Chronic Rapamycin Restores Brain Vascular Integrity and Function Through NO Synthase Activation and Improves Memory in Symptomatic Mice Modeling Alzheimer’s Disease

Vascular pathology is a major feature of Alzheimer's disease (AD) and other dementias. We recently showed that chronic administration of the target-of-rapamycin (TOR) inhibitor rapamycin, which extends lifespan and delays aging, halts the progression of AD-like disease in transgenic human (h)APP mice modeling AD when administered before disease onset. Here we demonstrate that chronic reduction of TOR activity by rapamycin treatment started after disease onset restored cerebral blood flow (CBF) and brain vascular density, reduced cerebral amyloid angiopathy and microhemorrhages, decreased amyloid burden, and improved cognitive function in symptomatic hAPP (AD) mice. Like acetylcholine (ACh), a potent vasodilator, acute rapamycin treatment induced the phosphorylation of endothelial nitric oxide (NO) synthase (eNOS) and NO release in brain endothelium. Administration of the NOS inhibitor L-NG-Nitroarginine methyl ester reversed vasodilation as well as the protective effects of rapamycin on CBF and vasculature integrity, indicating that rapamycin preserves vascular density and CBF in AD mouse brains through NOS activation. Taken together, our data suggest that chronic reduction of TOR activity by rapamycin blocked the progression of AD-like cognitive and histopathological deficits by preserving brain vascular integrity and function. Drugs that inhibit the TOR pathway may have promise as a therapy for AD and possibly for vascular dementias

MICROWAVE-INDUCED BISMUTH NITRATE-MEDIATED SELECTIVE HYDROLYSIS OF AMIDE

Microwave-induced selective hydrolysis of amide to the corresponding amine has been achieved with bismuth nitrate and montmorillonite KSF clay

Cytosolic dopamine determines hypersensitivity to blunt force trauma

Summary: The selective vulnerability of dopaminergic neurons to trauma-induced neurodegeneration is conserved across species, from nematodes to humans. However, the molecular mechanisms underlying this hypersensitivity to blunt force trauma remain elusive. We find that extravesicular dopamine, a key driver of Parkinson’s disease, extends its toxic role to the acute challenges associated with injury. Ectopic dopamine synthesis in serotonergic neurons sensitizes this resilient neuronal subtype to trauma-induced degeneration. While dopaminergic neurons normally maintain dopamine in a functional and benign state, trauma-induced subcellular redox imbalances elicit dopamine-dependent cytotoxicity. Cytosolic dopamine accumulation, through perturbations to its synthesis, metabolism, or packaging, is necessary and sufficient to drive neurodegeneration upon injury and during aging. Additionally, degeneration is further exacerbated by rapid upregulation of the rate-limiting enzyme in dopamine synthesis, cat-2, via the FOS-1 transcription factor. Fundamentally, our study in C. elegans unravels the molecular intricacies rendering dopaminergic neurons uniquely prone to physical perturbation across evolutionary lines

Chronic Rapamycin Restores Brain Vascular Integrity and Function Through NO Synthase Activation and Improves Memory in Symptomatic Mice Modeling Alzheimer’s Disease

Vascular pathology is a major feature of Alzheimer's disease (AD) and other dementias. We recently showed that chronic administration of the target-of-rapamycin (TOR) inhibitor rapamycin, which extends lifespan and delays aging, halts the progression of AD-like disease in transgenic human (h)APP mice modeling AD when administered before disease onset. Here we demonstrate that chronic reduction of TOR activity by rapamycin treatment started after disease onset restored cerebral blood flow (CBF) and brain vascular density, reduced cerebral amyloid angiopathy and microhemorrhages, decreased amyloid burden, and improved cognitive function in symptomatic hAPP (AD) mice. Like acetylcholine (ACh), a potent vasodilator, acute rapamycin treatment induced the phosphorylation of endothelial nitric oxide (NO) synthase (eNOS) and NO release in brain endothelium. Administration of the NOS inhibitor L-NG-Nitroarginine methyl ester reversed vasodilation as well as the protective effects of rapamycin on CBF and vasculature integrity, indicating that rapamycin preserves vascular density and CBF in AD mouse brains through NOS activation. Taken together, our data suggest that chronic reduction of TOR activity by rapamycin blocked the progression of AD-like cognitive and histopathological deficits by preserving brain vascular integrity and function. Drugs that inhibit the TOR pathway may have promise as a therapy for AD and possibly for vascular dementias

Measurement of the production cross section for a W boson in association with a charm quark in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceThe strange quark content of the proton is probed through the measurement of the production cross section for a W boson and a charm (c) quark in proton-proton collisions at a center-of-mass energy of 13 TeV. The analysis uses a data sample corresponding to a total integrated luminosity of 138 fb$^{-1}$ collected with the CMS detector at the LHC. The W bosons are identified through their leptonic decays to an electron or a muon, and a neutrino. Charm jets are tagged using the presence of a muon or a secondary vertex inside the jet. The W+c production cross section and the cross section ratio $R^\pm_\text{c}$ = $\sigma$(W$^+$+$\bar{\text{c}}$)/$\sigma$(W$^-$+$\text{c}$) are measured inclusively and differentially as functions of the transverse momentum and the pseudorapidity of the lepton originating from the W boson decay. The precision of the measurements is improved with respect to previous studies, reaching 1% in $R^\pm_\text{c}$. The measurements are compared with theoretical predictions up to next-to-next-to-leading order in perturbative quantum chromodynamics

Measurement of the production cross section for a W boson in association with a charm quark in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceThe strange quark content of the proton is probed through the measurement of the production cross section for a W boson and a charm (c) quark in proton-proton collisions at a center-of-mass energy of 13 TeV. The analysis uses a data sample corresponding to a total integrated luminosity of 138 fb$^{-1}$ collected with the CMS detector at the LHC. The W bosons are identified through their leptonic decays to an electron or a muon, and a neutrino. Charm jets are tagged using the presence of a muon or a secondary vertex inside the jet. The W+c production cross section and the cross section ratio $R^\pm_\text{c}$ = $\sigma$(W$^+$+$\bar{\text{c}}$)/$\sigma$(W$^-$+$\text{c}$) are measured inclusively and differentially as functions of the transverse momentum and the pseudorapidity of the lepton originating from the W boson decay. The precision of the measurements is improved with respect to previous studies, reaching 1% in $R^\pm_\text{c}$. The measurements are compared with theoretical predictions up to next-to-next-to-leading order in perturbative quantum chromodynamics

Measurement of the production cross section for a W boson in association with a charm quark in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceThe strange quark content of the proton is probed through the measurement of the production cross section for a W boson and a charm (c) quark in proton-proton collisions at a center-of-mass energy of 13 TeV. The analysis uses a data sample corresponding to a total integrated luminosity of 138 fb$^{-1}$ collected with the CMS detector at the LHC. The W bosons are identified through their leptonic decays to an electron or a muon, and a neutrino. Charm jets are tagged using the presence of a muon or a secondary vertex inside the jet. The W+c production cross section and the cross section ratio $R^\pm_\text{c}$ = $\sigma$(W$^+$+$\bar{\text{c}}$)/$\sigma$(W$^-$+$\text{c}$) are measured inclusively and differentially as functions of the transverse momentum and the pseudorapidity of the lepton originating from the W boson decay. The precision of the measurements is improved with respect to previous studies, reaching 1% in $R^\pm_\text{c}$. The measurements are compared with theoretical predictions up to next-to-next-to-leading order in perturbative quantum chromodynamics