Amyloid-beta/Fyn–Induced Synaptic, Network, and Cognitive Impairments Depend on Tau Levels in Multiple Mouse Models of Alzheimer’s Disease

Alzheimer\u27s disease (AD), the most common neurodegenerative disorder, is a growing public health problem and still lacks effective treatments. Recent evidence suggests that microtubule-associated protein tau may mediate amyloid-β peptide (Aβ) toxicity by modulating the tyrosine kinase Fyn.Weshowed previously that tau reduction prevents, and Fyn overexpression exacerbates, cognitive deficits in human amyloid precursor protein (hAPP) transgenic mice overexpressing Aβ. However, the mechanisms by which Aβ, tau, and Fyn cooperate in AD-related pathogenesis remain to be fully elucidated. Here we examined the synaptic and network effects of this pathogenic triad. Tau reduction prevented cognitive decline induced by synergistic effects of Aβ and Fyn. Tau reduction also prevented synaptic transmission and plasticity deficits in hAPP mice. Using electroencephalography to examine network effects, we found that tau reduction prevented spontaneous epileptiform activity in multiple lines of hAPP mice. Tau reduction also reduced the severity of spontaneous and chemically induced seizures in mice overexpressing both Aβ and Fyn. To better understand these protective effects, we recorded wholecell currents in acute hippocampal slices from hAPP mice with and without tau. hAPP mice with tau had increased spontaneous and evoked excitatory currents, reduced inhibitory currents, and NMDA receptor dysfunction. Tau reduction increased inhibitory currents and normalized excitation/inhibition balance and NMDA receptor-mediated currents in hAPP mice. Our results indicate that Aβ, tau, and Fyn jointly impair synaptic and network function and suggest that disrupting the copathogenic relationship between these factors could be of therapeutic benefit

Proteome-wide characterization of signalling interactions in the hippocampal CA4/DG subfield of patients with Alzheimer’s disease

Alzheimer's disease (AD) is the most common form of dementia; however, mechanisms and biomarkers remain unclear. Here, we examined hippocampal CA4 and dentate gyrus subfields, which are less studied in the context of AD pathology, in post-mortem AD and control tissue to identify possible biomarkers. We performed mass spectrometry-based proteomic analysis combined with label-free quantification for identification of differentially expressed proteins. We identified 4,328 proteins, of which 113 showed more than 2-fold higher or lower expression in AD hippocampi than in control tissues. Five proteins were identified as putative AD biomarkers (MDH2, PCLO, TRRAP, YWHAZ, and MUC19 isoform 5) and were cross-validated by immunoblotting, selected reaction monitoring, and MALDI imaging. We also used a bioinformatics approach to examine upstream signalling interactions of the 113 regulated proteins. Five upstream signalling (IGF1, BDNF, ZAP70, MYC, and cyclosporin A) factors showed novel interactions in AD hippocampi. Taken together, these results demonstrate a novel platform that may provide new strategies for the early detection of AD and thus its diagnosis

Genetic suppression of transgenic APP rescues hypersynchronous network activity in a mouse model of alzeimer\u27s disease

Alzheimer's disease (AD) is associated with an elevated risk for seizures that may be fundamentally connected to cognitive dysfunction. Supporting this link, many mouse models for AD exhibit abnormal electroencephalogram (EEG) activity in addition to the expected neuropathology and cognitive deficits. Here, we used a controllable transgenic system to investigate how network changes develop and are maintained in a model characterized by amyloid β (Aβ) overproduction and progressive amyloid pathology. EEG recordings in tet-off mice overexpressing amyloid precursor protein (APP) from birth display frequent sharp wave discharges (SWDs). Unexpectedly, we found that withholding APP overexpression until adulthood substantially delayed the appearance of epileptiform activity. Together, these findings suggest that juvenile APP overexpression altered cortical development to favor synchronized firing. Regardless of the age at which EEG abnormalities appeared, the phenotype was dependent on continued APP overexpression and abated over several weeks once transgene expression was suppressed. Abnormal EEG discharges were independent of plaque load and could be extinguished without altering deposited amyloid. Selective reduction of Aβ with a γ-secretase inhibitor has no effect on the frequency of SWDs, indicating that another APP fragment or the full-length protein was likely responsible for maintaining EEG abnormalities. Moreover, transgene suppression normalized the ratio of excitatory to inhibitory innervation in the cortex, whereas secretase inhibition did not. Our results suggest that APP overexpression, and not Aβ overproduction, is responsible for EEG abnormalities in our transgenic mice and can be rescued independently of pathology

