Angel Cedazo-Minguez Group
Mechanisms behind risk factors for Alzheimer disease (AD)
Over the years, genetic and epidemiological studies have reported gene or environmental factors that increase the risk for AD, suggesting that it is a disease of multifactorial origin. We aim to contribute to understand the effects of risk factors for AD: apolipoprotein E (apoE), serum cholesterol and cholesterol metabolites in the brain and to define to which extent these factors are secondary actors or driving forces for cognitive decline.
Apolipoprotein E, hypercholesterolemia and AD
ApoE is the main cholesterol transporter and the presence of the E4 isoform is the major risk factor for AD. High cholesterol levels in blood is another risk factor. Our hypothesis is that ApoE4 acts in synergy with environmental factors (like hypercholesterolemia) to affect signalling pathways involved in neurodegeneration. We use several in vivo and in vitro models to explore this hypothesis.
Functions of oxysterols in brain
Thioredoxin and Glutaredoxin functions in AD
Oxidative stress (OS) is one of the pathological events occurring in AD. The amyloid beta peptide (Abeta) induces OS and neuronal apoptosis. Glutaredoxin-1 (GRX1) and thioredoxin-1 (TRX1) modulate the redox homeostasis and inhibit the apoptosis signal-regulating kinase (ASK1). We reported that TRX1 levels are decreased in AD brains. We showed that Abeta neurotoxicity is mediated by GRX1 and TRX1 oxidations and ASK1 activation. A deregulation of GRX1 and TRX1 antioxidant systems could be important in AD pathogenesis.
|Angel Cedazo-Minguez||Associate Professor, PhD|
|Christa Maynard||Assistant Professor, PhD|
|Gorka Gerenu||PhD, Post doc|
|Raul Loera-Valencia||PhD, Post doc|
|Silvia Maioli||PhD, Post doc|
|Laura Mateos||PhD, Postdoc|
|Paula Merino-Serrais||PhD, Postdoc|
|Cristina Parrado||PhD, Post doc|
|Laura Paternain Markinez||PhD, Post doc|
|Patricia Rodriguez||PhD, Post doc|
|Anna Sandebring-Matton||PhD, Post doc|
|Muhammad al Mustafa Ismail||PhD student|
Bengt Winblad et al. Defeating Alzheimer's disease and other dementias: a priority for European science and society. The Lancet Neurology. Volume 15, No. 5, p455–532, April 2016. DOI: http://dx.doi.org/10.1016/S1474-4422(16)00062-4
Alterations in brain leptin signalling in spite of unchanged CSF leptin levels in Alzheimer's disease.
Aging Cell 2015 Feb;14(1):122-9
Thioredoxin-80 is a product of alpha-secretase cleavage that inhibits amyloid-beta aggregation and is decreased in Alzheimer's disease brain.
EMBO Mol Med 2012 Oct;4(10):1097-111
Toward a predictive model of Alzheimer's disease progression using capillary electrophoresis-mass spectrometry metabolomics.
Anal. Chem. 2012 Oct;84(20):8532-40
Macroautophagy-generated increase of lysosomal amyloid β-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells.
Autophagy 2011 Dec;7(12):1528-45
Side chain-oxidized oxysterols regulate the brain renin-angiotensin system through a liver X receptor-dependent mechanism.
J. Biol. Chem. 2011 Jul;286(29):25574-85
DJ-1 acts in parallel to the PINK1/parkin pathway to control mitochondrial function and autophagy.
Hum. Mol. Genet. 2011 Jan;20(1):40-50
Parkin deficiency disrupts calcium homeostasis by modulating phospholipase C signalling.
FEBS J. 2009 Sep;276(18):5041-52
Parkin-mediated ubiquitination regulates phospholipase C-gamma1.
J. Cell. Mol. Med. 2009 Sep;13(9B):3061-8
Apolipoprotein E epsilon4 magnifies lifestyle risks for dementia: a population-based study.
J. Cell. Mol. Med. 2008 Dec;12(6B):2762-71
Involvement of glutaredoxin-1 and thioredoxin-1 in beta-amyloid toxicity and Alzheimer's disease.
Cell Death Differ. 2006 Sep;13(9):1454-65