Defective regulation of the eIF2-eIF2B translational axis underlies depressive-like behavior in mice and correlates with major depressive disorder in humans.

Major depressive disorder (MDD) is a significant cause of disability in adults worldwide. However, the underlying causes and mechanisms of MDD are not fully understood, and many patients are refractory to available therapeutic options. Impaired control of brain mRNA translation underlies several neurodevelopmental and neurodegenerative conditions, including autism spectrum disorders and Alzheimer's disease (AD). Nonetheless, a potential role for mechanisms associated with impaired translational control in depressive-like behavior remains elusive. A key pathway controlling translation initiation relies on the phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α-P) which, in turn, blocks the guanine exchange factor activity of eIF2B, thereby reducing global translation rates. Here we report that the expression of EIF2B5 (which codes for eIF2Bε, the catalytic subunit of eIF2B) is reduced in postmortem MDD prefrontal cortex from two distinct human cohorts and in the frontal cortex of social isolation-induced depressive-like behavior model mice. Further, pharmacological treatment with anisomycin or with salubrinal, an inhibitor of the eIF2α phosphatase GADD34, induces depressive-like behavior in adult C57BL/6J mice. Salubrinal-induced depressive-like behavior is blocked by ISRIB, a compound that directly activates eIF2B regardless of the phosphorylation status of eIF2α, suggesting that increased eIF2α-P promotes depressive-like states. Taken together, our results suggest that impaired eIF2-associated translational control may participate in the pathophysiology of MDD, and underscore eIF2-eIF2B translational axis as a potential target for the development of novel approaches for MDD and related mood disorders.

Type I Hsp40s/DnaJs aggregates exhibit features reminiscent of amyloidogenic structures.

A rise in temperature triggers a structural change in the human Type I 40 kDa heat shock protein (Hsp40/DnaJ), known as DNAJA1. This change leads to a less compact structure, characterized by an increased presence of solvent-exposed hydrophobic patches and ß-sheet-rich regions. This transformation is validated by circular dichroism, thioflavin T binding, and Bis-ANS assays. The formation of this ß-sheet-rich conformation, which is amplified in the absence of zinc, leads to protein aggregation. This aggregation is induced not only by high temperatures but also by low ionic strength and high protein concentration. The aggregated conformation exhibits characteristics of an amyloidogenic structure, including a distinctive X-ray diffraction pattern, seeding competence (which stimulates the formation of amyloid-like aggregates), cytotoxicity, resistance to SDS, and fibril formation. Interestingly, the yeast Type I Ydj1 also tends to adopt a similar ß-sheet-rich structure under comparable conditions, whereas Type II Hsp40s, whether human or from yeast, do not. Moreover, Ydj1 aggregates were found to be cytotoxic. Studies using DNAJA1- and Ydj1-deleted mutants suggest that the zinc-finger region plays a crucial role in amyloid formation. Our discovery of amyloid aggregation in a C-terminal deletion mutant of DNAJA1, which resembles a spliced homolog expressed in the testis, implies that Type I Hsp40 co-chaperones may generate amyloidogenic species in vivo.

Histone deacetylase inhibition mitigates cognitive deficits and astrocyte dysfunction induced by amyloid-ß (Aß) oligomers.

BACKGROUND AND PURPOSE: Inhibitors of histone deacetylases (iHDACs) are promising drugs for neurodegenerative diseases. We have evaluated the therapeutic potential of the new iHDAC LASSBio-1911 in Aß oligomer (AßO) toxicity models and astrocytes, key players in neuroinflammation and Alzheimer's disease (AD). EXPERIMENTAL APPROACH: Astrocyte phenotype and synapse density were evaluated by flow cytometry, Western blotting, immunofluorescence and qPCR, in vitro and in mice. Cognitive function was evaluated by behavioural assays using a mouse model of intracerebroventricular infusion of AßO. KEY RESULTS: LASSBio-1911 modulates reactivity and synaptogenic potential of cultured astrocytes and improves synaptic markers in cultured neurons and in mice. It prevents AßO-triggered astrocytic reactivity in mice and enhances the neuroprotective potential of astrocytes. LASSBio-1911 improves behavioural performance and rescues synaptic and memory function in AßO-infused mice. CONCLUSION AND IMPLICATIONS: These results contribute to unveiling the mechanisms underlying astrocyte role in AD and provide the rationale for using astrocytes as targets to new drugs for AD.

