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Transgenic mice constitutively overexpressing the cytokine transforming growth factor-[beta]1 (TGF-[beta]1) (TGF mice) display cerebrovascular alterations as seen in Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID), but no or only subtle cognitive deficits. TGF-[beta]1 may exert part of its deleterious effects through interactions with angiotensin II (AngII) type 1 receptor (AT1R) signaling pathways. We test such interactions in the brain and cerebral vessels of TGF mice by measuring cerebrovascular reactivity, levels of protein markers of vascular fibrosis, nitric oxide synthase activity, astrogliosis, and mnemonic performance in mice treated (6 months) with the AT1R blocker losartan (10 mg/kg per day) or the angiotensin converting enzyme inhibitor enalapril (3 mg/kg per day). Both treatments restored the severely impaired cerebrovascular reactivity to acetylcholine, calcitonin gene-related peptide, endothelin-1, and the baseline availability of nitric oxide in aged TGF mice. Losartan, but not enalapril, significantly reduced astrogliosis and cerebrovascular levels of profibrotic protein connective tissue growth factor while raising levels of antifibrotic enzyme matrix metallopeptidase-9. Memory was unaffected by aging and treatments. The results suggest a pivotal role for AngII in TGF-p1-induced cerebrovascular dysfunction and neuroinflammation through AT1R-mediated mechanisms. Further, they suggest that AngII blockers could be appropriate against vasculopathies and astrogliosis associated with AD and VCID. Key words: losartan, enalapril, cerebrovascular reactivity, astrogliosis, TGF-[beta]1, AT1 receptors. Les souris transgeniques qui surexpriment constitutivement la cytokine << transforming growth factor-[beta]1 >> (TGF- [beta]1), denommees souris TGF, presentent des modifications vasculaires cerebrales semblables a celles observees dans la maladie d'Alzheimer (MA) et l'atteinte cognitive et la demence vasculaires (ACDV), mais avec peu ou pas de deficits cognitifs. Le TGF-[beta]1 pourrait exercer une partie de ses effets deleteres par des interactions avec les voies de signalisation du recepteur de type 1 (AT1R) de l'angiotensine II (AngII). Nous avons teste de telles interactions dans le cerveau et les vaisseaux cerebraux de souris TGF en mesurant la reactivite vasculaire cerebrale, les taux proteiques de marqueurs de la fibrose vasculaire et de la NO synthase, l'astrogliose et les performances mnemoniques chez des souris traitees pendant 6 mois avec le losartan (bloqueur des AT1R; 10 mg/kg par jour) ou de l'enalapril (inhibiteur de l'enzyme de conversion de l'angiotensine; 3 mg/kg par jour). Chez les souris TGF agees, les deux traitements ont retabli la reactivite gravement reduite des vaisseaux cerebraux a l'acetylcholine, au peptide relie au gene calcitonine, a l'endotheline-1, ainsi que la disponibilite de l'oxyde nitrique. Le losartan, mais pas l'enalapril, a permis de reduire l'astrogliose et les taux vasculaires cerebraux du facteur de croissance des proteines du tissu conjonctif tout en augmentant les taux de metallopeptidase 9 matricielle (une enzyme antifibrotique). La memoire des souris n'etait affectee ni par le vieillissement, ni par les traitements. Ces resultats suggerent un role central de l'AngII dans l'atteinte vasculaire cerebrale et la neuro-inflammation induites par le TGF-[beta]1 via des mecanismes impliquant l'activation des AT1R. De plus, ces resultats laissent entendre que les bloqueurs de l'AngII pourraient constituer des agents prometteurs contre les pathologies vasculaires et l'astrogliose associees a la MA et l'ACDV. Mots-cles : losartan, enalapril, reactivite vasculaire cerebrale, astrogliose, TGF-[beta]1, recepteurs AT1., Introduction Evidence suggests that the renin-angiotensin system (RAS) is altered in Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID) patients (Kehoe 2009), and that angiotensin receptor blockers can [...]

