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High levels of 27-hydroxycholesterol results in synaptic plasticity alterations in the hippocampus

Loera-Valencia, Raul, Vazquez-Juarez, Erika, Muñoz, Alberto, Gerenu, Gorka, Gómez-Galán, Marta, Lindskog, Maria, DeFelipe, Javier, Cedazo-Minguez, Angel, Merino-Serrais, Paula·2021·Scientific Reports
DOI 10.1038/s41598-021-83008-3PMC PMC7881004
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Abstract

Alterations in brain cholesterol homeostasis in midlife are correlated with a higher risk of developing Alzheimer’s disease (AD). However, global cholesterol-lowering therapies have yielded mixed results when it comes to slowing down or preventing cognitive decline in AD. We used the transgenic mouse model Cyp27Tg, with systemically high levels of 27-hydroxycholesterol (27-OH) to examine long-term potentiation (LTP) in the hippocampal CA1 region, combined with dendritic spine reconstruction of CA1 pyramidal neurons to detect morphological and functional synaptic alterations induced by 27-OH high levels. Our results show that elevated 27-OH levels lead to enhanced LTP in the Schaffer collateral-CA1 synapses. This increase is correlated with abnormally large dendritic spines in the stratum radiatum. Using immunohistochemistry for synaptopodin (actin-binding protein involved in the recruitment of the spine apparatus), we found a significantly higher density of synaptopodin-positive puncta in CA1 in Cyp27Tg mice. We hypothesize that high 27-OH levels alter synaptic potentiation and could lead to dysfunction of fine-tuned processing of information in hippocampal circuits resulting in cognitive impairment. We suggest that these alterations could be detrimental for synaptic function and cognition later in life, representing a potential mechanism by which hypercholesterolemia could lead to alterations in memory function in neurodegenerative diseases.

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Cited by

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Metadata

Authors
Loera-Valencia, R., Vazquez-Juarez, E., Muñoz, A., Gerenu, G., Gómez-Galán, M., Lindskog, M., DeFelipe, J., Cedazo-Minguez, A., & Merino-Serrais, P.
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2021-02-12
Volume
11
Issue
1
ISSN
2045-2322
DOI
10.1038/s41598-021-83008-3
PMC
PMC7881004
Cited by
37
References
8
Language
en
Licence
Funders
  • Margaretha af Ugglas Stiftelse
  • Gun och Bertil Stohnes Stiftelse
  • Karolinska Institutet fund for geriatric research
  • Stiftelsen Gamla Tjänarinnor
  • Tore Nilsson Stiftelse
  • Demensfonden
  • CONACYT (209252, 232099)
  • Lindhés Advokatbyra Foundation
  • Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CB06/05/0066)
  • Ministerio de Ciencia, Innovación y Universidades (PGC2018-094307-B-I00)
  • EMBO Long-Term Fellowship (ALFT 696-2013)
  • SSMF postdoctoral Fellowship
  • Juan de la Cierva (IJCI-2016-27658)

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