Monolithically Integratable Colliding Pulse Modelocked Laser Source for O-CDMA Photonic Chip Development

We demonstrate modelocking of a colliding-pulse mode-locked laser formed by 3-μm-deep etched-mirrors on an InP platform for integration with passive waveguide components. Timing jitter of 243 fs and pulse width of 10 ps were measured

Cost-effectiveness of CT perfusion for the detection of large vessel occlusion acute ischemic stroke followed by endovascular treatment:a model-based health economic evaluation study

Objectives:CT perfusion (CTP) has been suggested to increase the rate of large vessel occlusion (LVO) detection in patients suspected of acute ischemic stroke (AIS) if used in addition to a standard diagnostic imaging regime of CT angiography (CTA) and non-contrast CT (NCCT). The aim of this study was to estimate the costs and health effects of additional CTP for endovascular treatment (EVT)–eligible occlusion detection using model-based analyses. Methods: In this Dutch, nationwide retrospective cohort study with model-based health economic evaluation, data from 701 EVT-treated patients with available CTP results were included (January 2018–March 2022; trialregister.nl:NL7974). We compared a cohort undergoing NCCT, CTA, and CTP (NCCT + CTA + CTP) with a generated counterfactual where NCCT and CTA (NCCT + CTA) was used for LVO detection. The NCCT + CTA strategy was simulated using diagnostic accuracy values and EVT effects from the literature. A Markov model was used to simulate 10-year follow-up. We adopted a healthcare payer perspective for costs in euros and health gains in quality-adjusted life years (QALYs). The primary outcome was the net monetary benefit (NMB) at a willingness to pay of €80,000; secondary outcomes were the difference between LVO detection strategies in QALYs (ΔQALY) and costs (ΔCosts) per LVO patient. Results: We included 701 patients (median age: 72, IQR: [62–81]) years). Per LVO patient, CTP-based occlusion detection resulted in cost savings (ΔCosts median: € − 2671, IQR: [€ − 4721; € − 731]), a health gain (ΔQALY median: 0.073, IQR: [0.044; 0.104]), and a positive NMB (median: €8436, IQR: [5565; 11,876]) per LVO patient. Conclusion: CTP-based screening of suspected stroke patients for an endovascular treatment eligible large vessel occlusion was cost-effective. Clinical relevance statement.: Although CTP-based patient selection for endovascular treatment has been recently suggested to result in worse patient outcomes after ischemic stroke, an alternative CTP-based screening for endovascular treatable occlusions is cost-effective. Key Points: • Using CT perfusion to detect an endovascular treatment-eligible occlusions resulted in a health gain and cost savings during 10 years of follow-up. • Depending on the screening costs related to the number of patients needed to image with CT perfusion, cost savings could be considerable (median: € − 3857, IQR: [€ − 5907; € − 1916] per patient). • As the gain in quality adjusted life years was most affected by the sensitivity of CT perfusion-based occlusion detection, additional studies for the diagnostic accuracy of CT perfusion for occlusion detection are required.</p

Measurements of differential cross sections of Z/gamma*+jets+X events in proton anti-proton collisions at sqrt{s}=1.96 TeV

