Analysis of proteome alterations induced by sAPPalpha treatment of mouse primary neurons.
Final Report Abstract
The Amyloid Precursor Protein (APP) is a central player in Alzheimer disease pathology. This protein is processed into several cleavage products such as Aß, a peptide known to cause degeneration of neurons, and sAPPalpha, a cleavage product known to have rather protective properties. Past research on Alzheimer disease mainly focused on toxicity of Aß. The aim of my research project was to unravel molecular details about the protective cleavage product of APP, sAPPalpha. I first of all analyzed the proteome of neurons treated with sAPPalpha and uncovered a predominant effect of this protein on cyclin-dependent kinase 5 (CDK5) signaling. The kinase CDK5 was previously suggested to be the link between amyloid- and tau-pathology in Alzheimer disease as it interacts with central molecules of both pathways. Analysis of selected candidate proteins known to interact with CDK5 further confirmed a strong effect of sAPPalpha on this signalling pathway. Interestingly, my results also pointed towards a more complex mechanism where CDK5 is not only down-regulated but also trans-located from nucleus to cytoplasm after sAPPalpha exposure of neurons. Together, my results describe i) that sAPPalpha regulates CDK5 signaling in neurons, ii) the role of the known Alzheimer disease risk factor SORLA in this signaling cascade and iii) how this might contribute to the neurotrophic function of sAPPalpha. My study uncovered important new molecular details about sAPPalpha function in the brain and provides a basis for future therapeutic strategies.
Publications
- (2011) Kainate promotes alterations in neuronal RNA splicing machinery. Journal of Proteome Research, 1;10(4):1459-67
Rohe M, Nebrich G, Klein O, Mao L, Zabel C, Klose J and Hartl D
- (2012) Presymptomatic Alterations in Energy Metabolism and Oxidative Stress in the APP23 Mouse Model of Alzheimer Disease. Journal of Proteome Research, 11 (6): 3295–3304
Hartl D, Schuldt V, Forler S, Zabel C, Klose J and Rohe M
(See online at https://doi.org/10.1021/pr300021e) - (2013) Generation and Characterization of a Leishmania tarentolae Strain for Site-Directed in Vivo Biotinylation of Recombinant Proteins. Journal of Proteome Research, 2013 Dec 6;12(12):5512-9
Klatt S, Hartl D, Fauler B, Gagoski D, Castro-Obregón S, Konthr Z
(See online at https://doi.org/10.1021/pr400406c) - (2013) Production of glycosylated soluble amyloid precursor protein alpha (sAPPalpha) in Leishmania tarentolae. Journal of Proteome Research, 2013 Jan 4;12(1):396-403
Klatt S, Rohe M, Alagesan K, Kolarich D, Konthur Z and Hartl D
(See online at https://doi.org/10.1021/pr300693f) - (2013) Soluble alpha-APP (sAPPalpha) regulates CDK5 expression and activity in neurons. PLoSOne 11;8(6):e65920
Hartl D, Klatt S, Roch M, Konthur Z, Klose J, Willnow T, Rohe M
(See online at https://doi.org/10.1371/journal.pone.0065920) - (2013) SorLA-Mediated Trafficking of TrkB Enhances the Response of Neurons to BDNF. PLoSOne 19;8(8):e72164
Rohe M, Hartl D, Fjorback AW and Willnow TE
