Lipid raft ER signalosome malfunctions in menopause and Alzheimer's disease.
The increase in the incidence of Alzheimer's disease (AD) in old women may be attributable to estrogen deficiency, and estrogen replacement therapy may be useful in preventing or delaying the onset of this disease. In neuronal membranes, 17 beta-estradiol interacts with estrogen receptors (mERs) located in lipid raft signalosomes which trigger neuroprotective responses by anchoring to scaffolding caveolin-1 complexed with other proteins. We suggest that mER-signalosome malfunctions in AD and by menopause due to development of aberrations in these microstructures. Here, we report that mER dissociates from a voltage-dependent anion channel (VDAC), and that progressive dephosphorylation of VDAC1 enhances neurotoxicity. mER dissociates from caveolin-1 and other neuroprotective proteins, including insulin-like growth factor 1 receptor beta. Similar signalosome disarrangements are observed in AD patients. Moreover, in AD, lipid rafts exhibit alterations in lipid composition, and these changes cause an increase in liquid-ordered as compared to controls. Together, the data show that AD and menopause lead to disruption in the lipid raft structure, and disfunctioning of ER alpha and other neuroprotectors integrated into these signalosomes.
Laboratory of Cellular Neurobiology, Department of Basic Medical Sciences, Medicine Section, Faculty of Health Sciences, University of La Laguna, Santa Cruz de Tenerife; Spain.
Ana
A
Canerina-Amaro
Laboratory of Cellular Neurobiology, Department of Basic Medical Sciences, Medicine Section, Faculty of Health Sciences, University of La Laguna, Santa Cruz de Tenerife; Spain.
Luis G
LG
Hernandez-Abad
Institute of Neuropathology, Bellvitge University Hospital, University of Barcelona, IDIBELL, CIBERNED, Hospitalet de Llobregat, Barcelona; Spain.
Isidre
I
Ferrer
Associate Research Unit ULL-CSIC, Membrane Physiology and Biophysics, University of La Laguna, Sta. Cruz de Tenerife, Spain, Laboratory of Membrane Physiology and Biophysics, Department of Animal Biology, Edaphology and Geology, Biology Section, Faculty o.
David
D
Quinto-Alemany
Associate Research Unit ULL-CSIC, Membrane Physiology and Biophysics in Neurodegenerative and Cancer Diseases, 3Institute of Neuropathology,and Laboratory of Membrane Physiology and Biophysics, Department of Animal Biology, Edaphology and Geology, Biology.
Fatima
F
Mesa-Herrera
Laboratory of Membrane Physiology and Biophysics, Department of Animal Biology, Edaphology and Geology, Biology Section, Faculty of Experimental Sciences, University of La Laguna, Sta. Cruz de Tenerife, Spain,and2Associate Research Unit ULL-CSIC, Membrane.
Carla
C
Ferri
Laboratory of Cellular Neurobiology, Department of Basic Medical Sciences, Medicine Section, Faculty of Health Sciences, University of La Laguna, Santa Cruz de Tenerife, Spain.
Ricardo A
RA
Puertas-Avendano
Laboratory of Membrane Physiology and Biophysics, Department of Animal Biology, Edaphology and Geology, Biology Section, Faculty of Experimental Sciences, University of La Laguna, Sta. Cruz de Tenerife, Spain.
Mario
M
Diaz
Laboratory of Cellular Neurobiology, Department of Physiology, School of Medicine, La Laguna University, Tenerife, Spain, rmarin@ull.es.
Raquel
R
Marin
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D051242:Caveolin 1; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D008593:Menopause / Q000378:metabolism*; D008875:Middle Aged; D010766:Phosphorylation; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism
C495540:CAV1 protein, human; D051242:Caveolin 1; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C494762:VDAC1 protein, human; D050995:Voltage-Dependent Anion Channel 1