Keni Reid and Dr. John Kauwe, Biology Department
Alzheimer’s disease is a brain disorder caused by an irreversible degeneration of nerve cells. It is developed in response to a growth of proteins, tau tangles or amyloid plaques, which disrupt communication between neurons in the brain. Because the nerve cells no longer function, they die. It is estimated that as many as 5.1 million Americans may have Alzheimer’s disease and about one to four family members act as caregivers for each individual with Alzheimer’s disease. Many lives are affected by Alzheimer’s which has driven further and extensive research for solutions. However, despite much effort, the genetics of Alzheimer’s remains largely unknown. Most of what is known about the genetics are not helpful in predicting or diagnosing the disease which only emphasizes that much needed progress in the area of genetics.
Through innovative pedigree analysis of over 200 individuals with Alzheimer’s disease, we have discovered RAB10, a gene that has direct correlation with building up of amyloid plaques. Since its discovery, RAB10 has shown immense potential for the prevention of Alzheimer’s. Our results have shown that reduced expression of RAB10 also reduces the buildup of amyloid. Therefore, reducing RAB10 expression may protect high-risk individuals from Alzheimer’s disease which has major implications for the future of Alzheimer’s prevention and therapy. Our project seeks to confirm these results through further testing of RAB10 in vivo, or in living cells. By the end of our project, we will be closer to confirming the effectiveness of using it as a means of Alzheimer’s prevention and therapy.
We have gathered skin samples from willing participants that are known carriers and non-carriers of the RAB10 gene. We harvested their cells using induced pluripotent stem cell (IPSC) methods that allowed us to grow fibroblasts or undifferentiated cells. These “unassigned cells” were then used to become any type of cell we need. Using this to our advantage, we will induce the fibroblasts into becoming neurons through a series of events that will allow us to use them for further testing of the RAB10 gene. With these growing cells, we performed both a whole genome sequence analysis as well as a proteomics analysis. This allowed us to understand both the entire DNA sequence of the person as well as the proteins produced in their neuron cells. With this information, we have performed an analysis contrasting cells with RAB10 with those without RAB10 allowing us to pinpoint specific parts of the gene called SNPs (Single nucleotide polymorphisms) significant to the decrease of amyloid plaque.
Our results have shown that a SNP, identified as Rs142787485, shows significant contribution to amyloid plaque build-up. In the study of Alzheimer’s, we study two types of amyloid beta proteins, Aβ42 and Aβ40. Aβ40 is substantially better for our brains as they do not form dangerous plaques known in Alzheimer’s disease. Experimentally, we found that RAB10 expression is significantly higher in Alzheimer’s disease patients. We then demonstrated that knockdown of RAB10 resulted in a significant decrease in Aβ42 (p value = 0.0003) and in the Aβ42/Aβ40 ratio (p value = 0.0001) in our living neurons grown in our lab.
With this evidence, we see that RAB10 does, indeed, have significant potential towards a therapeutic prevention of Alzheimer’s Disease. Future research must be done moving towards experimental treatment of those with genetic risk of Alzheimer’s disease to determine actual effectiveness of RAB10 treatment in the fight against Alzheimer’s disease.