Silvia Maioli Group
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.
Mechanisms behind risk factors for Alzheimer disease (AD)
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.
Selected scientific 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 MA, 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 ZS, 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 PJ, 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 RF, 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 MA, Gil-Bea FJ, 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 KJ, McCoy MK, 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 KJ, Karpilovski E, Cookson MR, 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 YC, Goldberg MS, 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 KJ, Beilina A, van der Brug M, Cleland MM, 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 FJ, 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 RF, Miranda-Vizuete A, Jiménez A, Bogdanovic N, Winblad B, et al
Cell Death Differ 2006 Sep;13(9):1454-65