Understanding and Preventing Alzheimer's Disease-Related Protein Aggregation

The accumulation of misfolded proteins in the brain results in synaptic disfunction and neuronal death and plays a leading role in the onset of Alzheimer's Disease (AD). The two aggregating proteins that are implicated in AD are the amyloid beta protein (Abeta) and tau protein, which make up the plaques and tangles that are hallmarks of this disease. Here, ion mobility-mass spectrometry is used in combination with other experimental and theoretical techniques to analyze the aggregation of Abeta and tau. An initial, short set of ion mobility experiments highlight the role of charge in the aggregation of a fragment from an important segment of the tau sequence.;Next, the technique is used to probe the effect of familial Alzheimer's disease-related amino acid substitutions on the structure and aggregation of the amyloid beta protein. Results show that the mutations have a varied effect on the structure and early oligomer distribution of Abeta. Finally, the interactions of full-length Abeta with smaller Abeta fragments are examined. First, a study of a mixture of two naturally occurring forms of Abeta demonstrates that these proteins interact, altering the aggregation properties of the system. In a second set of experiments, a small C-terminal derived tetra-peptide of Abeta disrupts the aggregation of the full-length protein without disrupting the formation of amyloid fibrils, highlighting the complex relationship between Abeta aggregation and toxicity.