired peers and will be positively correlated with their cognitive function. We will test this hypothesis using quantification of neurogenic proxies in the dentate gyrus by immunohistochemical analysis, followed by testing the association between the extent of neurogenesis and cognition. These experiments will determine whether better cognitive performance may be correlated with more hippocampal neurogenesis. 2B) The profile of genes regulating cell proliferation and survival in SuperAgers compared to NCI. To test this hypothesis, NCI and SuperAgers tissue were subjected to a multi-omic approach, including single nucleus sequencing, spatial transcriptomics, and proteomics/lipidomics. Following the sequencing, single-cell resolution gene expression level data from newly formed immature neurons, neuroblasts, neural stem, and progenitor cells were acquired and levels of expression and pathway analysis were performed. These studies may unravel novel players underlying cognitive function and the signals that support and enhance hippocampal neurogenesis. In summary, this project is pioneer in its attempt to link AHN and cognition in humans. Moreover, this project will provide unprecedented information about potential modulators of AHN in MCI, AD, and in turn, in SuperAgers. Identifying the similarity between AHN modulators that play a role in AD and SuperAgers may provide a major insight into the mechanism underlying cognitive function in the human brain. These findings may provide new therapeutic targets for the prevention or attenuation of cognitive decline.