The applicant proposes to undertake a program of research that aims to reveal how Alzheimerís disease (AD) brain affects the biology of neural progenitor/stem cells. This aim is to understand if generation of new neurons (neurogenesis) in AD is dysfunctional and leads to a vulnerable environment for later occurring neurodegeneration. It will also investigate systemically what mechanisms are altered in the AD neural progenitors/stem cells that will generate potential drug targets. Using a broad molecular pproach to the study of NPC biology in AD-like environment, the candidate plans to answer two crucial and interrelated questions: first, how and why neurogenesis is altered in the AD brain and second, does adult neurogenesis contributes to the development of AD and related dementias. The study is built on the candidateís expertise in neural stem cell biology, functional neurogenomics and animal experimentation. This is a highly integrative approach that takes advantage of vast resources near the applican’s institution. Two experts in the neural stem cell biology are involved as mentors and co-investigators. Therefore, the chances for success are high. The project approaches a new and highly attractive area of investigation and the results will have direct impact on the design of future neuroreplacement therapies for AD and other neurological diseases.
It is estimated that the costs for Alzheimer’s disease (AD) patients in California will increase 83.5 percent in the period 2000 ($26 billion) to 2020 ($47.5 billion) and will grow another 60% from 2020 to 2040 ($75.5 billion). Total costs of caring for AD patients will nearly triple between 2000 and 2040 (Fox et al, 2001). The rapid aging of the U.S. population and Californians in particular makes it necessary to aggressively invest in the development of novel therapies reducing societal burden of Alzheimer's disease in the nearest future. A major challenge not addressed by existing therapeutic interventions for AD is the regeneration of lost neurons and neural circuitry to restore cognitive function. In the light of the above, stem cell based cell replacement therapies look particularly attractive and indeed this approach could revolutionize the whole field. However, mounting evidence indicates neurogenesis might be altered in AD brain raising the question of how feasible such approach would be if the AD environment proves to be toxic for newly introduced neural progenitor cells. This proposal aims to establish and understand the relationship between AD and functional neurogenesis allowing us to predict the possible outcomes of the stem cell therapy and manipulate the AD brain environment for more efficient cell replacement strategies. This work will also establish the link between existing and active functional adult neurogenesis (ANG) and neurodegeneration. The contribution of ANG in AD is not clear and needs to be investigated. By deciphering the mechanisms of ANG in AD brain, we might be able to manipulate endogenous neural progenitors, or control the fate of transplanted neural progenitors towards more efficient cell replacement for AD and other various neurological diseases. Therefore, the information obtained from this work will be fundamental for the design of future neuroreplacement therapies and will benefit the State of California directly.