We present cross section measurements for Z/gamma*+jets+X production, differential in the transverse momenta of the three leading jets. The data sample was collected with the D0 detector at the Fermilab Tevatron proton anti-proton collider at a center-of-mass energy of 1.96 TeV and corresponds to an integrated luminosity of 1 fb-1. Leading and next-to-leading order perturbative QCD predictions are compared with the measurements, and agreement is found within the theoretical and experimental uncertainties. We also make comparisons with the predictions of four event generators. Two parton-shower-based generators show significant shape and normalization differences with respect to the data. In contrast, two generators combining tree-level matrix elements with a parton shower give a reasonable description of the the shapes observed in data, but the predicted normalizations show significant differences with respect to the data, reflecting large scale uncertainties. For specific choices of scales, the normalizations for either generator can be made to agree with the measurements.Comment: Published in PLB. 11 pages, 3 figure

Measurement of the t-channel single top quark production cross section

The D0 collaboration reports direct evidence for electroweak production of single top quarks through the t-channel exchange of a virtual W boson. This is the first analysis to isolate an individual single top quark production channel. We select events containing an isolated electron or muon, missing transverse energy, and two, three or four jets from 2.3 fb^-1 of ppbar collisions at the Fermilab Tevatron Collider. One or two of the jets are identified as containing a b hadron. We combine three multivariate techniques optimized for the t-channel process to measure the t- and s-channel cross sections simultaneously. We measure cross sections of 3.14 +0.94 -0.80 pb for the t-channel and 1.05 +-0.81 pb for the s-channel. The measured t-channel result is found to have a significance of 4.8 standard deviations and is consistent with the standard model prediction.Comment: 7 pages, 6 figure

Search for right-handed W bosons in top quark decay

We present a measurement of the fraction f+ of right-handed W bosons produced in top quark decays, based on a candidate sample of $t\bar{t}$ events in the lepton+jets decay mode. These data correspond to an integrated luminosity of 230pb^-1, collected by the DO detector at the Fermilab Tevatron $p\bar{p}$ Collider at sqrt(s)=1.96 TeV. We use a constrained fit to reconstruct the kinematics of the $t\bar{t}$ and decay products, which allows for the measurement of the leptonic decay angle $\theta^*$ for each event. By comparing the $\cos\theta^*$ distribution from the data with those for the expected background and signal for various values of f+, we find f+=0.00+-0.13(stat)+-0.07(syst). This measurement is consistent with the standard model prediction of f+=3.6x10^-4.Comment: Submitted to Physical Review D Rapid Communications 7 pages, 3 figure

Measurement of the W boson mass

We present a measurement of the W boson mass in W -> ev decays using 1 fb^-1 of data collected with the D0 detector during Run II of the Fermilab Tevatron collider. With a sample of 499830 W -> ev candidate events, we measure M_W = 80.401 +- 0.043 GeV. This is the most precise measurement from a single experiment.Comment: As published in PR

Measurement of trilinear gauge boson couplings from WW + WZ to lnu jj events in pp-bar collisions at sqrt{s}=1.96 TeV

We present a direct measurement of trilinear gauge boson couplings at gammaWW and ZWW vertices in WW and WZ events produced in pp-bar collisions at sqrt{s}=1.96 TeV. We consider events with one electron or muon, missing transverse energy, and at least two jets. The data were collected using the D0 detector and correspond to 1.1/fb of integrated luminosity. Considering two different relations between the couplings at the gammaWW and ZWW vertices, we measure these couplings at 68% C.L. to be kappa_{gamma}=1.07^{+0.26}_{-0.29}, lambda =0.00^{+0.06}_{-0.06} and g_{1}^{Z}=1.04^{+0.09}_{-0.09} in a scenario respecting SU(2)_L x U(1)_Y gauge symmetry and kappa =1.04^{+0.11}_{-0.11} and lambda=0.00^{+0.06}_{-0.06} in an "equal couplings" scenario.Comment: 14 pages, 7 figures, published in Phys. Rev. D, updated to published versio