Effect of HSP60 on fibrillogenesis of A-beta amyloid peptide

Alzheimer's Disease (AD) is a neurodegenerative pathology representing the most common form of dementia in the elderly whose incidence dramatically increases with the aging of the population. The pathology is characterized by the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles in the brain. All these deposits are composed by well-ordered, ?-sheet rich, fibers of the Amyloid ? peptides (A?) produced by proteolysis of Amyloid Precursor Protein (APP) in residues of 39-43 amino acids [1]. There is a large evidence that small aggregates of A? peptide, formed in the initial state of the aggregation kinetic, are responsible for severe damage in the cerebral cells. These injuries especially consist of mitochondria alterations and modification of membrane permeability [2-3]. Among the questions still unanswered, the uncontrolled aggregation of amyloid beta peptide (A?) due to misfolding, is a crucial aim of study. Indeed, some therapeutic approaches are directed to inhibit the aggregation or to drive the unstable monomers towards the formation of harmless and stable aggregates [4]. In this context molecular chaperones are crucial in fighting aggregation or protein misfolding and in enhancing the disaggregation process of toxic derivatives by clearance mechanisms [5]. In this work the role of the mitochondrial chaperonin Hsp60 on the aggregation pathway of A? peptide was explored. Different biophysical techniques as fluorescence and circular dichroism spectroscopy, high performance liquid chromatography, isothermal titration calorimetry and atomic force microscopy (AFM) were used. On the whole, the experimental evidences indicate an interaction between A? and Hsp60 responsible for a significant slowdown of the aggregation kinetic and maintenance of the unordered secondary structure of A? peptide. Our results highlight the potential use of HSP60 in the development of innovative therapies for AD centered on the prevention of aggregation process. References: oThies, W., and Bleiler, L. (2013) Alzheimer's Association 2013 Alzheimer's disease facts and figures, Alzheimers Dement. 9, 208-245. oWalsh DM, Klyubin I, et al. (2002) Naturally secreted oligomers of amyloid ?-protein potently inhibit hippocampal longterm potentiation in vivo. Nature 416: 483-484. oKremer, J. J., Pallitto, M. M., Sklansky, D. J., and Murphy, R. M. (2000) Correlation of ?-Amyloid Aggregate Size and Hydrophobicity with Decreased Bilayer Fluidity of Model Membranes Biochemistry 39, 10309-10318. oUversky, V. N. (2010) Mysterious oligomerization of the amyloidogenic proteins, FEBS Journal 277, 2940-2953. oMuchowski PJ et al. (2005) Modulation of neurodegeneration by molecular chaperones, Nature Reviews Neuroscience 6, 11-22