[Frontiers in Bioscience, Scholar, 9, 111-126, January 1, 2017]

Lipid raft ER signalosome malfunctions in menopause and Alzheimer’s disease

Ana Canerina-Amaro 1, 2 , Luis G. Hernandez-Abad 1, 2 , Isidre Ferrer 3 , David Quinto-Alemany 2, 4 , Fatima Mesa-Herrera 2, 4 , Carla Ferri 2, 4 , Ricardo A. Puertas-Avendaño 1 , Mario Diaz 2, 4 , Raquel Marin 1, 2

1Laboratory of Cellular Neurobiology, Department of Basic Medical Sciences, Medicine Section, Faculty of Health Sciences, University of La Laguna, Santa Cruz de Tenerife, Spain, 2Associate Research Unit ULL-CSIC, Membrane Physiology and Biophysics in Neurodegenerative and Cancer Diseases, University of La Laguna, Sta. Cruz de Tenerife, Spain, 3Institute of Neuropathology, Bellvitge University Hospital, University of Barcelona, IDIBELL, CIBERNED, Hospitalet de Llobregat, Barcelona, Spain, 4Laboratory 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

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Experimental
    3.1. Materials
    3.2. Human brain samples
    3.3. Lipid raft isolation
    3.4. SDS-PAGE and two-dimensional gel electrophoresis
    3.5. Immunoblotting
    3.6. Immunoprecipitation assays
    3.7. Lipid analyses
    3.8. Statistical analyses
4. Results
    4.1. Distinct patterns of mERalpha-related signalosome in frontal cortex during menopausal stages and AD
    4.2. Disruption of mERalpha-related signalosome during menopausal stages and AD
    4.3. Progressive VDAC dephosphorylation in lipid raft samples from menopausal and AD subjects
    4.4. Lipid profiles in lipid rafts from pre-menopausal, post-menopausal and AD subjects
5. Discussion
6. Acknowledgements
7. References

1. ABSTRACT

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, 17β-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 ERalpha and other neuroprotectors integrated into these signalosomes.

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Abbreviations: ERα, Estrogen Receptor alpha; IGF-IRβ, insulin growth factor-1 receptor beta; CSD, caveolar scaffolding domain

Key Words: 17beta-estradiol, Lipid Rafts, Alzheimer’s Disease, Menopause, Estrogen Receptor Alpha, Voltage-dependent Anion Channel, Caveolin 1, Insulin Growth Factor-1 Receptor Beta, Membrane Lipids

Send correspondence to: Raquel Marin, Laboratory of Cellular Neurobiology, Department of Basic Medical Sciences, Medicine Section, Faculty of Health Sciences, University of La Laguna, Santa Cruz de Tenerife, Spain, Tel: 34-922319411, Fax:34-922319397, E-mail: rmarin@ull.edu.es