Neuroligin-1 Is Altered in the Hippocampus of Alzheimer\u27s Disease Patients and Mouse Models, and Modulates the Toxicity of Amyloid-Beta Oligomers

Synapse loss occurs early and correlates with cognitive decline in Alzheimer’s disease (AD). Synaptotoxicity is driven, at least in part, by amyloid-beta oligomers (Aβo), but the exact synaptic components targeted by Aβo remain to be identified. We here tested the hypotheses that the post-synaptic protein Neuroligin-1 (NLGN1) is affected early in the process of neurodegeneration in the hippocampus, and specifically by Aβo, and that it can modulate Aβo toxicity. We found that hippocampal NLGN1 was decreased in patients with AD in comparison to patients with mild cognitive impairment and control subjects. Female 3xTg-AD mice also showed a decreased NLGN1 level in the hippocampus at an early age (i.e., 4 months). We observed that chronic hippocampal Aβo injections initially increased the expression of one specific Nlgn1 transcript, which was followed by a clear decrease. Lastly, the absence of NLGN1 decreased neuronal counts in the dentate gyrus, which was not the case in wild-type animals, and worsens impairment in spatial learning following chronic hippocampal Aβo injections. Our findings support that NLGN1 is impacted early during neurodegenerative processes, and that Aβo contributes to this effect. Moreover, our results suggest that the presence of NLGN1 favors the cognitive prognosis during Aβo-driven neurodegeneration

Cognitive Deficits Following a Post-Myocardial Infarct in the Rat Are Blocked by the Serotonin-Norepinephrine Reuptake Inhibitor Desvenlafaxine

Myocardial infarction (MI) in animal models induces cognitive deficits as well as the activation of caspase in the limbic system; both can be blocked by 2 weeks of treatment following MI using tricyclic antidepressants or selective serotonin uptake blockers. Here we used three different treatment schedules to test the short- and long-term effects of the combined serotonin-norepinephrine reuptake inhibitor desvenlafaxine on post-MI-associated cognitive deficits and caspase activation. MI was induced in 39 young adult rats, and 39 rats served as sham-operated controls. Desvenlafaxine (3 mg/kg/day, i.p.) or saline was administered according to one of three schedules: (1) for 2 weeks, starting right after surgery; (2) for 16 weeks, starting 2 weeks after surgery; (3) for 16 weeks, starting right after surgery. Behavior was tested 2 weeks (social interaction, passive avoidance) and 16 weeks (forced swimming, Morris water maze) after surgery. Caspase-3 and caspase-6 activities were measured 16 weeks after surgery. At 2 and 16 weeks post-surgery, saline-treated MI rats displayed performance deficits compared to desvenlafaxine-treated rats, regardless of the treatment schedule. Caspase-3 activity was higher in the amygdala (medial and lateral) and hippocampal CA3 region in untreated MI rats, whereas caspase-6 activity was higher in the CA1 region. Caspase-6 activity correlated positively with deficits in the Morris water maze. These results indicate that, independently of treatment schedules, various treatment schedules with desvenlafaxine can prevent MI-associated cognitive deficits and decrease caspase activities in the limbic system

Neurotoxicity and Memory Deficits Induced by Soluble Low-Molecular-Weight Amyloid-β1-42 Oligomers Are Revealed In Vivo by Using a Novel Animal Model

Neuronal and synaptic degeneration are the best pathological correlates for memory decline in Alzheimer's disease (AD). Although the accumulation of soluble low-molecular-weight amyloid-β (Aβ) oligomers has been suggested to trigger neurodegeneration in AD, animal models overexpressing or infused with Aβ lack neuronal loss at the onset of memory deficits. Using a novel in vivo approach, we found that repeated hippocampal injections of small soluble Aβ(1-42) oligomers in awake, freely moving mice were able to induce marked neuronal loss, tau hyperphosphorylation, and deficits in hippocampus-dependent memory. The neurotoxicity of small Aβ(1-42) species was observed in vivo as well as in vitro in association with increased caspase-3 activity and reduced levels of the NMDA receptor subunit NR2B. We found that the sequestering agent transthyretin is able to bind the toxic Aβ(1-42) species and attenuated the loss of neurons and memory deficits. Our novel mouse model provides evidence that small, soluble Aβ(1-42) oligomers are able to induce extensive neuronal loss in vivo and initiate a cascade of events that mimic the key neuropathological hallmarks of AD.status: publishe

