Our lab is interested in understanding mechanisms involved in amyloid plaque pathogenesis in Alzheimer’s disease. Using animal models, cell culture models, and test-tube aggregation studies, we are investigating the the earliest stages of Abeta aggregation to understand the genesis of plaques. Recent studies suggest that Abeta may accumulate in intracellular compartments of neurons prior to the development of plaques. We are exploring the idea that Abeta is taken up in the endosomal/lysosomal system which normally degrades Abeta, but under pathological conditions (with increased production or decreased clearance of Abeta), may results in the accumulation and aggregation of Abeta in lysosomes. In the lysosome, Abeta is concentrated to levels 2-3 orders of magnitude higher than the extracellular concentration of Abeta. Here, there may be a competition between Abeta proteolysis vs. Abeta aggregation. We believe that intralysosomal aggregation may be favored by high concentrations of Abeta and low pH.
Using test-tube experiments, we are examining conditions that favor Abeta aggregation. For example, conditions that mimick the lysosomal environment (low pH, high Abeta concentration) are conducive for aggregation. We have found that intralysosomal aggregation is favored by Abeta1-42 but not Abeta1-40 (Abeta1-42 is believed to be more pathogenic). In addition, we have found that the fibril structure for Abeta1-42 is very different from Abeta1-40 fibrils under certain conditions of fibril growth.
We are also very interested in understanding how plaques grow in vivo using mouse models (APP/PS1 mice). Using 2-photon microscopy in living mice, we are able to observe the growth of individual plaques over days and weeks. By manipulating the microenvironment within the observed fields of view, we are able to study what factors influence plaque growth. We are finding that plaque growth is influenced by extracellular Abeta concentrations, glial cell activation, and neuronal activity.
The lab has recently found that activated astrocytes which appear around amyloid plaques may be involved in limiting plaque growth. By impairing astrocyte activity using gene deletion of GFAP and vimentin (two intermediate filaments that are expressed in activated astrocytes) in APP/PS1 mice, we have found that plaques accumulation is accelerated. Astrocytes in the GFAP/vimentin null APP/PS1 mice fail to send processes into the plaques. As a result the plaques are larger and more numerous. Thus, it appears that activated astrocytes “invade” plaques in an attempt to limit plaque growth. We are currently trying to understand mechanisms by which these cells may exert their plaque-limiting activity.