The ketamine metabolite (2R,6R)-hydroxynorketamine rescues hippocampal mRNA translation, synaptic plasticity and memory in mouse models of Alzheimer's disease.

INTRODUCTION: Impaired brain protein synthesis, synaptic plasticity, and memory are major hallmarks of Alzheimer's disease (AD). The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has been shown to modulate protein synthesis, but its effects on memory in AD models remain elusive. METHODS: We investigated the effects of HNK on hippocampal protein synthesis, long-term potentiation (LTP), and memory in AD mouse models. RESULTS: HNK activated extracellular signal-regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 signaling pathways. Treatment with HNK rescued hippocampal LTP and memory deficits in amyloid-ß oligomers (AßO)-infused mice in an ERK1/2-dependent manner. Treatment with HNK further corrected aberrant transcription, LTP and memory in aged APP/PS1 mice. DISCUSSION: Our findings demonstrate that HNK induces signaling and transcriptional responses that correct synaptic and memory deficits in AD mice. These results raise the prospect that HNK could serve as a therapeutic approach in AD. HIGHLIGHTS: The ketamine metabolite HNK activates hippocampal ERK/mTOR/S6 signaling pathways. HNK corrects hippocampal synaptic and memory defects in two mouse models of AD. Rescue of synaptic and memory impairments by HNK depends on ERK signaling. HNK corrects aberrant transcriptional signatures in APP/PS1 mice.

Effects of Gestational Exercise on Nociception, BDNF, and Irisin Levels in an Animal Model of ADHD.

Abnormal cognitive and sensorial properties have been reported in patients with psychiatric and neurodevelopmental conditions, such as attention deficit hyperactivity disorder (ADHD). ADHD patients exhibit impaired dopaminergic signaling and plasticity in brain areas related to cognitive and sensory processing. The spontaneous hypertensive rat (SHR), in comparison to the Wistar Kyoto rat (WKY), is the most used genetic animal model to study ADHD. Brain neurotrophic factor (BDNF), critical for midbrain and hippocampal dopaminergic neuron survival and differentiation, is reduced in both ADHD subjects and SHR. Physical exercise (e.g. swimming) promotes neuroplasticity and improves cognition by increasing BDNF and irisin. Here we investigate the effects of gestational swimming on sensorial and behavioral phenotypes, striatal dopaminergic parameters, and hippocampal FNDC5/irisin and BDNF levels observed in WKY and SHR. Gestational swimming improved nociception in SHR rats (p = 0.006) and increased hippocampal BDNF levels (p = 0.02) in a sex-dependent manner in adolescent offspring. Sex differences were observed in hippocampal FNDC5/irisin levels (p = 0.002), with females presenting lower levels than males. Our results contribute to the notion that swimming during pregnancy is a promising alternative to improve ADHD phenotypes in the offspring.

Human health risk assessment of mercury in highly consumed fish in Salvador, Brazil.

This work reports assessing risks to human health resulting from mercury levels in sardines (Sardinella brasiliensis), which have been highly consumed by the low-income population from Salvador, Brazil. Mercury was determined using the Direct Mercury Analysis (DMA) in fifty-one commercially acquired samples in seventeen neighborhoods. The mercury content on a wet basis ranged from 0.023 to 0.083 µg g-1 for an average value of 0.039 µg g-1. The estimated weekly intake (EWI), target hazard quotient (THQ), and maximum safe consuming quantity (MSCQ) were used in the toxicological assessment, and all these indices denoted that this food does not pose any risks to the human health of the population that consumes it. The development of this work was very significant because most sardines sold in Salvador originate from Todos os Santos Bay, which has a history of mercury contamination.

Synaptic proteasome is inhibited in Alzheimer's disease models and associates with memory impairment in mice.

