Objective: In familial hypercholesterolemia (FH), mutations in the low-density lipoprotein (LDL) receptor (LDLr) gene result in increased plasma LDL cholesterol. Clinical and preclinical studies have revealed an association between FH and hippocampus-related memory and mood impairment. We here asked whether hippocampal pathology in FH might be a consequence of compromised adult hippocampal neurogenesis.
Methods: We evaluated hippocampus-dependent behavior and neurogenesis in adult C57BL/6JRj and LDLr mice. We investigated the effects of elevated cholesterol and the function of LDLr in neural precursor cells (NPC) isolated from adult C57BL/6JRj mice in vitro.
Results: Behavioral tests revealed that adult LDLr mice showed reduced performance in a dentate gyrus (DG)-dependent metric change task. This phenotype was accompanied by a reduction in cell proliferation and adult neurogenesis in the DG of LDLr mice, suggesting a potential direct impact of LDLr mutation on NPC. Exposure of NPC to LDL as well as LDLr gene knockdown reduced proliferation and disrupted transcriptional activity of genes involved in endogenous cholesterol synthesis and metabolism. The LDL treatment also induced an increase in intracellular lipid storage. Functional analysis of differentially expressed genes revealed parallel modulation of distinct regulatory networks upon LDL treatment and LDLr knockdown.
Conclusions: Together, these results suggest that high LDL levels and a loss of LDLr function, which are characteristic to individuals with FH, might contribute to a disease-related impairment in adult hippocampal neurogenesis and, consequently, cognitive functions.
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http://dx.doi.org/10.1016/j.molmet.2019.09.002 | DOI Listing |
Eur J Neurol
January 2025
Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
Background: Temporal lobe epilepsy (TLE) can lead to structural brain abnormalities, with thalamus atrophy being the most common extratemporal alteration. This study used probabilistic tractography to investigate the structural connectivity between individual thalamic nuclei and the hippocampus in TLE.
Methods: Thirty-six TLE patients who underwent pre-surgical 3 Tesla magnetic resonance imaging (MRI) and 18 healthy controls were enrolled in this study.
Individual choices shape life course trajectories of brain structure and function beyond genes and environment. We hypothesized that individual task engagement in response to a learning program results in individualized learning biographies and connectomics. Genetically identical female mice living in one large shared enclosure freely engaged in self-paced, automatically administered and monitored learning tasks.
View Article and Find Full Text PDFAdults are capable of either differentiating or integrating similar events in memory based on which representations are optimal for a given situation. Yet how children represent related memories remains unknown. Here, children (7-10 years old) and adults formed memories for separate yet overlapping events.
View Article and Find Full Text PDFExp Physiol
January 2025
Department of Physiology, School of Medicine, University College Cork, Cork, Ireland.
Absence of the structural protein, dystrophin, results in the neuromuscular disorder Duchenne Muscular Dystrophy (DMD). In addition to progressive skeletal muscle dysfunction, this multisystemic disorder can also result in cognitive deficits and behavioural changes that are likely to be consequences of dystrophin loss from central neurons and astrocytes. Dystrophin-deficient mdx mice exhibit decreases in grey matter volume in the hippocampus, the brain region that encodes and consolidates memories, and this is exacerbated with ageing.
View Article and Find Full Text PDFAlzheimers Res Ther
January 2025
Laboratory for Clinical Neuroscience, Center for Biomedical Technology, Universidad Politécnica de Madrid, IdISSC, Crta M40, km38, Madrid, 28223, Spain.
Background: Dementia patients commonly present multiple neuropathologies, worsening cognitive function, yet structural neuroimaging signatures of dementia have not been positioned in the context of combined pathology. In this study, we implemented an MRI voxel-based approach to explore combined and independent effects of dementia pathologies on grey and white matter structural changes.
Methods: In 91 amnestic dementia patients with post-mortem brain donation, grey matter density and white matter hyperintensity (WMH) burdens were obtained from pre-mortem MRI and analyzed in relation to Alzheimer's, vascular, Lewy body, TDP-43, and hippocampal sclerosis (HS) pathologies.
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