Alzheimer's disease (AD) is the most common form of dementia and characterized at the neuropathological level by the combined occurrence of intraneuronal aggregates of the microtubule associated protein tau and extracellular β-amyloid plaques. Plaques contain β-amyloid peptides (Aβ) that derive from proteolytic processing of the β-amyloid precursor protein (APP) by proteases called β- and γ-secretase. By combining molecular cell biological and biochemical approaches, we investigate regulatory mechanisms in the generation and degradation of Aβ in cell culture and animal models. The research is focussed on the role of membrane lipids and post-translational protein modifications in the subcellular trafficking of APP as well as β- and γ-secretases. Several projects are incorporated into national and international research and educational initiatives.
SFB645, DFG - Collaborative Research Center
KFO177, DFG - Clinical research group
KNDD, BMBF - Competence network degenerative diseases,
EURON - European graduate school for Neuroscience.
Kumar, S. , N. Rezaei-Ghaleh,D. Terwel, D.R. Thal, M. Richard, M. Hoch, J.M. Mc Donald, U. Wüllner, K. Glebov, M.T. Heneka, D.M. Walsh, M. Zweckstetter, and J. Walter. Extracellular phosphorylation of the amyloid β-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimers disease. EMBO J. 30, 2255-2265 (2011).
Tamboli, I.Y., H. Hampel, T. Nguyen, K. Tolksdorf, B. Breiden, P.M. Mathews, P. Saftig, K. Sandhoff, and J. Walter. Sphingolipid storage affects autophagic metabolism of the amyloid precursor protein and promotes Aβ generation. J. Neurosci. 31, 1837-1849 (2011).
Tamboli, I.Y., K. Prager, D.R. Thal, K.M. Thelen, I. Dewachter, C.U. Pietrzik, P. St. George-Hyslop, S.S. Sisodia, B. DeStrooper, M.T. Heneka, M.A. Filippov, U. Müller, F. van Leuven, D. Lütjohann, and J. Walter. Loss of γ-secretase function impairs endocytosis of lipoprotein particles and membrane cholesterol homeostasis. J. Neurosci. 28, 12097-12106 (2008).
Wahle T., D.R. Thal, M. Sastre, A. Rentmeister, N. Bogdanovic, M. Famulok, M. T. Heneka, and J. Walter. GGA1 is expressed in the human brain and affects the generation of amyloid β-peptide. J. Neurosci., 26, 12838-12846 (2006).
van Echten-Deckert, G. & J. Walter. Sphingolipids - Critical players in Alzheimers disease. Prog. Lipid Res. 51, 378-393 (2012).
Walter, J: γ-Secretase, apolipoprotein E and cellular cholesterol metabolism. Curr. Alzheimer Res., in press (2011).
Walter, J. Control of β-amyloid generation by subcellular trafficking of the β-amyloid precursor protein and β-secretase. Neurodeg. Dis. 3, 247-254 (2006).