Real-time surveillance of airborne SARS-CoV-2 virus is a technological gap that has eluded the scientific community since the beginning of the COVID-19 pandemic. Offline air sampling techniques for ...SARS-CoV-2 detection suffer from longer turnaround times and require skilled labor. Here, we present a proof-of-concept pathogen Air Quality (pAQ) monitor for real-time (5 min time resolution) direct detection of SARS-CoV-2 aerosols. The system synergistically integrates a high flow (~1000 lpm) wet cyclone air sampler and a nanobody-based ultrasensitive micro-immunoelectrode biosensor. The wet cyclone showed comparable or better virus sampling performance than commercially available samplers. Laboratory experiments demonstrate a device sensitivity of 77-83% and a limit of detection of 7-35 viral RNA copies/m
of air. Our pAQ monitor is suited for point-of-need surveillance of SARS-CoV-2 variants in indoor environments and can be adapted for multiplexed detection of other respiratory pathogens of interest. Widespread adoption of such technology could assist public health officials with implementing rapid disease control measures.
Several neurotransmitter receptors activate signaling pathways that alter processing of the amyloid precursor protein (APP) into β-amyloid (Aβ). Serotonin signaling through a subset of serotonin ...receptors suppresses Aβ generation. We proposed that escitalopram, the most specific selective serotonin reuptake inhibitor (SSRI) that inhibits the serotonin transporter SERT, would suppress Aβ levels in mice.
We hypothesized that acute treatment with escitalopram would reduce Aβ generation, which would be reflected chronically with a significant reduction in Aβ plaque load.
We performed in vivo microdialysis and in vivo 2-photon imaging to assess changes in brain interstitial fluid (ISF) Aβ and Aβ plaque size over time, respectively, in the APP/presenilin 1 mouse model of Alzheimer disease treated with vehicle or escitalopram. We also chronically treated mice with escitalopram to determine the effect on plaques histologically.
Escitalopram acutely reduced ISF Aβ by 25% by increasing α-secretase cleavage of APP. Chronic administration of escitalopram significantly reduced plaque load by 28% and 34% at 2.5 and 5 mg/d, respectively. Escitalopram at 5 mg/kg did not remove existing plaques, but completely arrested individual plaque growth over time.
Escitalopram significantly reduced Aβ in mice, similar to previous findings in humans treated with acute dosing of an SSRI.
Abstract
The risk of developing Alzheimer’s disease is mediated by a combination of genetics and environmental factors, such as stress, sleep abnormalities and traumatic brain injury. Women are at a ...higher risk of developing Alzheimer’s disease than men, even when controlling for differences in lifespan. Women are also more likely to report high levels of stress than men. Sex differences in response to stress may play a role in the increased risk of Alzheimer’s disease in women.
In this study, we use in vivo microdialysis to measure levels of Aβ in response to acute stress in male and female mice. We show that Aβ levels are altered differently between female and male mice (APP/PS1 and wild-type) in response to stress, with females showing significantly increased levels of Aβ while most males do not show a significant change. This response is mediated through β-arrestin involvement in Corticotrophin Releasing Factor receptor signalling pathway differences in male and female mice as male mice lacking β-arrestin show increase in Aβ in response to stress similar to females.
Edwards et al. report that acute stress leads to a prolonged increase in Aβ levels in the hippocampus of female mice but not males. Male mice that lack β-arrestin show a similar Aβ response to that of females, providing clues to the underlying mechanism. The findings may have implications for sexual dimorphism in Alzheimer's disease.
