♦ Production of the Alzheimer-associated amyloid-β (Aβ) peptides is dependent on an initial β-secretase cleavage of the Aβ precursor protein APP. We investigate the proteolytic processing of APP to determine the mechanisms that promote APP processing by the non-amyloidogenic α-secretase in favor of β-secretase cleavage and that consequently will decrease the Aβ production.

description of the amyloid cascade

♦ Shedding of APP (by α- or β-secretase) and subsequent intramembrane proteolysis also result in other bioactive fragments than Aβ. We investigate the role of proteolytic processing of APP, and the closely related proteins APLP1 and APLP2, in cell signaling during neuronal differentiation. One goal is also to understand more general principles for surface-to-nucleus signaling mediated by regulated intramembrane-proteolysis (RIP).

♦ Aβ peptides are neurotoxic. At nM concentrations normal synaptic functions will be disturbed. Exposure to higher (μM) concentrations will induce apoptotic neuronal cell death. We use live cell imaging techniques to delineate the role of different caspases and calpains in axonal or dendritic degeneration and in Aβ-induced cell death. For this we have designed anchored FRET based sensors for specific caspases or calpains.

 
glia cells
Glial cells
 

 

♦Glial cells play important roles for neuronal survival and death. We also investigate the role of glial cells and inflammatory mediators in Aβ-induced neurodegeneration.

 

 
♦ There is a proposed link between type 2 diabetes and Alzheimer’s disease. We are trying to pin-point molecular mechanisms behind this link, with focus on the glucagon-like peptide 1 (GLP-1), insulin/insulin-like growth factors (IGF), inflammation, and protein O-GlcNAcylation.
 
KI labgroup

May 2011 Ylva Strååt, Tom Gatsinzi, Elena Ivanova, Kristin Jacobsen, Linda Tracy, Niina Koistinen, Veronica Ramberg, Kerstin Iverfeldt

Selected Publications:

Darsalia V, Mansouri S, Ortsater H, Olverling A, Nozadze N, Kappe C,  Iverfeldt K, Tracy LM, Grankvist N, Sjöholm Å, and Patrone C. Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats. Clinical Science, 122(9-10):473-483, 2012

 
Gatsinzi T, Iverfeldt K. Sensitization to TRAIL-induced apoptosis in human neuroblastoma SK-N-AS cells by NF-κB inhibitors is dependent on reactive oxygen species (ROS). Journal of Neurooncology,104: 459-472, 2011
 
Figueroa R, Ramberg V, Gatsinzi T, Samuelsson M, Zhang M, Iverfeldt K. Hallberg E. Anchored FRET sensors detect local caspase activation prior to neuronal degeneration. Molecular Neurodegeneration, 6: 35, 2011
 
Ramberg V, Tracy L, Samuelsson M, Nilsson LGN, & Iverfeldt K. The CCAAT/enhancer binding protein (C/EBP) δ is differently regulated by fibrillar and oligomeric forms of the Alzheimer amyloid-β peptide. Journal of Neuroinflammation, 8: 34, 2011
 
Jacobsen KT, Iverfeldt K. O-GlcNAcylation increases non-amyloidogenic processing of the amyloid-β precursor protein (APP). Biochemical Biophysical Research Communication, 404:882-886, 2011
 
Jacobsen KT, Adlerz L, Multhaup G, Iverfeldt K. Insulin-like growth factor-1 (IGF-1)-induced processing of amyloid-β precursor protein (APP) and APP-like protein 2 is mediated by different metalloproteinases. Journal of Biological Chemistry, 285:10223-10231, 2010
 
Jacobsen KT, Iverfeldt K. Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors. Cellular and Molecular Life Sciences, 66:2299-2318, 2009
 
Adlerz L, Holback S, Multhaup G, Iverfeldt K. IGF-1-induced processing of the amyloid precursor protein family is mediated by different signaling pathways. Journal of Biological Chemistry, 282:10203-10209, 2007
 
Fisher L, Samuelsson M, Jiang Y, Ramberg V, Figueroa R, Hallberg E, Langel U, Iverfeldt K. Targeting cytokine expression in glial cells by cellular delivery of an NF-κB decoy. Journal of Molecular Neuroscience, 31:209-219, 2007