Although epidemiological data associate hypertension with a strong predisposition to develop Alzheimer’s Disease, no mechanistic explanation exists so far. We developed a model of hypertension, obtained by Transverse Aortic Constriction, leading to alterations typical of Alzheimer’s Disease, such as amyloid plaques, neuroinflammation, Blood Brain Barrier dysfunction and cognitive impairment, shown here for the first time. The aim of this work was to investigate the mechanisms involved in Alzheimer’s Disease of hypertensive mice. We focused on RAGE, that critically regulates Aβ transport at the Blood Brain Barrier and could be influenced by vascular factors. The hypertensive challenge had an early and sustained effect on RAGE up-regulation in brain vessels of cortex and hippocampus. Interestingly, RAGE inhibition protected from hypertension-induced Alzheimer pathology, as showed by rescue from cognitive impairment and parenchymal Aβ deposition. The increased RAGE expression in TAC mice was induced by increased circulating AGEs and sustained by their later deposition in brain vessels. Interestingly, a daily treatment with an AGEs inhibitor or antioxidant prevented the development of Alzheimer’s traits. So far, Alzheimer pathology in experimental animal models has been recognized using only transgenic mice overexpressing amyloid precursor. This is the first study demonstrating that a chronic vascular insult can activate brain vascular RAGE, favoring parenchymal Aβ deposition and the onset of cognitive deterioration. Overall we demonstrate that RAGE activation in brain vessels is a crucial pathogenetic event in hypertension-induced Alzheimer’s Disease, suggesting that inhibiting this target can limit the onset of vascular-related Alzheimer.
The crucial role of the immune system in hypertension is now widely recognized. We previously reported that hypertensive challenges couple the nervous drive with immune system activation, but the physiological and molecular mechanisms of this connection are unknown. Here, we show that hypertensive challenges activate splenic sympathetic nerve discharge to prime immune response. More specifically, a vagus-splenic nerve drive, mediated by nicotinic cholinergic receptors, links the brain and spleen. The sympathetic discharge induced by hypertensive stimuli was absent in both coeliac vagotomized mice and in mice lacking α7nAChR, a receptor typically expressed by peripheral ganglionic neurons. This cholinergic-sympathetic pathway is necessary for T cell activation and egression on hypertensive challenges. In addition, we show that selectively thermoablating the splenic nerve prevents T cell egression and protects against hypertension. This novel experimental procedure for selective splenic denervation suggests new clinical strategies for resistant hypertension.
Hypertension is a health problem affecting over 1 billion people worldwide. How the immune system gets activated under hypertensive stimuli to contribute to blood pressure elevation is a fascinating enigma. Here we showed a splenic role for placental growth factor (PlGF), which accounts for the onset of hypertension, through immune system modulation. PlGF repressed the expression of the protein Timp3 (tissue inhibitor of metalloproteinases 3), through the transcriptional Sirt1-p53 axis. Timp3 repression allowed costimulation of T cells and their deployment toward classical organs involved in hypertension. We showed that the spleen is an essential organ for the development of hypertension through a noradrenergic drive mediated by the celiac ganglion efferent. Overall, we demonstrate that PlGF mediates the neuroimmune interaction in the spleen, organizing a unique and nonredundant response that allows the onset of hypertension.
Although PI3Kγ has been extensively investigated in inflammatory and cardiovascular diseases, the exploration of its functions in the brain is just at dawning. It is known that PI3Kγ is present in neurons and that the lack of PI3Kγ in mice leads to impaired synaptic plasticity, suggestive of a role in behavioral flexibility. Several neuropsychiatric disorders, such as attention-deficit/hyperactivity disorder (ADHD), involve an impairment of behavioral flexibility. Here, we found a previously unreported expression of PI3Kγ throughout the noradrenergic neurons of the locus coeruleus (LC) in the brainstem, serving as a mechanism that regulates its activity of control on attention, locomotion and sociality. In particular, we show an unprecedented phenotype of PI3Kγ KO mice resembling ADHD symptoms. PI3Kγ KO mice exhibit deficits in the attentive and mnemonic domains, typical hyperactivity, as well as social dysfunctions. Moreover, we demonstrate that the ADHD phenotype depends on a dysregulation of CREB signaling exerted by a kinase-independent PI3Kγ-PDE4D interaction in the noradrenergic neurons of the locus coeruleus, thus uncovering new tools for mechanistic and therapeutic research in ADHD.
ObjectiveTissue inhibitor of metalloproteinase 3 (TIMP3) is an extracellular matrix (ECM) bound protein, which has been shown to be downregulated in human subjects and experimental models with cardiometabolic disorders, including type 2 diabetes mellitus, hypertension and atherosclerosis. The aim of this study was to investigate the effects of TIMP3 on cardiac energy homeostasis during increased metabolic stress conditions.MethodsApoE−/−TIMP3−/− and ApoE−/− mice on a C57BL/6 background were subjected to telemetric ECG analysis and experimental myocardial infarction as models of cardiac stress induction. We used Western blot, qRT-PCR, histology, metabolomics, RNA-sequencing and in vivo phenotypical analysis to investigate the molecular mechanisms of altered cardiac energy metabolism.ResultsApoE−/−TIMP3−/− revealed decreased lifespan. Telemetric ECG analysis showed increased arrhythmic episodes, and experimental myocardial infarction by left anterior descending artery (LAD) ligation resulted in increased peri-operative mortality together with increased scar formation, ventricular dilatation and a reduction of cardiac function after 4 weeks in the few survivors. Hearts of ApoE−/−TIMP3−/− exhibited accumulation of neutral lipids when fed a chow diet, which was exacerbated by a high fat, high cholesterol diet. Metabolomics analysis revealed an increase in circulating markers of oxidative stress with a reduction in long chain fatty acids. Using whole heart mRNA sequencing, we identified apelin as a putative modulator of these metabolic defects. Apelin is a regulator of fatty acid oxidation, and we found a reduction in the levels of enzymes involved in fatty acid oxidation in the left ventricle of ApoE−/−TIMP3−/− mice. Injection of apelin restored the hitherto identified metabolic defects of lipid oxidation.ConclusionTIMP3 regulates lipid metabolism as well as oxidative stress response via apelin. These findings therefore suggest that TIMP3 maintains metabolic flexibility in the heart, particularly during episodes of increased cardiac stress.
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