Amyloid‐β (Aβ) peptide aggregation into soluble oligomers and insoluble plaques is a precipitating event in the pathogenesis of Alzheimer's disease (AD). Given that synaptic activity can regulate Aβ ...generation, we postulated that 5HT2A‐Rs may regulate Aβ as well. We treated APP/PS1 transgenic mice with the selective 5HT2A inverse agonists M100907 or Pimavanserin systemically and measured brain interstitial fluid (ISF) Aβ levels in real‐time using in vivo microdialysis. Both compounds reduced ISF Aβ levels by almost 50% within hours, but had no effect on Aβ levels in 5HT2A‐R knock‐out mice. The Aβ‐lowering effects of Pimavanserin were blocked by extracellular‐regulated kinase (ERK) and NMDA receptor inhibitors. Chronic administration of Pimavanserin by subcutaneous osmotic pump to aged APP/PS1 mice significantly reduced CSF Aβ levels and Aβ pathology and improved cognitive function in these mice. Pimavanserin is FDA‐approved to treat Parkinson's disease psychosis, and also has been shown to reduce psychosis in a variety of other dementia subtypes including Alzheimer's disease. These data demonstrate that Pimavanserin may have disease‐modifying benefits in addition to its efficacy against neuropsychiatric symptoms of Alzheimer's disease.
Read the Editorial Highlight for this article on page 560.
(A) Pimavanserin (Pim) reduces activity at 5HT2A‐Rs which indirectly leads to activation of NMDARs (B). Calcium influx through NMDARs causes phosphorylation and activation of the extracellular regulated kinase (ERK) (C). ERK likely directly phosphorylates an α‐secretase protease which increases its enzymatic activity (D). An increase in non‐amyloidogenic processing of APP suppresses Aβ generation (E). Acute Pimavanserin causes a sustained 40% decrease in brain interstitial fluid Aβ levels of mice, whereas a chronic administration to aged APP/PS1 mice that already contain Aβ pathology causes a 30% decrease in Aβ plaques as well as improves several behavioral measures.
This article has an Editorial Highlight, see https://doi.org/10.1111/jnc.15269
Amyloid-β (Aβ) peptide aggregation into soluble oligomers and insoluble plaques is a precipitating event in the pathogenesis of Alzheimer's disease (AD). Given that synaptic activity can regulate Aβ ...generation, we postulated that 5HT
-Rs may regulate Aβ as well. We treated APP/PS1 transgenic mice with the selective 5HT
inverse agonists M100907 or Pimavanserin systemically and measured brain interstitial fluid (ISF) Aβ levels in real-time using in vivo microdialysis. Both compounds reduced ISF Aβ levels by almost 50% within hours, but had no effect on Aβ levels in 5HT
-R knock-out mice. The Aβ-lowering effects of Pimavanserin were blocked by extracellular-regulated kinase (ERK) and NMDA receptor inhibitors. Chronic administration of Pimavanserin by subcutaneous osmotic pump to aged APP/PS1 mice significantly reduced CSF Aβ levels and Aβ pathology and improved cognitive function in these mice. Pimavanserin is FDA-approved to treat Parkinson's disease psychosis, and also has been shown to reduce psychosis in a variety of other dementia subtypes including Alzheimer's disease. These data demonstrate that Pimavanserin may have disease-modifying benefits in addition to its efficacy against neuropsychiatric symptoms of Alzheimer's disease. Read the Editorial Highlight for this article on page 560.
Airborne transmission via virus-laden aerosols is a dominant route for the transmission of respiratory diseases, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Direct, ...non-invasive screening of respiratory virus aerosols in patients has been a long-standing technical challenge. Here, we introduce a point-of-care testing platform that directly detects SARS-CoV-2 aerosols in as little as two exhaled breaths of patients and provides results in under 60 s. It integrates a hand-held breath aerosol collector and a llama-derived, SARS-CoV-2 spike-protein specific nanobody bound to an ultrasensitive micro-immunoelectrode biosensor, which detects the oxidation of tyrosine amino acids present in SARS-CoV-2 viral particles. Laboratory and clinical trial results were within 20% of those obtained using standard testing methods. Importantly, the electrochemical biosensor directly detects the virus itself, as opposed to a surrogate or signature of the virus, and is sensitive to as little as 10 viral particles in a sample. Our platform holds the potential to be adapted for multiplexed detection of different respiratory viruses. It provides a rapid and non-invasive alternative to conventional viral diagnostics.
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