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      Anandamide Effects in a Streptozotocin-Induced Alzheimer’s Disease-Like Sporadic Dementia in Rats

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          Abstract

          Alzheimer’s disease (AD) is characterized by multiple cognitive deficits including memory and sensorimotor gating impairments as a result of neuronal and synaptic loss. The endocannabinoid system plays an important role in these deficits but little is known about its influence on the molecular mechanism regarding phosphorylated tau (p-tau) protein accumulation – one of the hallmarks of AD –, and on the density of synaptic proteins. Thus, the aim of this study was to investigate the preventive effects of anandamide ( N-arachidonoylethanolamine, AEA) on multiple cognitive deficits and on the levels of synaptic proteins (syntaxin 1, synaptophysin and synaptosomal-associated protein, SNAP-25), cannabinoid receptor type 1 (CB 1) and molecules related to p-tau degradation machinery (heat shock protein 70, HSP70), and Bcl2-associated athanogene (BAG2) in an AD-like sporadic dementia model in rats using intracerebroventricular (icv) injection of streptozotocin (STZ). Our hypothesis is that AEA could interact with HSP70, modulating the level of p-tau and synaptic proteins, preventing STZ-induced cognitive impairments. Thirty days after receiving bilateral icv injections of AEA or STZ or both, the cognitive performance of adult male Wistar rats was evaluated in the object recognition test, by the escape latency in the elevated plus maze (EPM), by the tone and context fear conditioning as well as in prepulse inhibition tests. Subsequently, the animals were euthanized and their brains were removed for histological analysis or for protein quantification by Western Blotting. The behavioral results showed that STZ impaired recognition, plus maze and tone fear memories but did not affect contextual fear memory and prepulse inhibition. Moreover, AEA prevented recognition and non-associative emotional memory impairments induced by STZ, but did not influence tone fear conditioning. STZ increased the brain ventricular area and this enlargement was prevented by AEA. Additionally, STZ reduced the levels of p-tau (Ser199/202) and increased p-tau (Ser396), although AEA did not affect these alterations. HSP70 was found diminished only by STZ, while BAG2 levels were decreased by STZ and AEA. Synaptophysin, syntaxin and CB 1 receptor levels were reduced by STZ, but only syntaxin was recovered by AEA. Altogether, albeit AEA failed to modify some AD-like neurochemical alterations, it partially prevented STZ-induced cognitive impairments, changes in synaptic markers and ventricle enlargement. This study showed, for the first time, that the administration of an endocannabinoid can prevent AD-like effects induced by STZ, boosting further investigations about the modulation of endocannabinoid levels as a therapeutic approach for AD.

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          Most cited references80

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          CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation.

          Molecular chaperones, ubiquitin ligases and proteasome impairment have been implicated in several neurodegenerative diseases, including Alzheimer's and Parkinson's disease, which are characterized by accumulation of abnormal protein aggregates (e.g. tau and alpha-synuclein respectively). Here we report that CHIP, an ubiquitin ligase that interacts directly with Hsp70/90, induces ubiquitination of the microtubule associated protein, tau. CHIP also increases tau aggregation. Consistent with this observation, diverse of tau lesions in human postmortem tissue were found to be immunopositive for CHIP. Conversely, induction of Hsp70 through treatment with either geldanamycin or heat shock factor 1 leads to a decrease in tau steady-state levels and a selective reduction in detergent insoluble tau. Furthermore, 30-month-old mice overexpressing inducible Hsp70 show a significant reduction in tau levels. Together these data demonstrate that the Hsp70/CHIP chaperone system plays an important role in the regulation of tau turnover and the selective elimination of abnormal tau species. Hsp70/CHIP may therefore play an important role in the pathogenesis of tauopathies and also represents a potential therapeutic target.
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            Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease

            Summary Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions 1 . Memory decline in early stages of Alzheimer’s is mostly limited to episodic memory, for which the hippocampus (HPC) plays a crucial role 2 . However, it has been uncertain whether the observed amnesia in early stages of Alzheimer’s is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early Alzheimer’s, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are utilized, revealing a retrieval, rather than a storage impairment. Prior to amyloid plaque deposition, the amnesia in these mice is age-dependent 3–5 , which correlates with a progressive reduction of spine density of hippocampal dentate gyrus (DG) engram cells. We show that optogenetic induction of long-term potentiation (LTP) at perforant path (PP) synapses of DG engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of DG engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in early stages of Alzheimer’s disease.
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              Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer's disease.

