Eleni Tukuafu and Dr. John S. K. Kauwe, Biology

Introduction

It is estimated that 5.2 million Americans have Alzheimer’s disease. It is currently the 6th leading cause of death in America, killing around 500,000 seniors every year. A 68% increase of death from Alzheimer’s disease was observed from the year 2000 to 2010. These numbers are expected to continue climbing.

Alzheimer’s disease is the most common form of dementia and is characterized by the formation of extracellular betaamyloid plaques and intraneuronal tangles. Betaamyloid plaques are formed when an amyloidbeta precursor protein (APP), located on the surface of a neuron, is cleaved by enzymes and frees a protein called amyloid beta. This protein is normally cleared by the body, however, in Alzheimer’s disease it goes unregulated and begins to accumulate. This accumulation results in betaamyloid plaques, which are toxic to neurons (Li et al., 2014). Our research will focus on a rare exonic variant, TM2D3, which may play an important role in the betaamyloid pathology of LOAD.

Although TM2D3 has not previously been related to Alzheimer’s disease, recent gene based pathway analyses have identified potential links between TM2D3 and 28 genes implicated in Alzheimer’s. For example, TM2D3 has been associated with APP through NR3C1, a glucocorticoid receptor which regulates immune responses and constitutive activity of the central nervous system (Kajkowski et al.,2001). TM2D3 also shares extensive homology with the betaamyloid peptide binding protein (BBP), which binds to the betaamyloid peptide and promotes amyloid toxicity. Another homolog of TM2D3, Almondex (Amx), has been found to have a potential role in the Notch signaling pathway and amyloid metabolism (Michellod et al., 2003). The potential effect of the TM2D3 variant in LOAD is very strong. Understanding TM2D3 will help us determine the extent to which it contributes to the progression and development of Alzheimer’s disease, ultimately aiding researchers in finding an effective treatment.

Methodology

We have access to a cohort of 5,092 individuals from the Cache County Study on Memory, Health, and Aging. This study was collected from Cache County, Utah in 1995. Initially all of the subjects were reported to be nond emented. However, during the course of the study, 518 subjects developed Alzheimer’s disease. We will genotype the samples via qPCR. Aliquots of each sample will be transferred to 384 well qPCR plates and a Taqman genotyping assay designed to find and amplify the rare single nucleotide polymorphism (SNP) will be added. The SNP will be genotyped using Applied Biosystems ViiA 7 qPCR machine. Once we have obtained the data, we will perform logistic regression for analysis of association between genotype and risk for Alzheimer’s disease.

Results

Determining the involvement of the TM2D3 gene in the development of Alzheimer’s disease deemed an interesting topic of research, considering its role in the betaamyloid pathway. However, after performing logistic regression, we have found that the association of the TM2D3 gene with Alzheimer’s disease, with a frequency of .05%, was statistically insignificant. Although we expected about 3 individuals to have the variant, no one in the Cache County Study had the TM2D3 variant.

Conclusion

Unraveling the genetic architecture of Alzheimer’s disease through future research is an important feat that will allow researchers to find better, more effective treatment. The more we understand about the genes that are associated with developing Alzheimer’s disease, the closer we get to provide a means for early prediction and intervention.

Scholarly Sources

1. Kajkowski, E.M., Lo, C.F., Ning, X., Walker, S., Sofia, H.J., Wang, W., Edris, W., Chanda, P., Wagner, E., Vile, S., et al. (2001). Beta amyloid peptidei nduced apoptosis regulated by a novel protein containing a g protein activation module. J. Biol. Chem. 276. 18748 18756.
2. Li M., Guo K., Ikehara S. (2014). Stem Cell Treatment for Alzheimer’s disease. International Journal of Molecular Sciences. 15(10):19226 19238.
3. Michellod, M.A., Forquiqnon, F., Santamaria, P., and Randsholt, N.B. (2003). Differential requirements for the neurogenic gene almondex during Drosophila melanogaster development. Genesis 37, 113122.