Indiana University-Purdue University Indianapolis (IUPUI) / New neurons are generated throughout adulthood in two regions of the brain, the
dentate gyrus of the hippocampus, which is important for memory formation and
cognitive functions, and the sub-ventricular zone of the olfactory bulb, which is
important for the sense of smell, and are incorporated into hippocampal network
circuitry. Disruption of this process has been postulated to contribute to
neurodegenerative disorders including Alzheimer’s disease [1]. AD is the most
common form of adult-onset dementia and the number of patients with AD
escalates dramatically each year. The generation of new neurons in the dentate
gyrus declines with age and in AD. Many of the molecular players in AD are also
modulators of adult neurogenesis, but the genetic mechanisms influencing adult
neurogenesis in AD are unclear. The overall goal of this project is to identify
candidate genes and pathways that play a role in neurogenesis in the adult brain
and to test the hypotheses that 1) hippocampal neurogenesis-related genes and
pathways are significantly perturbed in AD and 2) neurogenesis-related pathways
are significantly associated with hippocampal volume and other AD-related
biomarker endophenotypes including brain deposition of amyloid-β and tau
pathology. First, potential modulators of adult neurogenesis and their roles in
neurodegenerative diseases were evaluated. Candidate genes that control the turnover process of neural stem cells/precursors to new functional neurons
during adult neurogenesis were manually curated using a pathway-based
systems biology approach. Second, a targeted neurogenesis pathway-based
gene analysis was performed resulting in the identification of ADORA2A as
associated with hippocampal volume and memory performance in mild cognitive
impairment and AD. Third, a genome-wide gene-set enrichment analysis was
conducted to discover associations between hippocampal volume and AD
related endophenotypes and neurogenesis-related pathways. Within the
discovered neurogenesis enriched pathways, a gene-based association analysis
identified TESC and ACVR1 as significantly associated with hippocampal volume
and APOE and PVLR2 as significantly associated with tau and amyloid beta
levels in cerebrospinal fluid. This project identifies new genetic contributions to
hippocampal neurogenesis with translational implications for novel therapeutic
targets related to learning and memory and neuroprotection in AD.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/13847 |
| Date | 15 May 2017 |
| Creators | Horgusluoglu, Emrin |
| Contributors | Saykin, Andrew J., Foroud, Tatiana, Shen, Li, Liu, Yunlong, Nho, Kwangsik |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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