Abstract
Increased blood–brain barrier (BBB) permeability and extensive neuronal changes have been described earlier in both healthy and pathological aging like apolipoprotein B-100 (APOB-100) and amyloid precursor protein (APP)–presenilin-1 (PSEN1) transgenic mouse models. APOB-100 hypertriglyceridemic model is a useful tool to study the link between cerebrovascular pathology and neurodegeneration, while APP–PSEN1 humanized mouse is a model of Alzheimer’s disease. The aim of the current study was to characterize the inflammatory changes in the brain with healthy aging and in neurodegeneration. Also, the cerebro-morphological and cognitive alterations have been investigated. The nose-to-brain delivery of a P-glycoprotein substrate model drug (quinidine) was monitored in the disease models and compared with the age-matched controls. Our results revealed an inflammatory balance shift in both the healthy aged and neurodegenerative models. In normal aging monocyte chemoattractant protein-1, stem cell factor and Rantes were highly upregulated indicating a stimulated leukocyte status. In APOB-100 mice, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF-BB), and interleukin-17A (IL-17A) were induced (vascular reaction), while in APP–PSEN1 mice resistin, IL-17A and GM-CSF were mostly upregulated. The nasal drug absorption was similar in the brain and blood indicating the molecular bypass of the BBB. The learning and memory tests showed no difference in the cognitive performance of healthy aged and young animals. Based on these results, it can be concluded that various markers of chronic inflammation are present in healthy aged and diseased animals. In APOB-100 mice, a cerebro-ventricular dilation can also be observed. For development of proper anti-aging and neuroprotective compounds, further studies focusing on the above inflammatory targets are suggested.
Highlights
During the last years, several publications reported the effect of healthy aging on the permeability of the blood–brain barrier (BBB) (Erdoet al., 2017; Bors et al, 2018; Erdoand Krajcsi, 2019)
The healthy aging was investigated in 14–21-month old rats, while the neurodegenerative processes were studied in amyloid precursor protein (APP)–PSEN1 and APOB-100 transgenic mice in the age of 9–13 months when the disease symptoms have already been developed (Bjelik et al, 2006; Bereczki et al, 2008; Hoyk et al, 2018)
The study focused on three main areas: the cerebral cytokine expression compared with healthy individuals; the anatomical and morphological changes in the brain using magnetic resonance imaging (MRI) compared with controls; and the examination of nasal barrier permeability for a P-gp substrate by in vivo dual-probe microdialysis
Summary
Several publications reported the effect of healthy aging on the permeability of the blood–brain barrier (BBB) (Erdoet al., 2017; Bors et al, 2018; Erdoand Krajcsi, 2019). The overexpression of APOB-100 protein in mice leads to elevated plasma triglyceride level even on normal chow diet (Bereczki et al, 2008; Lénárt et al, 2012). Several studies demonstrated that increased serum LDL and APOB-100 levels in Alzheimer’s disease patients are associated with the pathological symptoms (Tóth et al, 2020). The chronic hypertriglyceridemia due to high serum APOB-100 level may lead to the functional and morphological changes of the BBB, which have been described in this model (Hoyk et al, 2018). APOB-100 overexpressing mouse strain is a useful model to study the age-related cerebrovascular pathology and neurodegeneration induced by hyperlipidemia, as the symptoms develop after 7–8 months of age (Tóth et al, 2020)
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