Ewelina Czuba‑Pakuła1 · Jolanta Ochocińska2 · Sebastian Głowiński3 · Alicja Braczko4 · Ryszard T. Smoleński4 · Grażyna Lietzau1 · Przemysław Kowiański1,3
Received: 14 August 2024 / Accepted: 7 May 2025 © The Author(s) 2025
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1 Division of Anatomy and Neurobiology, Faculty of Medicine, Medical University of Gdansk, Dębinki 1, 80-211 Gdańsk, Poland
2 Department of Conservative Dentistry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
3 Institute of Health Sciences, Pomeranian University in Słupsk, Słupsk, Poland
4 Department of Biochemistry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
Abstract
Hypercholesterolemia (Hch) is a risk factor for cerebrovascular and neurodegenerative diseases, manifesting with symptoms that vary depending on damage to specific brain regions. Hch triggers inflammatory responses and cell death. However, the progression of these processes in relation to the duration of Hch and the location of pathology in the central nervous system remains unclear. Therefore, we aimed to investigate (1) the impact of age and duration of Hch on neuroinflammatory responses and programmed cell death in the brain and (2) the intensity of these processes in various brain areas during Hch. In this study, we used 3-, 6-, and 12-month-old male Apo E−/−/LDLR−/− double-knockout mice and age-matched wild-type C57BL/6 mice (control group). Concentrations of cytokines IL-1β, IL-4, and IL-6, as well as apoptotic mediators AIF and Cas-3, were measured using enzyme-linked immunosorbent assay in the whole brain and separately in the prefrontal cortex (PFCx), hippocampus (HIP), and striatum (STR). The results showed that the Hch-induced release of cytokines IL-1β and IL-6, decreased expression of IL-4, and elevated level of apoptotic markers AIF and Cas-3 correlated with Hch duration. The inflammatory response and expression of apoptotic markers were more pronounced in the HIP and STR compared to the PFCx. Our results indicate a correlation between the neurodegenerative effects of Hch and its duration and highlight the varying susceptibility of different brain areas to Hch-induced damage.
Graphical Abstract
Hypercholesterolemia (Hch)-induced inflammatory response and programmed cell death activation in the prefrontal cortex (PFCx), hippocampus (HIP), and striatum (STR) of 3-, 6-, and 12-month-old, Apo E−/−/LDLR−/− double-knockout mice. In three age-groups the Hch-induced response involved release of inflammatory cytokines (IL-1ß and IL-6), a decrease of anti-inflammatory (IL-4) cytokine level, and activation of programmed cell death markers (AIF and Cas-3). The inflam matory response and expression of apoptotic markers were more pronounced in the HIP and STR, compared to the PFCx.
Keywords Apoptosis · Atherosclerosis · Cytokines · Hypercholesterolemia · Neurodegeneration · Neuroinflammation
Introduction
Hypercholesterolemia (Hch) is a metabolic disorder classi fied among civilization diseases. It is also a known risk fac tor for several cardiovascular and neurodegenerative diseases (Lowe 2001; Taghizadeh et al. 2019; Leszek et al. 2021; Tucker et al. 2023). The role of Hch in the pathogenesis of these diseases stems from its ability to trigger numerous pathophysiological processes across various organs and tis sues (Ferroni et al. 2003a). Compared to other organs, cho lesterol metabolism in the central nervous system (CNS) is highly autonomous (Bahrami et al. 2020; Zhou et al. 2022). The unique aspect of cholesterol transformation in the brain is due to high level of energy metabolism (Ahmad et al. 2019; Ho et al. 2022), its involvement in myelin metabo lism (Berghoff et al. 2022; Barnes-Vélez et al. 2023), and its role in maintaining the integrity and function of the neuronal membranes and axodendritic system (Orth and Bellosta 2012; Martín et al. 2014). Physiological barriers, such as the blood–brain barrier (BBB), effectively prevent cholesterol transfer between the brain tissue and blood ves sels (Loura et al. 2001; Petrov et al. 2016). Given these con siderations, it can be assumed that Hch affects the function of each component of brain tissue, potentially leading to impaired myelin metabolism, BBB leakage, activation of neuroglia, induction of an inflammatory response, and cell death (Orth and Bellosta 2012; Gamba et al. 2015; Loera Valencia et al. 2019; Barnes-Vélez et al. 2023; de Dios et al. 2023). These processes are also involved in the development of neurodegenerative diseases (Petrov et al. 2016). Among the key mediators of inflammatory response are interleukin IL-1β, IL-4, and IL-6 (Black et al. 2011; Khan et al. 2023),
