Alzheimer's Disease

Alzheimer’s disease (AD) is a degenerative brain condition that results in dementia. It usually starts in late-middle or old age and is often characterized by progressive memory loss, impaired thinking, disorientation and changes in personality and mood. The disease is marked by the degeneration of brain neurons and the presence of neurofibrillary tangles and amyloid plaques. Both the tangles and plaques observed in the brains of AD patients are caused by protein aggregation. The tangles are composed of a protein called tau. In healthy neurons, this protein provides stabilization for the microtubule support structure within the cell. In AD, tau is hyperphosphorylated, causing it to aggregate and form insoluble tangles within the cell, resulting in cell death. The plaques are amyloid fibrils composed predominantly of a protein called amyloid beta (Aβ). Aβ is formed from a larger protein called amyloid precursor protein (APP) by enzymatic cleavage to produce peptides that have 40 or 42 amino acids. These peptides, Aβ40 and Aβ42, are normally cleared out of the brain in healthy individuals but in those afflicted with AD, the peptides, particularly Aβ42, accumulate extracellularly and form plaques.

While our investigation of the Aβ peptides has been in progress for a number of years in collaboration with Teplow and other experts, we have recently begun to include the protein tau in our studies, too. The major goals of our Aβ and tau research are to

• characterize the monomer structures of the proteins,
• investigate the mechanisms of oligomerization, and
• evaluate strategies to prevent protein aggregation

using mass spectrometry/ ion mobility methods in combination with molecular mechanics simulations.

For the Aβ peptides we started to address some of these issues in a series of papers:

•	Over-all shape of monomer and small oligomers	Amyloid β-Protein: Monomer Structure and Early Aggregation States of Aβ42 and its Pro19 Alloform J. Am. Chem. Soc. 2005, 127, 2075-2084
•	Structural details of the monomer • full-length Aβ42	Amyloid β-Protein Monomer Structure: A Computational and Experimental Study Protein Sci. 2006, 15, 420-428
	• Aβ(21-30) fragment (structural nucleation site)	Structure of the 21-30 Fragment of Amyloid β-Protein Protein Sci. 2006, 15, 1239-1247 Amyloid β-Protein: Experiment and Theory on the 21-30 Fragment J. Phys. Chem. B 2009, 113, 6041–6046
	• effect of mutations	Effects of Familial Mutations on the Folding Nucleation of the Alzheimer Amyloid β-Proteins J. Mol. Biol. 2008, 381, 221-228
•	Paranuclei	Amyloid-β Protein Oligomerization and the Importance of Tetramers and Dodecamers in the Aetiology of Alzheimer's Disease Nat. Chem. 2009, 1, 326-331 Intermolecular Interactions in Biomolecular Systems Examined by Mass Spectrometry Annu. Rev. Phys. Chem. 2007, 58, 511-533
•	Methods addressing the kinetics of isomerization and oligomerization	Investigation of Noncovalent Interactions in Deprotonated Peptides: Structural and Energetic Competition between Aggregation and Hydration J. Am. Chem. Soc. 2004, 126, 3261-3270 The Ion Mobility Mass Spectrometry Method and Its Application to Duplex Formation of Oligonucleotides and Aggregation of Proteins In: Advances in Mass Spectrometry, A. E. Ashcroft, G. Brenton, J. J. Monaghan (eds.), Amsterdam, Elsevier, 2004, Vol. 16, pp. 189-200
•	Collaborative effort Link to • Bowers' • Teplow's • Shea's • Bitan's Home Page	Elucidating Amyloid β-Protein Folding and Assembly: A Multidisciplinary Approach Acc. Chem. Res. 2006, 39, 635-645