endothelin-1 and Dementia

Cerebral endothelial dysfunction occurs in a spectrum of neurodegenerative diseases. Whether biomarkers of microvascular endothelial dysfunction can predict dementia is largely unknown. We explored the longitudinal association of midregional pro-atrial natriuretic peptide (MR-proANP), C-terminal endothelin-1 (CT-proET-1) and midregional proadrenomedullin (MR-proADM) with dementia and subtypes amongst community-dwelling older adults.. A population-based cohort of 5347 individuals (men, 70%; age, 69 ± 6 years) without prevalent dementia provided plasma for determination of MR-proANP, CT-proET-1 and MR-proADM. Three-hundred-and-seventy-three patients (7%) were diagnosed with dementia (120 Alzheimer's disease, 83 vascular, 102 mixed, and 68 other aetiology) over a period of 4.6 ± 1.3 years. Relations between baseline biomarker plasma concentrations and incident dementia were assessed using multivariable Cox regression analysis.. Higher levels of MR-proANP were significantly associated with increased risk of all-cause and vascular dementia (hazard ratio [HR] per 1 SD: 1.20, 95% confidence interval [CI], 1.07-1.36; P = 0.002, and 1.52; 1.21-1.89; P < 0.001, respectively). Risk of all-cause dementia increased across the quartiles of MR-proANP (p for linear trend = 0.004; Q4, 145-1681 pmol L. Elevated plasma concentration of MR-proANP is an independent predictor of all-cause and vascular dementia. Pronounced increase in CT-proET-1 indicates higher risk of vascular dementia.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Brain; Dementia; Endothelin-1; Endothelium, Vascular; Female; Follow-Up Studies; Humans; Male; Peptide Fragments; Prospective Studies; Protein Precursors; Risk Factors

BACKGROUND Ischemic stroke is widely recognized as a major health problem and social burden worldwide, and it usually leads to dementia. In this study, we aimed to better understand the pathogenesis in the development of dementia following ischemic stroke. MATERIAL AND METHODS We exploited miRNA database to search for the target for miR-125a and validated the found target using luciferase assay. Further, we performed real-time PCR and Western blot analysis to examine the expression of miR-125a and its target in the tissue samples. In addition, a polymorphism was genotyped and its association with post-stroke dementia was analyzed. RESULTS We identified enthothelin-1 (ET-1) as a target of miR-125a, and this relationship was validated using luciferase assay. Furthermore, transfection of miR-125a inhibitor substantially upregulated the expression of ET-1, while miR-125a and ET-1 siRNA caused downregulation of ET-1 in endothelial cells. In addition, we found that a polymorphism (rs12976445) interferes with the expression of miR-125a, which in turn caused an increase in the expression of ET-1 in human endothelial cells. Logistic regression analysis showed that rs12976445 is significantly associated with the risk of dementia after ischemic stroke. CONCLUSIONS Our study demonstrated the pathogenesis mechanism during the development of dementia after ischemic stroke by investigating the relationship between miR-125a and its target ET-1, promising a potential pathological solution for post-stroke dementia in the future.

Topics: 3' Untranslated Regions; Base Sequence; Brain Ischemia; Case-Control Studies; Dementia; Demography; Endothelin-1; Gene Expression Regulation; Genetic Predisposition to Disease; Human Umbilical Vein Endothelial Cells; Humans; Luciferases; MicroRNAs; Polymorphism, Single Nucleotide; RNA, Messenger; Stroke; Transfection

Endothelin-1 (ET-1) is synthesized by endothelial cells and astrocytes in stroke and in brains of Alzheimer's disease patients. Our transgenic mice with ET-1 overexpression in the endothelial cells (TET-1) showed more severe blood-brain barrier (BBB) breakdown, neuronal apoptosis, and glial reactivity after 2-hour transient middle cerebral artery occlusion (tMCAO) with 22-hour reperfusion and more severe cognitive deficits after 30 minutes tMCAO with 5 months reperfusion. However, the role of astrocytic ET-1 in contributing to poststroke cognitive deficits after tMCAO is largely unknown. Therefore, GET-1 mice were challenged with tMCAO to determine its effect on neurologic and cognitive deficit. The GET-1 mice transiently displayed a sensorimotor deficit after reperfusion that recovered shortly, then more severe deficit in spatial learning and memory was observed at 3 months after ischemia compared with that of the controls. Upregulation of TNF-α, cleaved caspase-3, and Thioflavin-S-positive aggregates was observed in the ipsilateral hemispheres of the GET-1 brains as early as 3 days after ischemia. In an in vitro study, ET-1 overexpressing astrocytic cells showed amyloid secretion after hypoxia/ischemia insult, which activated endothelin A (ETA) and endothelin B (ETB) receptors in a PI3K/AKT-dependent manner, suggesting role of astrocytic ET-1 in dementia associated with stroke by astrocyte-derived amyloid production.

Topics: Amyloidogenic Proteins; Animals; Astrocytes; Brain Edema; Brain Ischemia; Cognition; Dementia; Endothelin-1; Hippocampus; Humans; Hypoxia, Brain; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Nervous System Diseases

Numerous clinical and epidemiological reports indicate that patients with history of vascular illness such as stroke are more likely to develop dementia as the clinical manifestation of Alzheimer's disease. However, there are little data regarding the pathologic mechanisms that link vascular risk factors to the factors associated with dementia onset. We provide evidence that suggests intriguing detrimental interactions between stroke and β-amyloid (Aβ) toxicity in the hippocampus. Stroke was induced by unilateral striatal injection of endothelin-1, the potent vasoconstrictor. Aβ toxicity was modeled by bilateral intracerebroventricular injections of the toxic fragment Aβ. Gross morphologic changes in comorbid Aβ and stroke rats were enlargement of the lateral ventricles with concomitant shrinkage of the hippocampus. The hippocampus displayed a series of synergistic biochemical alterations, including microgliosis, deposition of Aβ precursor protein fragments, and cellular degeneration. In addition, there was bilateral induction of connexin43, reduced neuronal survival, and impaired dendritic development of adult-born immature neurons in the dentate gyrus of these rats compared with either rats alone. Behaviorally, there was impairment in the hippocampal-based discriminative fear-conditioning to context task indicating learning and memory deficit. These results suggest an insight into the relationship between hippocampal atrophy, pathology, and functional impairment. Our work not only highlights the exacerbated pathology that emerges when Aβ toxicity and stroke occur comorbidly but also demonstrates that this comorbid rat model exhibits physiopathology that is highly characteristic of the human condition.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Atrophy; Connexin 43; Dementia; Disease Models, Animal; Endothelin-1; Hippocampus; Humans; Injections, Intraventricular; Male; Stroke; Vasoconstrictor Agents