Tau hyperphosphorylation induced by the anesthetic agent ketamine/xylazine involved the calmodulin‐dependent protein kinase II

International audienceTau hyperphosphorylation is a major neuropathological hallmark of many neurodegenerative disorders such as Alzheimer's disease. Several anesthetics have been shown previously to induced marked tau hyperphosphorylation. Although the ketamine/xylazine mixture is one of the most commonly used anesthetic agents in animal research and veterinary practice, the effect of this anesthetic agent on tau phosphorylation still remains to be determined. Here, we found that ketamine-/xylazine-induced a rapid and robust hyperphosphorylation of tau in a dose-dependent manner under normothermic and hypothermic conditions in mice. When used together, ketamine and xylazine exerted a synergistic action on tau phosphorylation most strongly not only on epitopes S396 and S262, but also on other residues (T181, and S202/T205). We observed that activation of the calmodulin-dependent protein kinase II (CaMKII) is the major upstream molecular event leading to tau hyperphosphorylation following ketamine/xylazine anesthesia in mice. Moreover, we observed that intracerebroventricular injection of the selective CaMKII inhibitor KN93 attenuated tau hyperphosphorylation. Since ketamine/xylazine also had a marked impact on other key molecular signaling pathways involving the MAP/microtubule affinity-regulating kinase (MARK), extracellular signal-regulated kinase (ERK), and glycogen synthase kinase-3 (GSK3), our study calls for high caution and careful monitoring when using this anesthetic agent in laboratory animal settings across all fields of biological sciences in order to avoid artifactual results

Des textes dans l'espace public = Words in Public Space

"This graphically unique monograph examines the presence of literary art in public space and the relationship between words and places. Artists, critics, and historians share their perspectives on art works and practices that demonstrate an exceptional use of the written word. It is the first publication devoted explicitly to this original form of art, which has an undeniable influence on our rapport with space and the city." -- Publisher's website

Additional file 1 of Hippocampal injections of soluble amyloid-beta oligomers alter electroencephalographic activity during wake and slow-wave sleep in rats

Additional file 1: Table S1. Results of t-tests comparing BL and INJ for the activity of each frequency band for the central and frontal electrodes in Aβscr et Aβo groups. Table S2. Results of one-way ANOVAs comparing BL, D2 and D5 for the activity of each frequency band for the central and frontal electrodes in Aβscr et Aβo groups. Fig. S1. Additional variables related to sleep architecture for Aβscr- and Aβo-injected rats. A Percent time spent in wake, SWS and PS during the 12 h light (upper panel) and 12 h dark (lower panel) periods of BL and INJ days in Aβscr and Aβo groups. B Number of 4-s episodes of wakefulness and SWS. C Number of 8- and 16-min episodes of wake, and of 60-s episodes of SWS and PS in Aβscr and Aβo groups during BL and INJ. Aβscr n = 11, and Aβo n = 9. Fig. S2. Additional data concerning wake, SWS and PS spectral activity during BL and INJ in Aβo and Aβscr rats. A Spectral activity for each frequency band for the central and frontal electrodes. SWA: 0.5–5 Hz; theta: 5–9 Hz; alpha: 9–12 Hz; sigma: 12–16 Hz; beta1: 16–20 Hz; beta2: 20–30 Hz; gamma: 30–55 Hz. B Ratio of theta activity on gamma activity for the central (Aβo and Aβscr rats) and frontal (Aβscr rats) electrodes. C Ratio of theta activity on SWA for the central (Aβo and Aβscr rats) and frontal (Aβscr rats) electrodes. Aβscr n = 9, and Aβo n = 6. Fig. S3. Wake, SWS and PS spectral activity for each frequency band for the central and frontal electrodes at BL and at D2 and D5 in Aβscr-injected rats (n = 8). SWA: 0.5–5 Hz; theta: 5–9 Hz; alpha: 9–12 Hz; sigma: 12–16 Hz; beta1: 16–20 Hz; beta2: 20–30 Hz; gamma: 30–55 Hz

The Tyrosine Phosphatase STEP Is Involved in Age-Related Memory Decline

International audienc