Alzheimer?s disease (AD) is the most common form of adult-onset dementia and the number of patients with AD escalates dramatically each year. AD patients display hippocampal atrophy, memory impairment, and other cognitive and olfactory deficits. On the other hand, new neurons are generated throughout adulthood in two regions of the brain, the dentate gyrus of the hippocampus and the sub- ventricular zone of the olfactory bulb and are incorporated into hippocampal network circuitry. In adults, the annual turnover of stem cells into neurons is 1.75% with a modest decline during aging. By contrast, the estimated annualized hippocampal atrophy rate is 1.41% per year for cognitively normal older people and 4.66% for patients with AD pathology. Disruption of this process has been postulated to contribute to neurodegenerative diseases including AD. Alterations in hippocampal neurogenesis in AD could either provide protection by proliferation of neural progenitor cells or cause accelerated neural degeneration due to impairment of neuronal network and synaptic plasticity. Many of the molecular players in AD are also modulators of adult neurogenesis, but genetic mechanism underlying adult neurogenesis in AD is still unclear. Recently, we discussed potential modulators of adult neurogenesis and their roles in neurodegenerative diseases in a review paper. The overall goal of the proposed project is to identify candidate genes and pathways which play a role in neurogenesis in adult brain and to test our hypothesis that 1) the neurogenesis pathway is significantly associated with hippocampal volume and 2) hippocampal neurogenesis-related genes and pathways are significantly perturbed in AD. We will use a large-scale imaging genetics meta-analysis summary and multimodal neuroimaging (MRI, PET) and genome-wide genotyping data from several independent cohorts.
The specific Aims : (1) identify candidate genes associated with hippocampal neurogenesis using a pathway-based systems biology approach from publicly available databases and literature mining; (2) perform genome-wide gene-set enrichment analysis for hippocampal volume using a large-scale neuroimaging genetics meta-analysis (N~15,000); and (3) perform a neurogenesis-related targeted gene-based and pathway-based association analysis using AD-related biomarker endophenotypes. The proposed project will enable discovery of new genetic contributions to hippocampal neurogenesis and has strong translational potential to identify novel therapeutic targets related to learning and memory and AD neuroprotection.

Public Health Relevance

TO PUBLIC HEALTH AD is a progressive neurodegenerative condition with no validated disease modifying treatment. The fight against AD has increasingly become a top national priority. Identifying neurogenesis-related genes associated with AD provides valuable insights into the molecular mechanisms of AD and helps to identify new therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
1R03AG054936-01
Application #
9225314
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Wise, Bradley C
Project Start
2017-03-01
Project End
2019-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
1
Fiscal Year
2017
Total Cost
$71,867
Indirect Cost
$21,867
Name
Indiana University-Purdue University at Indianapolis
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202