I propose (1) to determine the molecular and cellular mechanisms by which apolipoprotein (apo) E4 impairs the generation of new neurons in the hippocampus of mice and (2) to explore whether apoE4-induced learning and memory impairments in mice can be rescued by stimulating the generation of new neurons or transplanting mouse or human neural stem cells expressing apoE3 into the hippocampus.
RATIONALE AND SIGNIFICANCE
In many mammals, including humans, new neurons are generated throughout life in the subgranular zone (SGZ) of the dentate gyrus in the hippocampus and may participate in learning and memory formation. Alzheimer’s disease (AD) causes progressive and irreversible cognitive loss, and there is no effective treatment. Since early loss of neurons in the hippocampus is a major pathological feature of AD, transplantation of neural stem cells into the hippocampus might be an effective treatment.
Among its neurobiological functions, apoE distributes lipids in the central nervous system for normal lipid metabolism and participates in neuronal repair and remodeling. However, its three isoforms (apoE2, apoE3, and apoE4) differ in their ability to accomplish these critical tasks. ApoE4 is a major risk factor for AD, is associated with a smaller hippocampus in humans, and impairs learning and memory in mice carrying human apoE4 gene.
This proposal builds on novel findings suggesting that apoE modulates the generation of new neurons in the hippocampus and that apoE4 contributes to the development of AD by impairing this process. Stimulating the generation of new neurons in the hippocampus or transplanting neural stem cells expressing apoE3 into the hippocampus might rescue the learning and memory impairments associated with apoE4 in AD. The outcome of the proposed studies will shed light on the cause of AD and will provide a foundation for the development of stem cell therapy in AD patients carrying the apoE4 gene, who account for ~50% of total AD cases.
Aim 1. To determine the molecular and cellular mechanisms by which apoE deficiency and apoE4 impair the generation of new neurons in the hippocampus in mice.
Aim 2. To test whether stimulating the generation of new neurons in the hippocampus improves the learning and memory deficits associated with apoE4 in mice.
Aim 3. To explore whether transplanting mouse or human neural stem cells expressing apoE3 into the hippocampus rescues the learning and memory impairments associated with apoE4 in mice.
CONTRIBUTION TO THE CALFORNIA ECONOMY:
A major goal of regenerative medicine is to repair damaged cells or tissue. My research focuses on (1) understanding the role of neuronal regeneration in learning and memory and (2) developing stem cell therapy for Alzheimer’s disease. Alzheimer's disease is the leading cause of dementia and is the fastest growing form of cognitive impairment in California, in the USA, and worldwide. My research could benefit the California economy by creating jobs in the biomedical sector. Ultimately, this study could help reduce the adverse impact of neurodegenerative diseases. Thereby, I hope to increase the productivity and enhance the quality of life for Californians.
The results of my studies will also help develop new technology that could contribute to the California biotechnology industry. The studies will characterize multiple lines of neural stem cells carrying apoE3, a protein protective to the brain, or apoE4, which is detrimental to the brain and is associated with increased risk of Alzheimer’s disease. These cell lines could be valuable for biotechnology companies and researchers who are screening for drug compounds targeting Alzheimer’s disease.
CONTRIBUTION TO THE HEALTH OF CALFORNIANS:
The most important contribution of the studies will be to improve the health of Californians. Diseases that are the target of regenerative medicine, such as Alzheimer’s disease, are major causes of mortality and morbidity, resulting in billions of dollars in healthcare costs and lost productivity. As we continue our efforts in medical research, we hope to one day unlock the secrets of brain development and repair. This knowledge will help medical researchers develop beneficial therapies beyond what is currently available and potentially improve the quality of life and life expectancy of patients with neurodegenerative diseases, such as Alzheimer’s disease.