Jin-Moo Lee, M.D., Ph.D.

Cerebrovascular Disease Section

Neurosciences Program

  • 314-747-1138

  • 314-362-9461

  • 314-362-9462

  • 8111

  • BJC Institute of Health, Rm 9606

  • leejm@wustl.edu

  • http://jmleelab.wustl.edu/

  • amyloid, apoptosis, Alzheimer’s disease, hypoxia, hypoxia-ischemia, ischemia

  • Pathogenesis of amyloid fibrils and amyloid plaques in AD mouse models

Research Abstract:

Our lab is interested in understanding the pathobiology of 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 under conditions that mimick the lysosomal environment. 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.

Finally, we are also very interested in understanding how plaques grow in vivo using mouse models. Using 2-photon microscopy, 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.

Selected Publications:

Hu X, Crick SL, Bu G, Frieden C, Pappu RV, Lee J-M. Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide, Proc Natl Acad Sci USA 2009 106(48):20324-9.

Zhang R, Hu X, Khant H, Ludtke SJ, Chiu W, Schmid MF, Frieden C, Lee J-M. Inter-protofilament interactions between Alzheimer’s Aβ1-42 peptides in amyloid fibrils revealed by cryo-EM. Proc Natl Acad Sci USA 2009 24:106(12): 4653-8.

Hu S, Yan P, Maslov K, Lee J-M, Wang LV. Intravital imaging of amyloid plaques in a transgenic mouse model using optical-resolution photacoustic microscopy. Optic Letters 2009 34(24): 3899-901.

Yan P, Bero A, Cirrito JR, Xiao Q, Hu X, Wang Y, Gonzales E, Holtzman DM, Lee J-M. Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice. J Neurosci 2009 29(34): 10706-14.

Yin KJ, Cirrito J, Yan P, Hu X, Xiao Q, Pan X, Bateman R, Song H, Hsu FF, Turk J, Xu J, Hsu CY, Mills J, Holtzman DM,Lee J-M. Matrix metalloproteinases expressed by astrocytes mediate extracellular Abeta catabolism. J Neurosci 2006 26:10939-10948.

Last Updated: 7/10/2014 11:27:51 AM

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