Projectdetails

Alzheimers disease (AD) is characterized by tau and A? aggregates and is thus a prime example of a protein folding disease. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) results in activation of the unfolded protein response (UPR) which is aimed to restore homeostasis, however, prolonged stress leads to cell death. We previously observed activation of the UPR in AD brain. In addition, we find that Rab6A, which mediates a retrograde trafficking pathway from the Golgi to the ER, is increased in AD neurons. We hypothesize that the Rab6A pathway serves to return misfolded proteins to the ER. Increased transport to the ER may therefore contribute to prolonged ER stress in AD. In fact, Rab6A levels correlate with the extent of ER stress in AD brain. Increased Rab6A levels suffice to induce ER stress in vitro.

Artikelen

• Dr. J.J.M. Hoozemans, E.S. van Haastert, D.A.T. Nijholt, A.J.M. Rozemuller, Prof. dr. P. Eikelenboom, Dr. W. Scheper The Unfolded Protein Reponse is activated in pretangle neurons in Alzheimer's disease hippocampus. Am. J. Pathol. pp. 174:4:1241-51
• Dr. S.M. Chafekar, D. Viertl, Dr. F. Baas, Dr. H.A. Lashuel, Dr. H. Malda, Prof. dr. E.W. Meijer, Dr. M. Merkx, Dr. W. Scheper (2007). Branched KLVFF tetramers strongly potentiate inhibition of B-amyloid aggregation. ChemBiochem. pp. 8(15):1857-1864
• Prof. dr. P.G. Barth, L. de Vries, P. Nikkels, Dr. E. Aronica, Dr. J.J.M. Hoozemans, Dr. W. Scheper, Dr. D. Troost (2007). Pontocerebellar hypoplasia type 2 (PCH-2) - a neuropathological update. Acta Neuropathol. pp. 114(4):373-86
• R. Zwart, Dr. F. Baas, Dr. S.M. Chafekar, Dr. J.J.M. Hoozemans, Dr. W. Scheper (2007). Ab1-42 induces mild endoplasmic reticulum stress in an aggregation state dependent manner. Antioxid redox sign. pp. 9(12)2245-54
• (2007). Activation of the unfolded protein response in Parkinson's disease. Biochem. Biophys. Res. Commun:. pp. 354:707-11
• (2007). Activation of the unfolded protein response in Parkinson's disease. Biochem. Biophys. Res Commun.. pp. 354:707-11
• (2007). Pin1 levels are downregulated during ER stress in human neuroblastoma cells. Neurogenetics. pp. 21-27
• (2007). Activation of the unfolded protein response in Parkinson's disease. Biochem. Biophys. Res. Commun.. pp. 707-711
• (2007). Rab6 is increased in Alzheimer's disease brain and correlates with endoplasmic reticulum stress. Neuropathol. Appl. Neurobiol.. pp. 523-532
• (2007). AB1-42 induces mild endoplasmic reticulum stress in an aggregation state dependent manner. Antioxid. Redox Sign.. pp. 2245-2254
• (2007). Pontocerebellar hypoplasia type 2 (PCH-2) - a neuropathological update. Acta Neuropathol.. pp. 373-386
• (2007). Branched KLVFF tetramers strongly potentiate inhibition of B-amyloid aggregation. ChemBiochem.. pp. 1857-1864
• (2008). Oligomer-specific Ab toxicity in cellmodels is mediated by selective uptake. Biochim Biophys Acta. pp. 523-531
• (2008). Increased Ab1-42 production sensitizes neuroblastoma cells for ER stress toxicity. Curr Alzh Res. pp. 469-574
• Dr. S.M. Chafekar, Dr. F. Baas, Dr. W. Scheper, Dr. H. VanderStichele, Dr. R. Veerhuis, Dr. R. Zwart (2008). Increased Ab-1-42 production sensitizes neuroblastoma cells for ER stress toxicity. Curr. Alzh. Res. pp. 5:469-574
• Dr. S.M. Chafekar, Dr. F. Baas, Dr. W. Scheper (2008). Oligomer-specific AB toxicity in cellmodels is mediated by selective uptake. Biochim Biophys Acta. pp. 1782: 523-531
• Dr. E.M. Hol, Dr. W. Scheper (2008). Protein quality control in neurodegeneration: walking the tight rope between health and disease. J. Mol. Neurosci. pp. 34: 23-33
• Dr. W. Scheper, Dr. J.J.M. Hoozemans (2009). Endoplasmic Reticulum Protein Quality Control in Neurodegenerative Disease: The good, the Bad and the Therapy. Curr. Med. Chem. pp. 16:(5):615-26
• L. de Kimpe, Dr. W. Scheper (2009). From Alpha to Omega with Abeta: Targeting the multiple molecular appearances of the pathogenic peptide in Alzheimer's disease. Curr. Med. Chem. In press. In press. pp. 
• M. van Dijk, J. van Bezu, A. Poutsma, A.J. Rozemuller, Prof. dr. M.A. Blankenstein, Dr. C.B.M. Oudejans, Dr. W. Scheper, R. Veerhuis (2009). The pre-eclampsia gene STOX1 controls a conserved pathway in placenta and brain upregulated in late-onset Alzheimer's disease. J. Alzheimers Dis. In press. In press. pp. 
• E. van Someren, Dr. P.J. Lucassen, Dr. W. Scheper (2009). Neurogenisis and the unfolded protein respons; new cellular and molecular avenues in sleep research. Sleep Medicine Revieuws. pp. 13(3):183-6

Proefschriften

• Dr. S.M. Chafekar The aggregation state of B-amyloid in Alzheimer's Disease, . Universiteit van Amsterdam. promotiedatum 
• (2008). The aggregration state of B-amyloid in Alzheimer's disease. . promotiedatum  . ISBN 9789090230580.

Bijdragen aan boeken

• (2007). In AB peptide and Alzheimer's disease. in: The involvement of AB in the neuroinflammatory response. : . pp. 
• Dr. J.J.M. Hoozemans, Dr. W. Scheper (2009). In Protein folding and misfolding: Neurodegenerative diseases. in: Endoplasmic reticulum stress in neurodegeneration. : . pp. 111-132
• Dr. F. Baas, Dr. S.M. Chafekar, Prof. dr. P. Eikelenboom, Dr. J.J.M. Hoozemans, Dr. W. Scheper (2010). Frontiers in Medicinal Chemistry. in: Always around, never the same: Pathways of amyloid beta induced neurodegeneration throughout the pathogenic cascade of Alzheimer's disease.. : . pp.