Altering Brain Amyloidosis by Intra-Lingual and Extra-Nasal Exposure of Aß Aggregates.

Extensive experimental and human-derived evidence suggest that misfolded Aß particles spread similarly to infectious prions. Moreover, peripheral administration of Aß seeds accelerates brain amyloidosis in both susceptible experimental animals and humans. The mechanisms and elements governing the transport of misfolded Aß from the periphery to the brain are not fully understood, although circulation and retrograde axonal transport have been proposed. Here, we demonstrate that injection of Aß seeds in the tongue, a highly innervated organ, substantially accelerates the appearance of plaques in Tg2576 mice. In addition, the extra-nasal exposure of Aß aggregates increased amyloid pathology in the olfactory bulb. Our results show that exposing highly innervated tissues to Aß seeds accelerates AD-like pathological features, and suggest that Aß seeds can be transported from peripheral compartments to the brain by retrograde axonal transport. Research in this direction may be relevant on different fronts, including disease mechanisms, diagnosis, and risk-evaluation of potential iatrogenic transmission of Aß misfolding.

Amyloid pathology arrangements in Alzheimer's disease brains modulate in vivo seeding capability.

Amyloid-ß (Aß) misfolding is one of the hallmark pathological features of Alzheimer's disease (AD). AD can manifest with diverse symptomatology including variable rates of cognitive decline, duration of clinical disease, and other detrimental changes. Several reports suggest that conformational diversity in misfolded Aß is a leading factor for clinical variability in AD, analogous to what it has been described for prion strains in prion diseases. Notably, prion strains generate diverse patterns of misfolded protein deposition in the brains of affected individuals. Here, we tested the in vivo prion-like transmission features of four AD brains displaying particular patterns of amyloidosis. AD brains induced different phenotypes in recipient mice, as evaluated by their specific seeding activity, as well as the total amount of Aß deposited surrounding vascular structures and the reactivity of amyloid pathology to thioflavin S. Our results support the notion that AD-subtypes are encoded in disease-associated Aß. Further research exploring whether AD include a spectrum of different clinical conditions or syndromes may pave the way to personalized diagnosis and treatments.

Cotinine Enhances Fear Extinction and Astrocyte Survival by Mechanisms Involving the Nicotinic Acetylcholine Receptors Signaling.

Fear memory extinction (FE) is an important therapeutic goal for Posttraumatic stress disorder (PTSD). Cotinine facilitates FE in rodents, in part due to its inhibitory effect on the amygdala by the glutamatergic projections from the medial prefrontal cortex (mPFC). The cellular and behavioral effects of infusing cotinine into the mPFC on FE, astroglia survival, and the expression of bone morphogenetic proteins (BMP) 2 and 8, were assessed in C57BL/6 conditioned male mice. The role of the α4ß2- and α7 nicotinic acetylcholine receptors (nAChRs) on cotinine's actions were also investigated. Cotinine infused into the mPFC enhanced contextual FE and decreased BMP8 expression by a mechanism dependent on the α7nAChRs. In addition, cotinine increased BMP2 expression and prevented the loss of GFAP + astrocytes in a form independent on the α7nAChRs but dependent on the α4ß2 nAChRs. This evidence suggests that cotinine exerts its effect on FE by modulating nAChRs signaling in the brain.

Correction to: Intranasal Cotinine Plus Krill Oil Facilitates Fear Extinction, Decreases Depressive-Like Behavior, and Increases Hippocampal Calcineurin A Levels in Mice.

The original version of this article unfortunately contained mistake in its Funding inforation.

Intranasal Cotinine Plus Krill Oil Facilitates Fear Extinction, Decreases Depressive-Like Behavior, and Increases Hippocampal Calcineurin A Levels in Mice.

Failure in fear extinction is one of the more troublesome characteristics of posttraumatic stress disorder (PTSD). Cotinine facilitates fear memory extinction and reduces depressive-like behavior when administered 24 h after fear conditioning in mice. In this study, it was investigated the behavioral and molecular effects of cotinine, and other antidepressant preparations infused intranasally. Intranasal (IN) cotinine, IN krill oil, IN cotinine plus krill oil, and oral sertraline were evaluated on depressive-like behavior and fear retention and extinction after fear conditioning in C57BL/6 mice. Since calcineurin A has been involved in facilitating fear extinction in rodents, we also investigated changes of calcineurin in the hippocampus, a region key on contextual fear extinction. Short-term treatment with cotinine formulations was superior to krill oil and oral sertraline in reducing depressive-like behavior and fear consolidation and enhancing contextual fear memory extinction in mice. IN krill oil slowed the extinction of fear. IN cotinine preparations increased the levels of calcineurin A in the hippocampus of conditioned mice. In the light of the results, the future investigation of the use of IN cotinine preparations for the extinction of contextual fear memory and treatment of treatment-resistant depression (TRD) in PTSD is discussed.

Cotinine Plus Krill Oil Decreased Depressive Behavior, and Increased Astrocytes Survival in the Hippocampus of Mice Subjected to Restraint Stress.

Restraint stress (RS) is a condition affecting millions of people worldwide. The investigation of new therapies to alleviate the consequences of prolonged RS is much needed. Cotinine, a nicotine-derivative, has shown to prevent the decrease in cerebral synaptic density, working memory deficits, anxiety, and depressive-like behavior after prolonged restraint stress (RS) in mice. Furthermore, post-treatment with cotinine reduced the adverse effects of chronic RS on astrocyte survival and architecture. On the other hand, the nutritional supplement krill oil (KO), has shown to be beneficial in decreasing depressive-like behavior and oxidative stress. In this study, in the search for effective preventative treatments to be used in people subjected to reduced mobility, the effect of co-treatment with cotinine plus KO in mice subjected to prolonged RS was investigated. The results show that cotinine plus KO prevented the loss of astrocytes, the appearance of depressive-like behavior and cognitive impairment induced by RS. The use of the combination of cotinine plus KO was more effective than cotinine alone in preventing the depressive-like behavior in the restrained mice. The potential use of this combination to alleviate the psychological effects of reduced mobility is discussed.

Intranasal cotinine improves memory, and reduces depressive-like behavior, and GFAP+ cells loss induced by restraint stress in mice.

Posttraumatic stress disorder (PTSD), chronic psychological stress, and major depressive disorder have been found to be associated with a significant decrease in glial fibrillary acidic protein (GFAP) immunoreactivity in the hippocampus of rodents. Cotinine is an alkaloid that prevents memory impairment, depressive-like behavior and synaptic loss when co-administered during restraint stress, a model of PTSD and stress-induced depression, in mice. Here, we investigated the effects of post-treatment with intranasal cotinine on depressive- and anxiety-like behaviors, visual recognition memory as well as the number and morphology of GFAP+ immunoreactive cells, in the hippocampus and frontal cortex of mice subjected to prolonged restraint stress. The results revealed that in addition to the mood and cognitive impairments, restraint stress induced a significant decrease in the number and arborization of GFAP+ cells in the brain of mice. Intranasal cotinine prevented these stress-derived symptoms and the morphological abnormalities GFAP+ cells in both of these brain regions which are critical to resilience to stress. The significance of these findings for the therapy of PTSD and depression is discussed.