              Microglial activation is an invariant feature of Alzheimer's disease (AD). It is noteworthy that cannabinoids are neuroprotective by preventing β-amyloid (Aβ)-induced microglial activation both in vitro and in vivo. On the other hand, the phytocannabinoid cannabidiol (CBD) has shown anti-inflammatory properties in different paradigms. In the present study, we compared the effects of CBD with those of other cannabinoids on microglial cell functions in vitro and on learning behavior and cytokine expression after Aβ intraventricular administration to mice. CBD, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone [WIN 55,212-2 (WIN)], a mixed CB(1)/CB(2) agonist, and 1,1-dimethylbutyl-1-deoxy-Δ(9)-tetrahydrocannabinol [JWH-133 (JWH)], a CB(2)-selective agonist, concentration-dependently decreased ATP-induced (400 μM) increase in intracellular calcium ([Ca(2+)](i)) in cultured N13 microglial cells and in rat primary microglia. In contrast, 4-[4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl]-6,6-dimethyl-bicyclo[3.1.1]hept-2-ene-2-methanol [HU-308 (HU)], another CB(2) agonist, was without effect. Cannabinoid and adenosine A(2A) receptors may be involved in the CBD action. CBD- and WIN-promoted primary microglia migration was blocked by CB(1) and/or CB(2) antagonists. JWH and HU-induced migration was blocked by a CB(2) antagonist only. All of the cannabinoids decreased lipopolysaccharide-induced nitrite generation, which was insensitive to cannabinoid antagonism. Finally, both CBD and WIN, after subchronic administration for 3 weeks, were able to prevent learning of a spatial navigation task and cytokine gene expression in β-amyloid-injected mice. In summary, CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD. Given that CBD lacks psychoactivity, it may represent a novel therapeutic approach for this neurological disease.
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                Author and article information

                Contributors
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                21 September 2018
                2018
                : 12
                : 653
                Affiliations
                [1] 1Center for Mathematics, Computing and Cognition, Universidade Federal do ABC , São Bernardo do Campo, Brazil
                [2] 2Center for Natural and Human Sciences, Universidade Federal do ABC , São Bernardo do Campo, Brazil
                [3] 3Faculty of Medicine, University of Coimbra , Coimbra, Portugal
                [4] 4Center for Neuroscience and Cell Biology (CNC), University of Coimbra , Coimbra, Portugal
                Author notes

                Edited by: Fabricio A. Pamplona, Entourage Phytolab, Brazil

                Reviewed by: Salim Yalcin Inan, Meram Faculty of Medicine, Turkey; Mychael V. Lourenco, Universidade Federal do Rio de Janeiro, Brazil; Vincenzo Micale, Università di Catania, Italy; Grasielle Clotildes Kincheski, Universidade Federal do Rio de Janeiro, Brazil

                *Correspondence: Daniel C. Carrettiero, daniel.carrettiero@ 123456ufabc.edu.br Tatiana L. Ferreira, tatiana.ferreira@ 123456ufabc.edu.br

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Neuroscience

                Article
                10.3389/fnins.2018.00653
                6176656
                30333717
                7667ac6d-2ff9-4884-9bd1-f27ff34acd7b
                Copyright © 2018 Moreira-Silva, Carrettiero, Oliveira, Rodrigues, dos Santos-Lopes, Canas, Cunha, Almeida and Ferreira.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 05 April 2018
                : 30 August 2018
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 91, Pages: 14, Words: 0
                Funding
                Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo 10.13039/501100001807
                Award ID: 2014/14661-1
                Award ID: 2016/24773-3
                Award ID: 2015/02991-0
                Award ID: 2015/23426-9
                Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico 10.13039/501100003593
                Award ID: 429894/2016-3
                Award ID: 449102/2014-9
                Funded by: Fundação para a Ciência e a Tecnologia 10.13039/501100001871
                Award ID: POCI-01-0145-FEDER-007440
                Award ID: PTDC/NEU-NMC/4154/2016
                Categories
                Neuroscience
                Original Research

                Neurosciences
                endocannabinoid,cb1,hsp70,bag2,phosphorylated tau,fear conditioning,object recognition memory,prepulse inhibition

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