JDFAF has just funded a breakthrough research project integrating the expertise and resources of researchers at three University of California campuses.

The John Douglas French Alzheimer's Foundation has just funded a breakthrough research project integrating the expertise and resources of researchers at three University of California campuses. 

Researchers at UCSF (led by Bruce Miller, MD), UCLA (led by Giovanni Coppola, MD and Daniel Geschwind, MD, PhD), and UCSB (led by Kenneth Kosik, MD) will employ three different forms of the very latest genomic technologies to probe variation across the entire genome to identify patterns of gene expression that define the varied types and stages of neurodegeneration, and to evaluate repertoires of immune cells at the single-cell level to allow better tracking of disease progression and inter-individual variation in disease.

The entire project will be under the direction of the Foundation's Chief Medical Officer, Bruce L. Miller, MD, who was recently elected to the National Academy of Medicine.

These groundbreaking studies leverage and integrate the unique expertise of the research teams at the three universities, and are driven by new advances in technology that have brought new tools to the study of genomics, while dramatically driving down the costs for these studies.  

Simultaneously, the massive and creative efforts at UCSF to collect large numbers of healthy elders and patients in the preclinical, early and more advanced stages of differing dementias, and the detection of new isolated populations in the Basque-country in Spain, and Columbia, South America will make these studies unique, powerful and transformative.  

Variation across the genome provides the biological foundation from which brain health is maintained and disease occurs during aging. By understanding the genetic contributions to specific forms of early-onset forms of frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD) we can gain a better understanding of the biological changes that promote risk for these diseases across the lifespan. Conversely, by characterizing individuals who benefit from healthy cognitive aging we can gain insight into factors that may protect the aging brain and promote better function. 

Studying patients from both groups will enable better identification of individuals at risk for neurodegeneration and will provide new biological targets for treating disease. Although genes that cause familial forms of FTLD and AD have been identified, most of the genetic contribution to these disorders remains unknown. In addition to genes encoding proteins directly involved in disease pathology, evidence is mounting to support the role of immune dysregulation and inflammation as important contributors to both neurodegeneration and healthy cognitive aging. 

New Research Project to Examine the Role of Microglia in Alzheimer’s Disease Using Cellular Reprogramming

The John Douglas French Alzheimer's Foundation has funded an important new research project under the direction of Justin Ichida, PhD, of the University of Southern California, Department of Stem Cell Biology and Regenerative Medicine. 

The research project—Examining the Role of Microglia in Alzheimer’s Disease Using Cellular Reprogrammingapplies new techniques to enable researchers to gain a better understanding of how genetic differences affect the functioning of Microglia, and the risk for Alzheimer’s disease.

Microglia are a type of immune cell that make up about 15% of the cells in the brain. Microglia scavenge throughout the central nervous system removing infectious agents, damaged neurons, and plaques. Interestingly, recent studies suggest that genetic differences that increase the risk of developing Alzheimer’s disease (AD) may do so by altering microglial function rather than nerve cell function. This is because many of the genes or gene control regions that have been recently linked to AD are predicted to predominantly affect microglia. 

However, studying how AD-associated genetic changes affect human microglial function has been challenging because obtaining microglia from biopsies is difficult. To address this problem, Dr. Ichida and his team have developed a method called “cellular reprogramming” that enables the generation of human microglia from biopsied skin or blood cells. This approach has been used to produce functional nerve cells and other cell types from patients, but not microglia. Dr. Ichida’s team will couple this procedure with a technique called CRISPR that allows the introduction of genetic changes that increase AD risk into microglia in a petri dish. 

The research project will test the hypothesis that genetic differences that increase AD risk do so in part by altering microglial function. They will do this by examining microglial function in the presence or absence of two different genetic changes that are strongly associated with AD. The impact of this study will be to 1) determine if AD-associated genetic changes cause disease-relevant alterations in human microglial function and 2) establish this approach as a powerful platform for studying the role of microglia in AD.