Cerebral Small Vessel Disease Is Associated with Dysregulation in the Ubiquitin Proteasome System and Other Major Cellular Pathways in Specific Brain Regions

Abstract

Background/Aims: Cerebral small vessel disease (SVD) is characterized by periventricular white matter (WM) changes and can lead to vascular dementia, the second most common form of age-dependent dementia. The pathogenesis of the disease remains poorly understood, and studies of its molecular basis are limited. By profiling gene expression of dissected postmortem brain tissue in SVD patients and comparisons with tissue of nonneurological controls, we aimed to identify genes and processes that are involved in the pathogenesis of SVD to gain new pathogenetic insights. Methods: We performed genome-wide expression analyses in postmortem brain tissue samples dissected from frontal, temporal, and occipital lobes as well as basal nuclei comprising thalamus, basal ganglia, and hippocampus from 5 SVD cases and 5 nonaffected control cases. Cellular pathways associated with differently expressed genes were identified in each brain region individually. Results: This analysis disclosed regional differences, with frontal lobe and thalamus showing the highest numbers of genes with significantly altered expression. Biological functions and pathways associated with changed gene expression depicted brain area-specific defective pathways. Vessel-associated functions, such as increased extracellular matrix-receptor interactions and cell adhesion molecules, were enhanced in all regions. Inflammation and apoptosis were induced particularly in basal nuclei and temporal and occipital regions. Interestingly, genes associated with the ubiquitin-dependent proteolysis (ubiquitin proteasome system) pathway were downregulated in the frontal lobe and in the thalamus, leading to the formation of protein aggregates. Conclusion: This analysis deciphers brain region-specific molecular processes to increase the present knowledge of SVD pathology and determine new potential therapeutic targets.

Vascular and neural transcriptomics reveal stage-dependent pathways to inflammation and cognitive dysfunction in a rat model of hypertension

“…In neural tissue Pld1, Nppa (down at 8, 25 and 34 weeks), Atp11b, Zfp462 (down at 34 weeks) and RT1 (up at 24 weeks) were similarly dysregulated (Supplementary Figure 1). 18…”

“…In all three age groups SHRSP and Wistar rats were injected i.p. with 18 F-FDG (1 to 2 mL, diluted in saline). The youngest age group received 21.7 ± 2.5 MBq 18 F-FDG, for the other two age groups the dose was increased to 43.2 ± 4.2 MBq for better signal-to-noise ratios.…”

“…After 30 min animals were anaesthetized with 2% isoflurane in 60% oxygen and placed on a thermostatically heated animal bed. PET-scanning in a small-animal PET/MR (Nanoscan, Mediso, Budapest, HUN) started 45 min after 18 F-FDG injection. Static PET scans of the head were performed followed by T1-weighted GRE MR imaging for anatomical correlations and attenuation correction.…”

“…If fed a normal diet, non-transgenic spontaneously hypertensive stroke-prone rats (SHRSP), perfectly mimic this vulnerable hypertensive patient population in its initial and preclinical disease stages by combining arterial hypertension development and a polygenetic susceptibility to CSVD [16]. The frontal predilection of hypertensive pathology has been underlined by cognitive testing, magnetic resonance imaging (MRI) and a human microarray study in which the frontal cortex exhibited the most gene expression alterations [17][18][19][20][21]. Here, we investigated the frontal cortex of initial hypertensive (6-8 weeks) animals, that mimic newly diagnosed hypertension in midlife humans and of two older stroke-free age groups, that represent stages of early (24-25 weeks) and late chronic (32-34 weeks) hypertension.…”

Cerebral Small Vessel Disease (CSVD) – Lessons From the Animal Models

“…Protease activity and HTRA1 gene mutations differ according to their locus, and these differences might correlate with the severity of the vascular changes and leukoencephalopathy (Nozaki et al, 2016). TGF-β signaling was found to be associated with downregulated genes in the basal ganglia of patients with CSVD, suggesting an absence of TGF-β-induced detrimental effects on vSMCs in this area (Ritz et al, 2017). In addition to the contribution of genetic mutations in monogenic CSVD, several genetic variants are also related to sporadic CSVD, that is, genetic mutations in amyloid CSVD and the involvement of oxidative phosphorylation gene mutations in CSVD related to lacunar infarcts.…”