Penn Alzheimer's Disease Core Center 2014 Pilot Research Grants
The NIH-funded Penn Alzheimer's Disease Core Center was able to award 2 full Pilot Research Grants in support of disease research. Congratulations to this year's awardees, Zahra Fakhraai, PhD, and Rachel Gross, MD.
- Zahra Fakhraai, PhD
"The Effect of Surface Interactions on the Early Stages of A-Beta Fibril Growth"
The Amyloid beta (A-Beta) peptide is the main component of amyloid plaques observed in the brains of patients with Alzheimer's disease. Recent studies suggest that oligomers and protofibrils formed during the early stages of amyloid formation are neurotoxic and may be the cause of the disease. However, due to limitations with existing experimental techniques, determining the structure of these nanometer-sized oligomers and protofibrils is difficult. For example, labeling and staining can cause changes in the folding kinetics that are indistinguishable from real physical effects.
We have recently employed a new label-free sample preparation procedure that allows us to immobilize A-Beta peptide on various substrates and study the structure of aggregates in solution. This technique also allows us to study the evolution of the structure due to substrate interactions under various experimental conditions. Our preliminary studies suggest that under certain conditions, amyloid fibril formation rates are increased significantly in the vicinity of a substrate. For example, under the conditions where the peptides are loosely bound to the surface, extremely long fibrils are formed on the surface within the structure and assembly of these fibrils are strongly influenced by small chemical modifications in the peptide sequence and the substrate properties.
Under physiological conditions, amyloid plaques form through complex electrostatic and hydrophobic interactions of peptides near membrane surfaces. It is hypothesized that surface interactions catalyze fibril formation. The proposed studies will allow us to understand amyloid fibril formation in the oligomeric stage, follow the nucleation and growth of fibrils close to surfaces of varying properties, and measure fibril formation rates under physiologically relevant conditions. These studies would also be technologically important for understanding the challenges associated with using dye molecules in measurements of fibril growth rate and other bio-imaging applications. Our label-free technique can be used to systematically study the effect of labeling on the aggregation rate and morphology.
My group has extensive experience with atomic force microscopy (AFM 22-24) and other AFM based experimental techniques. We apply these techniques to study physical properties of polymers and other soft materials in nanometer length scales. These methods can be efficiently used to study oligomeric stages of fibril formation. Funding provided by the Penn ADCC will provide crucial support necessary for my group to use this expertise to study structures important for understanding the origins of Alzheimer's disease and other neurodegenerative disorders.
- Rachel G. Gross, MD
"Radionuclide Imaging of Amyloid Plaques and Basal Ganglionic Dopamine in the Parkinson Brain"
Cognitive impairment (CI) affects up to 80% of patients with Parkinson's disease (PD) during the course of the illness and impacts greatly on quality of life, independence, caregiver burden, and healthcare cost. The pathophysiology of CI in PD is not fully understood, but it is likely that abnormally aggregated synuclein/Lewy body and amyloid/Alzheimer's disease (AD) pathology are major contributors. Predicting which individual patients will develop CI presents a major challenge for the biomarker research community and for PD drug discovery. In this study, we propose to use radionuclide positron emission tomography (PET) imaging of amyloid burden and nigro-striatal dopamine deficiency as markers, respectively, of AD and Lewy body pathology to investigate the relationship between these pathological changes and cognitive decline in PD. We expect that amyloid burden and dopamine deficiency will correlate with CI, but that those patients with both abnormal amyloid and dopamine scans will have more severe CI than those with abnormal dopamine scans alone. We hypothesize that dopamine deficiency will be related to a frontal/executive profile of cognitive dysfunction commonly seen in PD, while amyloid burden will be associated with posterior cortical deficits more characteristic of AD, including memory, language, and visuospatial dysfunction. We will also include amyloid and dopamine imaging in a multi-dimensional predictive model to improve our ability to assess risk of cognitive decline in patients with PD. We hypothesize that greater amyloid burden at baseline will be predictive of cognitive decline two years later. Accurate assessment of the risk of CI has enormous implications for patient care, participant selection for clinical trials, and discovery of new therapeutics.