The Role of the Vascular System in Degenerative Diseases: Mechanisms and Implications

Degenerative diseases, encompassing a wide range of conditions affecting various organ systems, pose significant challenges to global healthcare systems. This comprehensive review explores the intricate interplay between the vascular system and degenerative diseases, shedding light on the underlying mechanisms and profound implications for disease progression and management. The pivotal role of the vascular system in maintaining tissue homeostasis is highlighted, as it serves as the conduit for oxygen, nutrients, and immune cells to vital organs and tissues. Due to the vital role of the vascular system in maintaining homeostasis, its dysfunction, characterized by impaired blood flow, endothelial dysfunction, and vascular inflammation, emerges as a common denominator of degenerative diseases across multiple systems. In the nervous system, we explored the influence of vascular factors on neurodegenerative diseases such as Alzheimer’s and Parkinson’s, emphasizing the critical role of cerebral blood flow regulation and the blood–brain barrier. Within the kidney system, the intricate relationship between vascular health and chronic kidney disease is scrutinized, unraveling the mechanisms by which hypertension and other vascular factors contribute to renal dysfunction. Throughout this review, we emphasize the clinical significance of understanding vascular involvement in degenerative diseases and potential therapeutic interventions targeting vascular health, highlighting emerging treatments and prevention strategies. In conclusion, a profound appreciation of the role of the vascular system in degenerative diseases is essential for advancing our understanding of degenerative disease pathogenesis and developing innovative approaches for prevention and treatment. This review provides a comprehensive foundation for researchers, clinicians, and policymakers seeking to address the intricate relationship between vascular health and degenerative diseases in pursuit of improved patient outcomes and enhanced public health

Supplemental Material - Rho-Kinase inhibition decreases focal cerebral ischemia-induced glial activation in rats

Supplemental Material for Rho-Kinase inhibition decreases focal cerebral ischemia-induced glial activation in rats by Abdullah Md Sheikh, Shozo Yano, Shingo Mitaki, Shatera Tabassum, Shuhei Yamaguchi and Atsushi Nagai in Journal of Central Nervous System Disease</p

Supplemental Material - Rho-Kinase inhibition decreases focal cerebral ischemia-induced glial activation in rats

Supplemental Material for Rho-Kinase inhibition decreases focal cerebral ischemia-induced glial activation in rats by Abdullah Md Sheikh, Shozo Yano, Shingo Mitaki, Shatera Tabassum, Shuhei Yamaguchi and Atsushi Nagai in Journal of Central Nervous System Disease</p

Alteration of Neural Stem Cell Functions in Ataxia and Male Sterility Mice: A Possible Role of β-Tubulin Glutamylation in Neurodegeneration

Ataxia and Male Sterility (AMS) is a mutant mouse strain that contains a missense mutation in the coding region of Nna1, a gene that encodes a deglutamylase. AMS mice exhibit early cerebellar Purkinje cell degeneration and an ataxic phenotype in an autosomal recessive manner. To understand the underlying mechanism, we generated neuronal stem cell (NSC) lines from wild-type (NMW7), Nna1 mutation heterozygous (NME), and Nna1 mutation homozygous (NMO1) mouse brains. The NNA1 levels were decreased, and the glutamylated tubulin levels were increased in NMO1 cultures as well as in the cerebellum of AMS mice at both 15 and 30 days of age. However, total β-tubulin protein levels were not altered in the AMS cerebellum. In NMO1 neurosphere cultures, β-tubulin protein levels were increased without changes at the transcriptional level. NMO1 grew faster than other NSC lines, and some of the neurospheres were attached to the plate after 3 days. Immunostaining revealed that SOX2 and nestin levels were decreased in NMO1 neurospheres and that the neuronal differentiation potentials were reduced in NMO1 cells compared to NME or NMW7 cells. These results demonstrate that the AMS mutation decreased the NNA1 levels and increased glutamylation in the cerebellum of AMS mice. The observed changes in glutamylation might alter NSC properties and the neuron maturation process, leading to Purkinje cell death in AMS mice

Analysis of Cerebral Small Vessel Changes in AD Model Mice

Amyloid β (Aβ) peptide is deposited in the brains of sporadic Alzheimer’s disease (AD) due to impaired vessel-dependent clearance. To understand the mechanisms, we investigated time-dependent cerebrovascular changes in AD model mice. Cerebrovascular and other pathological changes were analyzed in AD model mice (J20 strain) aging from 2 to 9 months by immunostaining. At 2 months, Aβ was only intraneuronal, whereas vessels were positive from 3 months in J20 mice. Compared to wild-type (WT), vessel density was increased at 2 months but decreased at 9 months in J20 mice, claudin-5 levels were decreased, and vascular endothelial growth factor (VEGF) levels were increased in the cortex and hippocampus of J20 mice brain at all time points. Albumin extravasation was evident from 3 months in J20 brains. Collagen 4 was increased at 2 and 3 months. Aquaporin 4 was spread beyond the vessels starting from 3 months in J20, which was restricted around the vessel in wild-type mice. In conclusion, the study showed that an early decrease in claudin-5 was associated with VEGF expression, indicating dysfunction of the blood–brain barrier. Decreased claudin-5 might cause the leakage of blood constituents into the parenchyma that alters astrocyte polarity and its functions

Time-Dependent Analysis of Plasmalogens in the Hippocampus of an Alzheimer’s Disease Mouse Model: A Role of Ethanolamine Plasmalogen

Plasmalogens are alkenyl-acyl glycerophospholipids and decreased in post-mortem Alzheimer’s disease (AD) brains. The aim of this study is to investigate the time-dependent changes of plasmalogens in the hippocampus of an AD model mouse (J20). Plasmalogen levels at 3, 6, 9, 12 and 15 months were analyzed by liquid-chromatography-targeted-multiplexed-selected-reaction-monitoring-tandem-mass-spectrometry (LC-SRM/MS). Reactive oxygen species (ROS) levels were evaluated using dichlorofluorescein diacetate (DCF-DA). Plasmalogen synthesizing enzyme glycerone-phosphate O-acyltransferase (GNPAT) and late endosome marker Rab7 levels were quantified by Western blotting. GNPAT localization, changes of neuronal and glial cell numbers were evaluated by immunostaining. Compared to wild-type mice (WT), total plasmalogen-ethanolamine, but not plasmalogen-choline levels, were increased at 9 months and subsequently decreased at 15 months in J20 mice. A principal component analysis of plasmalogen-ethanolamine species could separate WT and J20 mice both at 9 and 15 months. Both GNPAT and Rab7 protein were increased in J20 mice at 9 months, whereas GNPAT was decreased at 15 months. ROS levels were increased in J20 mice except for 9 months. Our results suggest that increased plasmalogen-ethanolamine could counteract ROS levels and contribute to the phagocytosis process in J20 mice at 9 months. Such results might indicate a transient protective response of plasmalogen-ethanolamine in AD conditions