RAGE Inhibition in Microglia Prevents Ischemia-Dependent Synaptic Dysfunction in an Amyloid-Enriched Environment

This is the published version. Copyright 2014 Origlia et. al.Ischemia is known to increase the deleterious effect of β-amyloid (Aβ), contributing to early cognitive impairment in Alzheimer's disease. Here, we investigated whether transient ischemia may function as a trigger for Aβ-dependent synaptic impairment in the entorhinal cortex (EC), acting through specific cellular signaling. We found that synaptic depression induced by oxygen glucose deprivation (OGD) was enhanced in EC slices either in presence of synthetic oligomeric Aβ or in slices from mutant human amyloid precursor protein transgenic mice (mhAPP J20). OGD-induced synaptic depression was ameliorated by functional suppression of RAGE. In particular, overexpression of the dominant-negative form of RAGE targeted to microglia (DNMSR) protects against OGD-induced synaptic impairment in an amyloid-enriched environment, reducing the activation of stress-related kinases (p38MAPK and JNK) and the release of IL-1β. Our results demonstrate a prominent role for the RAGE-dependent neuroinflammatory pathway in the synaptic failure induced by Aβ and triggered by transient ischemia

Visual acuity is reduced in alpha 7 nicotinic receptor knockout mice.

PURPOSE Nicotinic receptors (nAChRs) are part of a heterogeneous family of pentameric ligand-gated ion channels that are widely expressed in the visual system. The impact of α7 homomeric nAChRs on visual function was investigated using mutant mice lacking the α7 nicotinic receptor subunit. METHODS The spatial resolution limit was measured in α7 knockout (α7 KO) and age-matched control mice using three independent methods: an operant behavioral visual task (Prusky maze), cortical visual evoked potentials (VEPs), and the pattern electroretinogram (PERG) evoked by alternating gratings of different spatial frequencies and contrasts. RESULTS Visual acuity measured by means of the visual water maze task was significantly decreased in the α7 KO mice and, concordantly, there was a reduction of the cortical spatial resolution limit measured by VEPs. However, the PERG was normal in α7 KO mice, compared with control mice. The use of fluorescently tagged cholera toxin showed that projections from the retina segregate normally in α7 KO mice and, in line with this, the visual cortical responses elicited by stimulating either eye were normally balanced in both visual cortices and showed no retinotopic anomalies. CONCLUSIONS These findings indicate that the absence of the α7 nicotinic subunit reduces visual acuity. Because the cortical output has an abnormal spatial resolution but retinal output is preserved, it can be concluded that the low visual acuity was due to a deficit specifically present in the visual cortex

Involvement of p38 MAPK in Synaptic Function and Dysfunction

Many studies have revealed a central role of p38 MAPK in neuronal plasticity and the regulation of long-term changes in synaptic efficacy, such as long-term potentiation (LTP) and long-term depression (LTD). However, p38 MAPK is classically known as a responsive element to stress stimuli, including neuroinflammation. Specific to the pathophysiology of Alzheimer's disease (AD), several studies have shown that the p38 MAPK cascade is activated either in response to the Aβ peptide or in the presence of tauopathies. Here, we describe the role of p38 MAPK in the regulation of synaptic plasticity and its implication in an animal model of neurodegeneration. In particular, recent evidence suggests the p38 MAPK α isoform as a potential neurotherapeutic target, and specific inhibitors have been developed and have proven to be effective in ameliorating synaptic and memory deficits in AD mouse models

Aβ-Dependent Inhibition of LTP in Different Intracortical Circuits of the Visual Cortex: The Role of RAGE

This is the publisher's version, also available electronically from http://iospress.metapress.com/content/u12738257q258710/?issue=1&genre=article&spage=59&issn=1387-2877&volume=17Oligomeric amyloid-β (Aβ) interferes with long term potentiation (LTP) and cognitive processes, suggesting that Aβ peptides may play a role in the neuronal dysfunction which characterizes the early stages of Alzheimer's disease (AD). Multiple lines of evidence have highlighted RAGE (receptor for advanced glycation end-products) as a receptor involved in Aβ-induced neuronal and synaptic dysfunction. In the present study, we investigated the effect of oligomeric soluble Aβ_{1-42} on LTP elicited by the stimulation of different intracortical pathways in the mouse visual cortex. A variety of nanomolar concentrations (20–200 nM) of Aβ_{1-42} were able to inhibit LTP in cortical layer II-III induced by either white matter (WM-Layer II/III) or the layer II/III (horizontal pathway) stimulation, whereas the inhibition of LTP was more susceptible to Aβ_{1-42}, which occurred at 20 nM of Aβ, when stimulating layer II-III horizontal pathway. Remarkably, cortical slices were resistant to nanomolar Aβ_{1-42} in the absence of RAGE (genetic deletion of RAGE) or blocking RAGE by RAGE antibody. These results indicate that nanomolar Aβ inhibits LTP expression in different neocortical circuits. Crucially, it is demonstrated that Aβ-induced reduction of LTP in different cortical pathways is mediated by RAGE

