Author:
Loera-Valencia Raul,Vazquez-Juarez Erika,Muñoz Alberto,Gerenu Gorka,Gómez-Galán Marta,Lindskog Maria,DeFelipe Javier,Cedazo-Minguez Angel,Merino-Serrais Paula
Abstract
AbstractAlterations 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.
Funder
Margaretha af Ugglas Stiftelse
Gun och Bertil Stohnes Stiftelse
Karolinska Institutet fund for geriatric research
Stiftelsen Gamla Tjänarinnor
Tore Nilsson Stiftelse
Demensfonden
CONACYT
Lindhés Advokatbyra Foundation
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
Ministerio de Ciencia, Innovación y Universidades
EMBO Long-Term Fellowship
SSMF postdoctoral Fellowship
Juan de la Cierva
Publisher
Springer Science and Business Media LLC
Cited by
23 articles.
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