Background and Purpose: Inward rectifier potassium (KIR) channels are key effectors of vasodilatation in neurovascular coupling (NVC). KIR channels expressed in cerebral endothelial cells (ECs) have been confirmed as essential modulators of NVC. Alzheimer's disease (AD) and cerebrovascular disease (CVD) impact on EC‐KIR channel function, but whether oxidative stress or inflammation explains this impairment remains elusive. Experimental Approach We evaluated KIR channel function in intact and EC‐denuded pial arteries of wild‐type (WT) and transgenic mice overexpressing a mutated form of the human amyloid precursor protein (APP mice, recapitulating amyloid β‐induced oxidative stress seen in AD) or a constitutively active form of TGF‐β1 (TGF mice, recapitulating inflammation seen in cerebrovascular pathology). The benefits of antioxidant (catalase) or anti‐inflammatory (indomethacin) drugs also were investigated. Vascular and neuronal components of NVC were assessed in vivo. Key Results: Our findings show that (i) KIR channel‐mediated maximal vasodilatation in APP and TGF mice reaches only 37% and 10%, respectively, of the response seen in WT mice; (ii) KIR channel dysfunction results from KIR2.1 subunit impairment; (iii) about 50% of K+‐induced artery dilatation is mediated by EC‐KIR channels; (iv) oxidative stress and inflammation impair KIR channel function, which can be restored by antioxidant and anti‐inflammatory drugs; and (v) inflammation induces KIR2.1 overexpression and impairs NVC in TGF mice. Conclusion and Implications: Therapies targeting both oxidative stress and inflammation are necessary for full recovery of KIR2.1 channel function in cerebrovascular pathology caused by AD and CVD. [ABSTRACT FROM AUTHOR]

Vasodilatory prostaglandins play a key role in neurovascular coupling (NVC), the tight link between neuronal activity and local cerebral blood flow, but their precise identity, cellular origin and the receptors involved remain unclear. Here we show in rats that NMDA-induced vasodilation and hemodynamic responses evoked by whisker stimulation involve cyclooxygenase-2 (COX-2) activity and activation of the prostaglandin E2 (PgE2) receptors EP2 and EP4. Using liquid chromatography-electrospray ionization-tandem mass spectrometry, we demonstrate that PgE2 is released byNMDAin cortical slices. The characterization of PgE2 producing cells by immunohistochemistry and single-cell reverse transcriptase-PCR revealed that pyramidal cells and not astrocytes are the main cell type equipped for PgE2 synthesis, one third expressing COX-2 systematically associated with a PgE2 synthase. Consistent with their central role in NVC, in vivo optogenetic stimulation of pyramidal cells evoked COX-2-dependent hyperemic responses in mice. These observations identify PgE2 as the main prostaglandin mediating sensory-evoked NVC, pyramidal cells as their principal source and vasodilatory EP2 and EP4 receptors as their targets. [ABSTRACT FROM AUTHOR]

The whisker-to-barrel cortex is widely used to study neurovascular coupling, but the cellular basis that underlies the perfusion changes is still largely unknown. Here, we identified neurons recruited by whisker stimulation in the rat somatosensory cortex using double immunohistochemistry for c-Fos and markers of glutamatergic and GABAergic neurons, and investigated in vivo their contribution along with that of astrocytes in the evoked perfusion response. Whisker stimulation elicited cerebral blood flow (CBF) increases concomitantly with c-Fos upregulation in pyramidal cells that coexpressed cyclooxygenase-2 (COX-2) and GABA interneurons that coexpressed vasoactive intestinal polypeptide and/or choline acetyltransferase, but not somatostatin or parvalbumin. The evoked CBF response was decreased by blockade of NMDA (MK-801, -37%), group I metabotropic glutamate (MPEP+LY367385, -40%), and GABA-A (picrotoxin, -31%) receptors, but not by GABA-B, VIP, or muscarinic receptor antagonism. Picrotoxin decreased stimulus-induced somatosensory evoked potentials and CBF responses. Combined blockade of GABA-A and NMDA receptors yielded an additive decreasing effect (-61%) of the evoked CBF compared with each antagonist alone, demonstrating cooperation of both excitatory and inhibitory systems in the hyperemic response. Blockade of prostanoid synthesis by inhibiting COX-2 (indomethacin, NS-398), expressed by ∼40% of pyramidal cells but not by astrocytes, impaired the CBF response (-50%). The hyperemic response was also reduced (-40%) after inhibition of astroglial oxidative metabolism or epoxyeicosatrienoic acids synthesis. These results demonstrate that changes in pyramidal cell activity, sculpted by specific types of inhibitory GABA interneurons, drive the CBF response to whisker stimulation and, further, that metabolically active astrocytes are also required. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that cerebrovascular dysfunction is an important factor in the pathogenesis of Alzheimer's disease (AD). Using aged (∼16 months) amyloid precursor protein (APP) transgenic mice that exhibit increased production of the amyloid-β (Aβ) peptide and severe cerebrovascular and memory deficits, we examined the capacity of in vivo treatments with the antioxidants N-acetyl-L-cysteine (NAC) and tempol, or the peroxisome proliferator-activated receptor γ agonist pioglitazone to rescue cerebrovascular function and selected markers of AD neuropathology. Additionally, we tested the ability of pioglitazone to normalize the impaired increases in cerebral blood flow (CBF) and glucose uptake (CGU) induced by whisker stimulation, and to reverse spatial memory deficits in the Morris water maze. All compounds fully restored cerebrovascular reactivity of isolated cerebral arteries concomitantly with changes in proteins regulating oxidative stress, without reducing brain Aβ levels or Aβ plaque load. Pioglitazone, but not NAC, significantly attenuated astroglial activation and improved, albeit nonsignificantly, the reduced cortical cholinergic innervation. Furthermore, pioglitazone completely normalized the CBF and CGU responses to increased neuronal activity, but it failed to improve spatial memory. Our results are the first to demonstrate that late pharmacological intervention with pioglitazone not only overcomes cerebrovascular dysfunction and altered neurometabolic coupling in aged APP mice, but also counteracts cerebral oxidative stress, glial activation, and, partly, cholinergic denervation. Although early or combined therapy may be warranted to improve cognition, these findings unequivocally point to pioglitazone as a most promising strategy for restoring cerebrovascular function and counteracting several AD markers detrimental to neuronal function. [ABSTRACT FROM AUTHOR]