Microglial Receptor for Advanced Glycation End Product-Dependent Signal Pathway Drives β-Amyloid-Induced Synaptic Depression and Long-Term Depression Impairment in Entorhinal Cortex

This is the publisher's version, also available electronically from http://www.jneurosci.org/content/30/34/11414Overproduction of β-amyloid (Aβ) is a pathologic feature of Alzheimer's disease, leading to cognitive impairment. Here, we investigated the impact of cell-specific receptor for advanced glycation end products (RAGE) on Aβ-induced entorhinal cortex (EC) synaptic dysfunction. We found both a transient depression of basal synaptic transmission and inhibition of long-term depression (LTD) after the application of Aβ in EC slices. Synaptic depression and LTD impairment induced by Aβ were rescued by functional suppression of RAGE. Remarkably, the rescue was only observed in slices from mice expressing a defective form of RAGE targeted to microglia, but not in slices from mice expressing defective RAGE targeted to neurons. Moreover, we found that the inflammatory cytokine IL-1β (interleukin-1β) and stress-activated kinases [p38 MAPK (p38 mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase)] were significantly altered and involved in RAGE signaling pathways depending on RAGE expression in neuron or microglia. These findings suggest a prominent role of microglial RAGE signaling in Aβ-induced EC synaptic dysfunction

Treatment with 1,25-dihydroxyvitamin D3 preserves glomerular slit diaphragm-associated protein expression in experimental glomerulonephritis

In this study, we investigated the effect of 1,25(OH)2D3on proteinuria and on the alteration of slit diaphragm-associated proteins induced by anti-Thy 1.1 in Wistar rats. Four groups of animals were studied: group I, anti-Thy 1.1 treated rats; group II, anti-Thy1.1 treated group that at day 2, after the onset of overt proteinuria, started the treatment with 1,25(OH)2D3; group III, normal control rats injected with vehicle alone; group IV, rats that received only 1,25(OH)2D3. At day 2, in group I and II, before the administration of 1,25(OH)2D3, protein excretion was significantly increased when compared to controls. Overt proteinuria was maintained until day 14 in group I whereas in group II protein excretion was significantly reduced from day 3 to day 14. Moreover, treatment with 1,25(OH)2D3abrogated podocytes injury, detected as desmin expression and loss of nephrin and zonula occludens-1 (ZO-1), two slit diaphragm-associated proteins, and glomerular polyanion staining, that were observed in group I. In conclusion, these results suggest that 1,25(OH)2D3administrated with a therapeutic regiment may revert proteinuria, counteracting glomerular podocyte injury

Conjunctivally Applied BDNF Protects Photoreceptors from Light-Induced Damage

Purpose: To test whether the topical eye treatment with BDNF prevents the effects of continuous light exposure (LE) in the albino rat retina. Methods: Two groups of albino rats were used. The first group of rats received an intraocular injection of BDNF (2 lL, 1 lg/lL) before LE, while the second group was treated with one single drop of BDNF (10 lL, 12 lg/lL) dissolved in different types of solutions (physiological solution, the polysaccharide fraction of Tamarind gum, TSP, and sodium carboxy methyl cellulose), at the level of conjunctival fornix before LE. The level of BDNF in the retina and optic nerve was determined by enzyme-linked immunosorbent assay. We recorded the flash electroretinogram (fERG) in dark adapted rats 1 week after LE. At the end of the recording session, the retinas were removed and labeled so that the number of photoreceptors nuclear rows and thickness of the outer nuclear layer was analyzed. Results: Intravitreal injection of BDNF before LE prevented fERG impairment. Different ophthalmic preparations were used for topical eye application; the TSP resulted the most suitable vehicle to increase BDNF level in the retina and optic nerve. Topical eye application with BDNF/TSP before LE partially preserved both fERG response and photoreceptors. Conclusions: Topical eye treatment with BDNF represents a suitable, noninvasive tool to increase the retinal content of BDNF up to a level capable of exerting neuroprotection toward photoreceptors injured by prolonged LE. Translational Relevance: A collyrium containing BDNF may serve as an effective, clinically translational treatment against retinal degeneration

