Poster Presentation 12th Australian Peptide Conference 2017

Comparative study of properties of familial Alzheimer's disease (FAD) mutants of the amyloid-β peptide (#75)

Sritama Bose 1 , Govindasamy Mugesh 1
  1. Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, Karnataka, India

Amyloid-β peptide, formed by proteolytic cleavage of the amyloid precursor protein (APP), self assemble to form insoluble amyloid fibrils or plaques in the brain of patients suffering from the neurodegenerative Alzheimer’s disease (AD) and is widely regarded as the causative agent of the same. However, many research and observations now indicate that it is not the insoluble fibrils but the soluble oligomeric state of amyloid-β which are more toxic and adversely affect the neurons and synapses. The aggregation prone amyloid-β peptides exhibit extensive polymorphism in solution and exist in multiple assembly states differing in size and conformation, some of which exhibit pathophysiological effects distinct from each other. Thus recent researches are directed towards isolating and identifying specific species responsible for toxicity1. Another factor affecting amyloid-β toxicity is mutation. Cases of hereditary familial Alzheimer’s disease (FAD) and heritable form of cerebral amyloid angiopathy (CAA) have been successfully linked to mutations in genes responsible for processing of APP and formation of amyloid-β. Some of these mutations also occur in APP itself and fall within the amyloid-β domain producing mutated amyloid-β peptides often with enhanced toxicity. Studies are directed towards gaining deeper insight into the role of these mutations on the toxicity of the peptides2. We have synthesized several FAD mutants of amyloid-β peptides with high purity using efficient microwave assisted solid phase peptide synthesis. The main objective of this study is to prepare and characterize them in specific aggregation states and systematically compare some of their biophysical and biochemical properties. Previously reported protocols have successfully employed size exclusion chromatography to isolate wild type amyloid-β in specific aggregation states3. We have extended the same protocol to isolate and characterize different aggregation states for the FAD mutant counterparts and comparison of their properties were carried out using techniques like fluorescence spectroscopy, microscopy etc.

  1. Benilova, I.; Karran, E.; Strooper, B. D. Nature Neurosci. 2012, 15, 349
  2. Hatami, A.; Monjazeb, S.; Milton, S.; Glabe, C. G. J. Biol. Chem. 2017, 292, 3172.
  3. Jan, A.; Hartley, D. M.; Lashuel, H. A. Nat. Protoc. 2010, 5, 1186.