CIRM Quick Links
Related Links
Right Column
RN1-00545-1: Neural progenitors and Alzheimer's disease
Recommendation: Recommended if funds available
Scientific Score: 58
First Year Funds Requested: $354,796
Total Funds Requested: $1,778,040
Public Abstract (provided by applicant)
The applicant proposes to undertake a program of research that aims to reveal how Alzheimer’s disease (AD) brain affects the biology of neural progenitor cells. This aim is to understand if 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 that will generate potential drug targets. Using a broad molecular approach 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 candidate’s expertise in neural stem cell biology, functional neurogenomics and animal experimentation. This is a highly integrative approach that takes advantage of vast resources in [REDACTED] and the neighboring [REDACTED] campus. Two experts in the neural stem cell biology are involved as mentors and co-investigators, [REDACTED] and [REDACTED]. 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.
Statement of Benefit to California (provided by applicant)
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.
Review
SYNOPSIS: This proposal aims to understand the relationship between an Alzheimer’s disease (AD)-like pathological environment and functional neurogenesis in order to clarify the disease’s pathogenesis and to facilitate cell replacement therapies in AD. Recent studies suggest that there are abnormalities in neurogenesis in AD. A recent investigation demonstrated that environmental “enrichment” of an AD mutant mouse led to a delay in neuropathological abnormalities. The reason for the effect of enrichment may relate to neurogenesis. The applicant hypothesizes that there is a relationship between early development and late onset neurodegeneration, which involves neural proliferation and cell fate decisions, and that dysfunctional adult neurogenesis facilitates the development of AD. The applicant proposes to use mouse models of AD to investigate the integrity of neurogenesis at early and late stages of development.
STRENGTHS AND WEAKNESSES OF THE RESEARCH PLAN: The PI proposes three aims. In the first aim, the PI will investigate the effect of AD on the function of neural progenitor cells (NPCs). The hypothesis being tested is that the AD-like environment affects aspects of embryonic and adult NPC proliferation and differentiation. The PI will explore NPC proliferation and differentiation in control and mutant mouse models of AD from embryonic stages through maturity. The PI presents rather striking preliminary data from one mouse model of AD.
The hypothesis underlying the second aim is that there are specific regulatory pathways activated in adult progenitors in response to the AD-like environment and that neurodegenerative processes affect these regulatory pathways in the NPCs of the AD mice. In this aim, the PI will generate reporter:AD mutant mice, NPCs will be obtained at different stages of life, and gene expression will be analyzed. Genes of interest will be further investigated. These investigations will clearly yield a large amount of data that may be difficult to analyze. One potential shortcoming identified by the PI is that post-transcriptional changes important in AD-induced perturbations in neurogenesis will not be assessed. The reviewers noted the PI is very experienced with these techniques and at least one reviewer described the PI as “expert at microarray” and further noted that one of the PI’s mentors characterized him/her as not just an “informatics person.” At least one reviewer regarded this aim as a potential fishing trip.
In the third aim, adult neurogenesis (ANG) in AD mouse models will be ablated by different methods to determine the effect at the molecular, histological and behavioral level, thus testing the hypothesis that ANG ablation facilitates the development of AD. These studies are of interest in view of recent data suggesting that “enrichment” leads to delayed pathology of AD mutant mice.
The reviewers regarded these as interesting experiments because they highlight the effect of ANG on AD and because they focus on early embryonic events as being important in the pathogenesis of neurodegenerative diseases. However, a reviewer was concerned that the applicant did not cite or was unaware of relevant publications in prominent journal(s) in this area of research, including one study on endogenous stem cell differentiation in AD- transgenic mice, and other studies in mutant mice, indicating that the mutant environment modulated the differentiation of transplanted neural stem cells. A reviewer also noted that there are no AD mice, rather that the AD mouse models described in the proposal are transgenic mice carrying a human mutant gene found in familial AD, which may only represent certain aspects of AD pathologies. From this reviewer’s point of view, more targeted mechanistic studies to investigate the effect of each pathological change in AD on the stem cells may be desired, rather than in vivo studies.