Visual acuity is reduced in lpha 7 nicotinic receptor knockout mice

PURPOSE. Nicotinic receptors (nAChRs) are part of a heterogeneous family of pentameric ligand-gated ion channels that are widely expressed in the visual system. The impact of ␣7 homomeric nAChRs on visual function was investigated using mutant mice lacking the ␣7 nicotinic receptor subunit. METHODS. The spatial resolution limit was measured in ␣7 knockout (␣7 KO) and age-matched control mice using three independent methods: an operant behavioral visual task (Prusky maze), cortical visual evoked potentials (VEPs), and the pattern electroretinogram (PERG) evoked by alternating gratings of different spatial frequencies and contrasts. RESULTS. Visual acuity measured by means of the visual water maze task was significantly decreased in the ␣7 KO mice and, concordantly, there was a reduction of the cortical spatial resolution limit measured by VEPs. However, the PERG was normal in ␣7 KO mice, compared with control mice. The use of fluorescently tagged cholera toxin showed that projections from the retina segregate normally in ␣7 KO mice and, in line with this, the visual cortical responses elicited by stimulating either eye were normally balanced in both visual cortices and showed no retinotopic anomalies. CONCLUSIONS. These findings indicate that the absence of the ␣7 nicotinic subunit reduces visual acuity. Because the cortical output has an abnormal spatial resolution but retinal output is preserved, it can be concluded that the low visual acuity was due to a deficit specifically present in the visual cortex. (Invest Ophthalmol Vis Sci. 2012;53:1211-1218) DOI:10.1167/iovs.11-8007 N icotinic receptors (nAChRs) represent a heterogeneous family of ion channels that are differently expressed in the nervous system. There are 12 subunit genes that derive from a common ancestral gene: 9 ␣ subunits (␣2 to ␣10) and 4 ␤ subunits (␤2 to ␤4). Neuronal nAChRs fall into two main classes: homomeric or heteromeric ␣-bungarotoxin (␣Bgtx)-sensitive receptors consisting of ␣7, ␣8, or ␣7-␣8 and/or ␣10 subunits and ␣Bgtx-insensitive heteromeric receptors consisting of ␣2-␣6 and ␤2-␤4 subunits. Nicotinic AChRs are permeable to Na ϩ , K ϩ , and Ca 2ϩ ions, and their cation permeability is influenced by their subunit composition. The ␣7 subunit that forms native pentameric homomeric receptors is highly expressed in the hippocampus, hypothalamus, and neocortex of rodents. 1 Alpha-7 knockout (KO) mice, which are characterized by the loss of ␣Bgtx receptors and the lack of nicotineevoked fast desensitizing currents in neurons, 2 are viable with apparently normal brain anatomy. In terms of behavior, the performance of ␣7 KO mice in the classic Morris water maze test, the Pavlovian conditioned fear test and the prepulse inhibition paradigm are similar to those of wild-type (WT) mice, which suggests that the absence of ␣7 nAChRs has little impact on normal, baseline behavioral responses. 3 Moreover, ␣7 KO mice show a reduced anxietyrelated response, 3 whereas only mice lacking both the ␣7 and the ␤2 nAChR subunits show impaired learning and memory in a passive avoidance test, and enhanced motor activity on the rota rod. 6 Although ␣7 KO mice are widely used in behavioral studies, no attempt has been made to characterize their visual function. The ␣7 subunit is widely expressed in the visual system, particularly in the retina and retinal input recipient regions such as the dorsolateral geniculate nucleus (dLGN), the superior colliculus, and the visual cortex

Microglial extracellular vesicles induce Alzheimer’s diseaserelated cortico-hippocampal network dysfunction.

β-Amyloid is one of the main pathological hallmarks of Alzheimer’s disease and plays a major role in synaptic dysfunction. It has been demonstrated that β-amyloid can elicit aberrant excitatory activity in cortical-hippocampal networks, which is associated with behavioural abnormalities. However, the mechanism of the spreading of β-amyloid action within a specific circuitry has not been elucidated yet. We have previously demonstrated that the motion of microglia-derived large extracellular vesicles carrying β-amyloid, at the neuronal surface, is crucial for the initiation and propagation of synaptic dysfunction along the entorhinal–hippocampal circuit. Here, using chronic EEG recordings, we show that a single injection of extracellular vesicles carrying β-amyloid into the mouse entorhinal cortex could trigger alterations in the cortical and hippocampal activity that are reminiscent of those found in Alzheimer’s disease mouse models and human patients. The development of EEG abnormalities was associated with progressive memory impairment as assessed by an associative (object-place context recognition) and non-associative (object recognition) task. Importantly, when the motility of extracellular vesicles, carrying β-amyloid, was inhibited, the effect on network stability and memory function was significantly reduced. Our model proposes a new biological mechanism based on the extracellular vesicles–mediated progression of β-amyloid pathology and offers the opportunity to test pharmacological treatments targeting the early stages of Alzheimer’s disease