Understanding Alzheimer’s Disease: Molecular Analysis of A- beta Accumulation

1. Understanding Alzheimer’s Disease: Molecular Analysis of A-beta Accumulation Conclusions Alzheimer’s disease was officially diagnosed in a patient in 1906 by AloisAlzheimers and named in 1910 by Emil Kraepelin. The disease causes a loss in brain function and gradually exacerbateover time. It adversely affects memory, thinking, and behavior. AD is considered amonumental problem in present day society. A recent census concluded that 35 million people, including 5 million Americans, have been diagnosed with the disease. For their treatment, it costs roughly 600 billion dollars. [3] Scientists, here at Rensselaer, are interested in finding a cure for AD by studying the structural mechanism (of important poly peptides), nuclear magnetic resonance, molecular dynamics simulations, biochemistry and biophysics. These scientists, who work at the Biotech Center, are researching ways to eradicate Alzheimer's Disease by studying the aggregation of a specific protein named Abeta. By understanding how Abeta binds, the drug perturbation industry for AD may ameliorate. Three eminent professors at the Biotech center inspired us to study more extensively about A-Beta and AD. We heard these professors present their research/results at the 2nd Biotechnology Public Interest Forum. The speakers included Dr. Chunyu Wang, Dr. Wilfredo (Freddie) and Dr. Peter Tessier. The professors research focused on several aspects of AD that dealt with the structural mechanism of Amyloid beta (Aβ or Abeta), which is a peptide of 36 –43 amino acids processed by the Amyloid precursor protein known to be associated with both types of AD. The disease can either be sporadic or familial and is caused by mutations. Study of Abeta’s structure shall hopefully aid in drug prediction and eradicate AD. Introduction - Abstract Inspiration Figures Associate Professor of Biology, Dr. Chunyu Wang focused on Abeta40 and Abeta42 (The Yin and Yang of AD). Although these peptides might only vary by two amino acids, their structural components are much more different. Wang realized that a patient with AD had an increased ratio of Abeta42 to Abeta40. It is predicted that aggregation of Abeta42 causes increased familial AD and that Abeta40 may eventually prevent and cure AD. Wang wanted to further tackle how the structure of Abeta42 is related to toxicity and memory loss. Using silicon screening, both structures have been mapped out. Wang then knew that Abeta and Cyclophilin D join together causing harmful molecules to leak out in a process called mitochondrial dysfunction. Hence, he is currently leading projects on how Abeta and Cyclophilin D interact. Only four drugs are currently on the market based on the acetylcholine receptor. With Wang’s research, perhaps more drugs can be put out. Associate Professor of Chemistry and popular General Chemistry Lecturer, Dr. Wilfredo (Freddie) Colon focused on Abeta accumulation. He believes that the disease needs to be delayed not cured and wants to know why Abetaaccumulates. Currently, scientists do not know what triggers accumulation in 95% of AD. Dr. Colon believes that the protein degradation machinery is compromised causing Abeta toxic species to be difficult to degrade. Some factors that might compromise theprotein degradation system of an individual include aging, genetic factors, external factors such as damage caused by exposure or inflation, overproduction of Abeta, and deficiencies in the metabolism. However, some toxic A-beta species may be resistant to degradation due to kinetic stability – this has to do with being trapped. Abnormal loss or gain of kinetic stability can result in AD, Parkinson’s disease, or even Mad Cow disease. Colon hypothesized that the toxic Abeta species that are kinetically stable might play a pathological role in AD. Hence, he wanted to discover and implement a biomarker approach. Dr. Peter Tessier, is the assistant professor of Chemical and Biological Engineering. Dr. Tessier reviewed some of the general concepts of AD describing it as one of the greatest challenges of our time and how a neuron with Amyloid plague results in AD. His research focused on how the proteins were packed, and how different packing arrangements result in either benign formations or toxic formations. He is currently working on changing the shapes or disassociating the proteins that aggregate back into monomers. Dr. Michael Hanna, Dr. Chunyu Wang, DrWilfredo Colon, Dr. Peter Tessier, Ms. Bianca Pier Results Acknowledgements References [1] "AMYLOID BETA-PROTEIN (HUMAN, 25-35) TRIFLUOROACETATE | 131602-53-4." ChemicalBook---Chemical Search Engine. Web. 05 Dec. 2011. <http://www.chemicalbook.com/ChemicalProductProperty_EN_CB7297245.htm>. [2] "Common Properties of Alzheimer’s Amyloid-beta and a Beta-solenoid Hemoglobin Protease of E. Coli." Groentech Blog. Web. 05 Dec. 2011. <http://groentech.blogspot.com/2011/04/common-properties-of-alzheimers-amyloid.html>. [3] "Alzheimer's Disease - PubMed Health." Web. 05 Dec. 2011. <http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001767/>. 1Rensselaer Polytechnic Institute - Department of Biology ; 2Barton Hal 3414 - 1999 Burdett Avenue - Troy, NY 12180-3599 Jayanth(Jay) Krishnan1,2, Catherine (Cat) Mahoney1,2 Structural and Molecular Representations of Amyloid Beta [1], [2] 1) The increased ratio Abeta42 to Abeta40 is characteristic of AD. This can contribute to drug prediction to prolong the effects of AD. A drug with Abeta40 may be the cure for AD 2) Abeta and Cyclophilin D interact causing harmful effects. The study of how they interact can offer insights for pharmaceutical perturbation of drugs 3) Abeta’skinetic stability causes it to refrain from degradation may have a role in causing AD 4) Disassociation of proteins into monomers may be the way to cure AD Primary Objective