- Center for Dementia Research, Nathan Kline Institute
By utilizing various in vitro cell models as well as transgenic mice, I investigate:
The over-expression of important trafficking and regulatory proteins of the neuronal endosomal/lysosomal system, such as the mannose 6-phosphate receptors and various rab GTPases and CatD. These proteins are up-regulated very early in sporadic Alzheimer’s disease, and the effect of their over-expression will highlight changes in APP metabolism.
The relationship between endosomal proteolysis of APP and presenilin function, including specific cleavage at residues 40 or 42.
Developing and perfecting tools and methods, primarily monoclonal antibodies and related assays such as IP and ELISAs, that will allow us to detect metabolites of APP with great sensitivity and specificity.
Mathews PM, Guerra CB, Jiang Y, Grbovic OM, Kao BH, Schmidt SD, Dinakar R, Mercken M, Hille-Rehfeld A, Rohrer J, Mehta P, Cataldo AM, Nixon RA. (2002) Alzheimer's disease-related overexpression of the cation-dependent mannose 6-phosphate receptor increases Abeta secretion: role for altered lysosomal hydrolase distribution in beta-amyloidogenesis. J Biol Chem. 277:5299-307.
Mathews PM, Jiang Y, Schmidt SD, Grbovic OM, Mercken M, Nixon RA. (2002) Calpain activity regulates the cell surface distribution of amyloid precursor protein. Inhibition of clapains enhances endosomal generation of beta-cleaved C-terminal APP fragments. J Biol Chem. 277:36415-24.
Mathews PM, Guerra CB, Jiang Y, Kao BH, Dinakar R, Mehta P, Cataldo AM, Nixon RA. (2001) Accelerated Ab generation in a cell model of Alzheimer’s disease-related endosomal-lysosomal system upregulation. Alzheimer's Disease: Advances in Etiology, Pathogenesis and Therapeutics (Iqbal K, Sisodia SS, Winblad B, editors), John Wiley & Sons, Ltd., Chichester, UK, 461-467.
Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chisti MA, Horne P, Heslin D, French J, Nixon RA, Mercken M, Fraser PE, Bergeron C, St. George-Hyslop P, Westaway D. (2000) Ab-immunization reduces spatial memory impairment and dense cored amyloid plaque burden in an animal model of Alzheimer’s disease without affecting brain Ab-peptide levels. Nature. 408:979-982.
Mathews PM, Cataldo AM, Kao BH, Rudnicki AG, Qin X, Yang JL, Jiang Y, Picciano M, Hulette C, Dole K, Lippa CF, Bird TD, Knochlin D, Walter J, Haass C, Lévesque L, Fraser PE, Andreadis A, Nixon RA. (2000) Brain expression and endoproteolysis of presenilin1 and presenilin 2 in sporadic and familial, early-onset Alzheimer's disease. Molecular Medicine. 6:878-891.
Jiang, Y. and D. W. McGee. (1998) Regulation of human lymphocyte IL-4 secretion by intestinal epithelial cell-derived interleukin-7 and transforming growth factor. Clinical Immunology and Immunopathology. 88(3): 287-296.
McGee, D. W., M. E. Goodrich and Jiang, Y. (1998) Intestinal epithelial cell-derived cytokines regulate mucosal B cell immunoglobulin secretion. In "Cytokines, Cholera, and the Gut" (G. T. Keusch and M. Kawakami), pp. 21-27. IOS Press Inc., Burke, USA.
Chishti MA, Chen F, Mathews PM, Mercken M, Yu G, Strome R, Rogaev E, Levesque G, Ikeda M, Yau H, Holes E, Loukides J, Bi Q, Janus C, Mastrangelo P, Ebeling C, Jiang Y, Schmidt SD, Nixon RA, Mount HTJ, Fraser PE, Roxmahel R, Carlson GA, St. George-Hyslop P, Westaway D. Mutant PS1 and PS2 Rescue Skeletal and g-42-secretase deficits in PS1 null mice but have divergent effects on g-40-secretase. submitted.
Schmidt SD, Jiang Y, Jacobsen SP, Refolo LM, Duff K, Nixon RA, Mercken M, Mathews PM. Quantitative detection of Ab and amyloid precursor protein C-terminal fragments in wild-type and AD transgenic mouse models. (in preparation).
Grbovic OM, Mathews PM, Jiang Y, Schmidt SD, Dinikar R, Corvera S, Nixon RA, Cataldo AM. Modeling of Alzheimer’s disease-related endocytic upregulation by rab5 overexpression increases amyloid precursor protein b-C-terminal fragment and Ab generation. (in preparation).
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