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

Raul Loera-Valencia,Marta Gómez-Galán,Alberto Muñoz,Gorka Gerenu,Maria Lindskog,Angel Cedazo-Minguez,Javier Defelipe,Paula Merino-Serrais,Erika Vazquez-Juarez

doi:10.1038/s41598-021-83008-3

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.

Highlights

Alterations in brain cholesterol homeostasis in midlife are correlated with a higher risk of developing Alzheimer’s disease (AD)
The present study aimed to test whether the alterations in neuronal morphology observed previously in CA1 of Cyp27Tg mice[22] would correlate with synaptic plasticity dysfunction in the hippocampus
We performed longterm potentiation (LTP) in brain slices of young adult Cyp27Tg mice and found an altered LTP response compared to WT mice

Summary

Results

Differences in spine volume did not show statistical significance between groups when it was analyzed as an average (WT, 0.15 ± 0.01 μm[3]; n = 25 dendrites; Cyp27Tg, 0.17 ± 0.07 μm[3]; n = 19 dendrites; unpaired Mann Whitney test; p > 0.05; Fig. 4D); as a function of the distance from the soma (Two-way ANOVA, p > 0.05; F = 2.37; Fig. 4E); or using frequency distribution (Kolmogorov–Smirnov, p > 0.05; Fig. 4F). The numbers of synaptopodin immunoreactive (ir) puncta were analyzed in the stratum radiatum from CA1 region in WT and Cyp27Tg mice (Fig. 5) This analysis was performed at two different distances from the pyramidal layer: 20–80 μm and 100–160 μm (Fig. 5B, C).

Discussion

Findings

Methods