Angel Cedazo-Minguez Group

Mechanisms behind risk factors for Alzheimer disease (AD)    

Research focus

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), diabetes, 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

The metabolism of cholesterol results in the production of several oxysterols, of which the peripherally-produced 27OHC and the brain-produced 24S-OH have been suggested to play a role in AD pathogenesis.  However very little is known about the biological role of these oxysterols, with the exception of its affinity for LXR receptors. We have discovered new functions of 24S-OH and 27OHC in brain, related with memory consolidation and vascular regulation. Our findings suggest that these molecules are much more than subproducts of the cellular metabolism, and can be regarded as signalling molecules of importance for normal brain function as well as for neurodegeneration.

 

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Selected publications

Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons.
Rodriguez-Rodriguez P, Sandebring-Matton A, Merino-Serrais P, Parrado-Fernandez C, Rabano A, Winblad B, et al
Brain 2017 Dec;140(12):3269-3285

27-Hydroxycholesterol impairs neuronal glucose uptake through an IRAP/GLUT4 system dysregulation.
Ismail M, Mateos L, Maioli S, Merino-Serrais P, Ali Z, Lodeiro M, et al
J. Exp. Med. 2017 03;214(3):699-717

Toward common mechanisms for risk factors in Alzheimer's syndrome.
Medina M, Khachaturian Z, Rossor M, Avila J, Cedazo-Minguez A
Alzheimers Dement (N Y) 2017 Nov;3(4):571-578

Defeating Alzheimer's disease and other dementias: a priority for European science and society.
Winblad B, Amouyel P, Andrieu S, Ballard C, Brayne C, Brodaty H, et al
Lancet Neurol 2016 Apr;15(5):455-532

Alterations in brain leptin signalling in spite of unchanged CSF leptin levels in Alzheimer's disease.
Maioli S, Lodeiro M, Merino-Serrais P, Falahati F, Khan W, Puerta E, et al
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.
Gil-Bea F, Akterin S, Persson T, Mateos L, Sandebring A, Avila-Cariño J, et al
EMBO Mol Med 2012 Oct;4(10):1097-111

Toward a predictive model of Alzheimer's disease progression using capillary electrophoresis-mass spectrometry metabolomics.
Ibáñez C, Simó C, Martín-Álvarez P, Kivipelto M, Winblad B, Cedazo-Mínguez A, et al
Anal. Chem. 2012 Oct;84(20):8532-40

Macroautophagy-generated increase of lysosomal amyloid β-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells.
Zheng L, Terman A, Hallbeck M, Dehvari N, Cowburn R, Benedikz E, et al
Autophagy 2011 Dec;7(12):1528-45

Side chain-oxidized oxysterols regulate the brain renin-angiotensin system through a liver X receptor-dependent mechanism.
Mateos L, Ismail M, Gil-Bea F, Schüle R, Schöls L, Heverin M, et al
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.
Thomas K, McCoy M, Blackinton J, Beilina A, van der Brug M, Sandebring A, et al
Hum. Mol. Genet. 2011 Jan;20(1):40-50

Parkin deficiency disrupts calcium homeostasis by modulating phospholipase C signalling.
Sandebring A, Dehvari N, Perez-Manso M, Thomas K, Karpilovski E, Cookson M, et al
FEBS J. 2009 Sep;276(18):5041-52

Parkin-mediated ubiquitination regulates phospholipase C-gamma1.
Dehvari N, Sandebring A, Flores-Morales A, Mateos L, Chuan Y, Goldberg M, et al
J. Cell. Mol. Med. 2009 Sep;13(9B):3061-8

Mitochondrial alterations in PINK1 deficient cells are influenced by calcineurin-dependent dephosphorylation of dynamin-related protein 1.
Sandebring A, Thomas K, Beilina A, van der Brug M, Cleland M, Ahmad R, et al
PLoS ONE 2009 May;4(5):e5701

Activity-regulated cytoskeleton-associated protein in rodent brain is down-regulated by high fat diet in vivo and by 27-hydroxycholesterol in vitro.
Mateos L, Akterin S, Gil-Bea F, Spulber S, Rahman A, Björkhem I, et al
Brain Pathol. 2009 Jan;19(1):69-80

Apolipoprotein E epsilon4 magnifies lifestyle risks for dementia: a population-based study.
Kivipelto M, Rovio S, Ngandu T, Kåreholt I, Eskelinen M, Winblad B, et al
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.
Akterin S, Cowburn R, Miranda-Vizuete A, Jiménez A, Bogdanovic N, Winblad B, et al
Cell Death Differ. 2006 Sep;13(9):1454-65

Dissertations

Atiqur Rahman, 2006, Karolinska Institutet, Studies on apolipoprotein E and high cholesterol diet as risk factors for neurodegeneration.

Daniel Famer, 2007, Karolinska Institutet, Implications of cholesterol and cholesterol-lowering therapy in Alzheimer's disease.

Susanne Akterin, 2008, Karolinska Institutet, Role of cholesterol metabolism alterations in Alzheimer's disease pathogenesis.

Hatem HA Sallam, 2009, Karolinska Institutet, Labmed. Pharmacological and Analytical studies on the cyclin dependent kinase inhibitors.

Nodi Dehvari, 2009, Karolinska Institutet, Effects of Alzheimer's and Parkinson's disease gene mutation on cell signaling.

Anna Sandebring, 2010, Karolinska Institutet, Mechanisms of action of autosomal recessive juvenile parkinsonism gene mutations.

Torbjörn Persson, 2015, Karolinska Institutet, Thioredoxin-1 in Alzheimer Disease

Muhammad Al Mustafa Ismail, 2016, Karolinska Institutet, Deciphering the role of 27 hydroxycholesterol in neurodegeneration