Overall the reviewers found the proposal interesting. It describes a huge amount of work that will undoubtedly generate a massive amount of data. There was some concern that the proposed microarray studies were a ‘fishing expedition’. The technical expertise of the applicant was acknowledged. Some of the reviewers believed that this expertise, in conjunction with the preliminary data, suggest the feasibility of obtaining new useful information that could provide insights into the relationship of stem cells to AD and its potential for treatment.
QUALIFICATIONS AND POTENTIAL OF THE PRINCIPAL INVESTIGATOR: The PI appears to be an industrious person with creative ideas. The PI has an excellent background and training to carry out this proposal. In particular, the PI’s position for 7 years in a lab known for the application of genomic screening methods to understand the genetic basis of human cognitive specializations and neurodegenerative disease, and current associations with collaborators noted for expertise in neurology and neurological disorders, has strengthened the applicant’s background. The PI obtained a PhD in Europe, then spent several years initially as a post-doc and then as a staff scientist in a university neurology department. These activities were in a lab known for the application of genomic screening methods to the study of neurodegenerative disease as noted above. The PI has recently started a tenure track appointment in Neurology at the applicant institution and is head of the neuroscience division there.
This proposal involves a two key nearby collaborators who will ensure access to core facilities. One of the collaborators will serve as a primary mentor to the applicant; the other collaborator has also agreed to be a mentor to the applicant.
While the number of publications by the applicant is not huge, they are of good quality (since 2005 there are publications in three top-tier journals). The applicant lists more than twenty publications with 4 first authored refereed papers since 2000, including relevant papers in well-known journals. Many of these publications involve microarray studies, and the applicant’s mentor notes that s/he “has excellent insight into how one approaches array data.”
The PI is a collaborator on a multi year NIH grant, co-PI on a one year NIH grant, co-PI on a grant from a charitable foundation, and PI on a grant related to gene expression in ALS.
The reviewers were concerned about the scientific environment at the institution with respect to neuroscience and stem cells. In addition, details related to mentoring of the applicant and to guidance related to the preparation for tenure were not provided. Furthermore, there was concern that neither the PI nor the two mentors had strong expertise in AD. These issues raised concerns for the career development of the applicant in AD stem cell therapy and the likelihood of becoming a leader in the stem cell field.
INSTITUTIONAL COMMITMENT TO PRINCIPAL INVESTIGATOR: The letter of commitment in this application jointly from the head of Neurology and the head of the institution describes the facilities. These include FACS, confocal microscopes, and a vivarium. The letter does state that the institution is “..deeply committed to promoting stem cell research on campus,” and the governing board has established a seed grant program providing funds for investigators to pursue stem cell research projects on campus. In addition, there is an advisory committee for stem cell research. Note was made that “we are actively recruiting young investigators to the campus, including some whose interests lie in the field of stem cell research,” but no further details about this are provided. No mention of guidance of the candidate with respect to a preparation for tenure or its likelihood was given. No details about the extent of scholarly pursuit among faculty at this institution were detailed. One reviewer noted that it seemed as if the applicant will have to stand alone at present in this institution as the “stem-cell scientist.” In many ways, the letter from the mentor and collaborator was a much stronger letter. These aspects of the proposal raise concerns that the institution will not be an optimal environment for fostering the applicant’s career, and lowered the reviewers’ enthusiasm.
DISCUSSION: The strengths of this proposal include uniform interest by the reviewers in the research focus on the impact of an Alzheimer’s disease-like environment on embryonic and adult neurogenesis, and agreement that the PI was a creative and industrious investigator who was well-trained and is an expert in microarrays. The main weaknesses of the proposal were concerns about the institutional commitment to providing a strong scientific environment for stem cell research and for providing guidance for obtaining tenure. There was some concern that the applicant was a “lone wolf”. The reviewers noted collaboration with and mentoring from two scientists at the neighboring institution but also noted that details on the mentoring was lacking. There was some concern that neither the applicant nor the collaborators have a strong background in the AD field, and that the PI does not seem to have acquired adequate knowledge of the field (as one example of this, important, relevant publications were not cited in the research proposal).
The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:
- None