Nucleic Acid Aptamer Selection Against Amyloid Precursor Protein to Prevent Neurodegeneration in Down’s Syndrome and Alzheimer’s Disease

Nucleic Acid Aptamer Selection Against Amyloid Precursor Protein to Prevent Neurodegeneration in Down’s Syndrome and Alzheimer’s Disease

Charisma DeSai - Fall 2013

In the United States, approximately 5.2 million people have Alzheimer’s Disease and more than 400,000 individuals have Down’s Syndrome (Texas Department of State Health Services) (National Down Syndrome Society). These conditions are well-known, but as of yet, no definitive cause or cure has been found for either. Alzheimer’s disease is the most common form of dementia in the human population. Amyloid plaques and neurofibrillary tangles form in the brain, and the malfunction or loss of neurons causes changes in memory and brain function. Many patients with Down’s syndrome also develop Alzheimer’s later in life, but earlier than normal adults. Amyloid deposition associated with Alzheimer’s disease is present in all Down’s syndrome patients older than 30 (Egensperger 113).

Amyloid precursor protein (APP) is a transmembrane glycoprotein that is spliced into multiple peptides. Evidence suggests that APP and its derivative, beta amyloid, may contribute to Alzheimer’s disease. The beta amyloid protein makes up the plaques that form in the brains of Alzheimer’s patients. The amyloid hypothesis states that accumulation of beta-amyloid in the brain is the primary cause of Alzheimer’s disease pathogenesis (Hermey 8). Down’s syndrome patients have elevated APP levels since the gene for this protein is located on chromosome 21 (Arai 290). A small minority of Alzheimer’s disease patients (approximately five percent) have an inherited form of the disease associated with an autosomal dominant disorder that is linked to mutations in the genes APP (Van Dijk 712).

The amyloid hypothesis suggests that reducing the amount of beta-amyloid would mitigate the symptoms of Alzheimer’s disease (Hermey 8). Aptamers have unique advantages for medical treatment since they are highly specific, efficiently produced, can be modified for added functions, and have very low immunogenicity. An aptamer against APP would help reduce the amount of plaques by reducing its functionality and preventing the creation of beta amyloid protein.  By inhibiting this pathway, the formation of plaques from the beta amyloid protein could be reduced or perhaps even prevented. This aptamer may even help prevent the development of dementia in people with Down’s syndrome as they age or individuals with familial Alzheimer’s disease.

Figure 1. The role of Amyloid Precursor Protein, which is cleaved into beta amyloid protein. By inhibiting APP, formation of amyloid plaques in the brain and neuronal death could be prevented.

Specific Aim 1: Selection of RNA aptamers against Amyloid Precursor Protein

The Amyloid Precursor Protein (APP) differentiates into multiple proteins. One of these is beta amyloid, which leads to the formation of plaques in the brain and consecutive nerve cell death. Thus, the selection of RNA aptamers against APP will inhibit the role of beta amyloid in neuronal death.

Ordering information:

Vendor: My Bio Source

Product Catalog number: MBS204227

Vendor Website: http://www.mybiosource.com/datasheet.php?products_id=204227

Vendor Telephone: 1-858-633-0165

Cost per Unit: 100 µg for $335

Cost per round: $23.26

Sources:

"Alzheimer's Disease - Questions and Answers." Alzheimer' S Disease Questions and Answers. Texas Department of State Health Services, 14 May 2013. Web. 20 Aug. 2013.

Arai, Y., Suzuki, A., Masashi, M., and Takashima, S. "Developmental and aging changes in the expression of amyloid precursor protein in Down syndrome brains." Brain and Development 19.4 (1997): 290-294.

"Down Syndrome Facts." NDSS.org. National Down Syndrome Society, 2012. Web. 01 Sept. 2013.

Egensperger, R., Weggen, S. Multhaup, N., Schnabel, F., Beyreuther, K., and Bayer, T. "Reverse relationship between β-amyloid precursor protein and β-amyloid peptide plaques in Down’s syndrome versus sporadic/familial Alzheimer’s disease." Acta neuropathologica 97.2 (1999): 113-118.

Hermey, Guido. "Targeting amyloid precursor protein." Annals of neurology 69.1 (2011): 8-10.

Roizen, N. J., and Patterson, D. "Down's syndrome." The Lancet 361.9365 (2003): 1281-1289.

Van Dijk, R., Fischer, D., Sluijs, J., Sonnemans, M., Hobo, B., Mercken, L., Mann, D., Hol, E., and van Leeuwen, F. "Frame shifted amyloid precursor protein found in Alzheimer's disease and Down's syndrome increases levels of secreted amyloid β40." Journal of neurochemistry 90.3 (2004): 712-723.

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First Progress Report:  Link to First Progress Report

Second Progress Report: Link to Second Progress Report
Final Progress Report: Link to Final Progress Report