Contributions of glial cells to neuroenergetics have been the focus of extensive debate. Here we provide positron emission tomography evidence that activation of astrocytic glutamate transport via the excitatory amino acid transporter GLT-1 triggers widespread but graded glucose uptake in the rodent brain. Our results highlight the need for a reevaluation of the interpretation of [ 18 F]FDG positron emission tomography data, whereby astrocytes would be recognized as contributing to the [ 18 F]FDG signal.

High brain levels of amyloid-β (Aβ) and transforming growth factor-β1 (TGF-β1) have been implicated in the cognitive and cerebrovascular alterations of Alzheimer's disease (AD). We sought to investigate the impact of combined increases in Aβ and TGF-β1 on cerebrovascular, neuronal, and mnemonic function using transgenic mice overproducing these peptides (A/T mice). In particular, we measured cerebrovascular reactivity, evoked cerebral blood flow and glucose uptake during brain activation, cholinergic status, and spatial memory, along with cerebrovascular fibrosis, amyloidosis, and astrogliosis, and their evolution with age. An assessment of perfusion and metabolic responses was considered timely, given ongoing efforts for their validation as AD biomarkers. Relative to wild-type littermates, A/T mice displayed an early progressive decline in cerebrovascular dilatory ability, preserved contractility, and reduction in constitutive nitric oxide synthesis that establishes resting vessel tone. Altered levels of vasodilator-synthesizing enzymes and fibrotic proteins, resistance to antioxidant treatment, and unchanged levels of the antioxidant enzyme, superoxide dismutase-2, accompanied these impairments. A/T mice featured deficient neurovascular and neurometabolic coupling to whisker stimulation, cholinergic denervation, cerebral and cerebrovascular Aβ deposition, astrocyte activation, and impaired Morris water maze performance, which gained severity with age. The combined Aβ- and TGF-β1-driven pathology recapitulates salient cerebrovascular, neuronal, and cognitive AD landmarks and yields a versatile model toward highly anticipated diagnostic and therapeutic tools for patients featuring Aβ and TGF-β1 increments.

Accumulating evidence suggests that cerebrovascular dysfunction is an important factor in the pathogenesis of Alzheimer's disease (AD). Using aged ( approximately 16 months) amyloid precursor protein (APP) transgenic mice that exhibit increased production of the amyloid-beta (Abeta) peptide and severe cerebrovascular and memory deficits, we examined the capacity of in vivo treatments with the antioxidants N-acetyl-L-cysteine (NAC) and tempol, or the peroxisome proliferator-activated receptor gamma agonist pioglitazone to rescue cerebrovascular function and selected markers of AD neuropathology. Additionally, we tested the ability of pioglitazone to normalize the impaired increases in cerebral blood flow (CBF) and glucose uptake (CGU) induced by whisker stimulation, and to reverse spatial memory deficits in the Morris water maze. All compounds fully restored cerebrovascular reactivity of isolated cerebral arteries concomitantly with changes in proteins regulating oxidative stress, without reducing brain Abeta levels or Abeta plaque load. Pioglitazone, but not NAC, significantly attenuated astroglial activation and improved, albeit nonsignificantly, the reduced cortical cholinergic innervation. Furthermore, pioglitazone completely normalized the CBF and CGU responses to increased neuronal activity, but it failed to improve spatial memory. Our results are the first to demonstrate that late pharmacological intervention with pioglitazone not only overcomes cerebrovascular dysfunction and altered neurometabolic coupling in aged APP mice, but also counteracts cerebral oxidative stress, glial activation, and, partly, cholinergic denervation. Although early or combined therapy may be warranted to improve cognition, these findings unequivocally point to pioglitazone as a most promising strategy for restoring cerebrovascular function and counteracting several AD markers detrimental to neuronal function.