The proteasome plays key roles in synaptic plasticity and memory by regulating protein turnover, quality control, and elimination of oxidized/misfolded proteins. Here, we investigate proteasome function and localization at synapses in Alzheimer's disease (AD) post-mortem brain tissue and in experimental models. We found a marked increase in ubiquitinylated proteins in post-mortem AD hippocampi compared to controls. Using several experimental models, we show that amyloid-ß oligomers (AßOs) inhibit synaptic proteasome activity and trigger a reduction in synaptic proteasome content. We further show proteasome inhibition specifically in hippocampal synaptic fractions derived from APPswePS1ΔE9 mice. Reduced synaptic proteasome activity instigated by AßOs is corrected by treatment with rolipram, a phosphodiesterase-4 inhibitor, in mice. Results further show that dynein inhibition blocks AßO-induced reduction in dendritic proteasome content in hippocampal neurons. Finally, proteasome inhibition induces AD-like pathological features, including reactive oxygen species and dendritic spine loss in hippocampal neurons, inhibition of hippocampal mRNA translation, and memory impairment in mice. Results suggest that proteasome inhibition may contribute to synaptic and memory deficits in AD.

Association of the fibronectin type III domain-containing protein 5 rs1746661 single nucleotide polymorphism with reduced brain glucose metabolism in elderly humans.

Fibronectin type III domain-containing protein 5 (FNDC5) and its derived hormone, irisin, have been associated with metabolic control in humans, with described FNDC5 single nucleotide polymorphisms being linked to obesity and metabolic syndrome. Decreased brain FNDC5/irisin has been reported in subjects with dementia due to Alzheimer's disease. Since impaired brain glucose metabolism develops in ageing and is prominent in Alzheimer's disease, here, we examined associations of a single nucleotide polymorphism in the FNDC5 gene (rs1746661) with brain glucose metabolism and amyloid-ß deposition in a cohort of 240 cognitively unimpaired and 485 cognitively impaired elderly individuals from the Alzheimer's Disease Neuroimaging Initiative. In cognitively unimpaired elderly individuals harbouring the FNDC5 rs1746661(T) allele, we observed a regional reduction in low glucose metabolism in memory-linked brain regions and increased brain amyloid-ß PET load. No differences in cognition or levels of cerebrospinal fluid amyloid-ß42, phosphorylated tau and total tau were observed between FNDC5 rs1746661(T) allele carriers and non-carriers. Our results indicate that a genetic variant of FNDC5 is associated with low brain glucose metabolism in elderly individuals and suggest that FNDC5 may participate in the regulation of brain metabolism in brain regions vulnerable to Alzheimer's disease pathophysiology. Understanding the associations between genetic variants in metabolism-linked genes and metabolic brain signatures may contribute to elucidating genetic modulators of brain metabolism in humans.

Oxytocin attenuates microglial activation and restores social and non-social memory in APP/PS1 Alzheimer model mice.

Alzheimer's disease (AD) is characterized by neurodegeneration, memory loss, and social withdrawal. Brain inflammation has emerged as a key pathogenic mechanism in AD. We hypothesized that oxytocin, a pro-social hypothalamic neuropeptide with anti-inflammatory properties, could have therapeutic actions in AD. Here, we investigated oxytocin expression in experimental models of AD, and evaluated the therapeutic potential of treatment with oxytocin. Amyloid-ß peptide oligomers (AßOs) reduced oxytocin expression in vitro and in vivo, and treatment with oxytocin prevented microglial activation induced by AßOs in purified microglial cultures. Treatment of aged APP/PS1 mice, a mouse model of AD, with intranasal oxytocin attenuated microglial activation and favored deposition of Aß in dense core plaques, a potentially neuroprotective mechanism. Remarkably, treatment with oxytocin alleviated social and non-social memory impairments in aged APP/PS1 mice. Our findings point to oxytocin as a potential therapeutic target to reduce brain inflammation and correct memory deficits in AD.

Determination and evaluation of the ecological risk of mercury in different granulometric fractions of sediments from a public supply river in Brazil.

This work reports the quantification of total mercury in sediments collected in periods with and without rain from the Joanes River, Bahia, Brazil. Determinations were made using Direct Mercury Analysis (DMA), the accuracy of which was confirmed with two certified reference materials. The highest total mercury concentrations were found at the sampling point close to commercial areas and large residential condominiums. On the other hand, the lowest levels were found in the site close to a mangrove region. The geoaccumulation index was applied to the total mercury results, evidencing low contamination in the region studied. The contamination factor showed that of the seven stations investigated, four samples collected in the rainy season showed moderate contamination. The results of the ecological risk assessment were utterly consistent with the contamination factor data. This study showed that the smaller sediment particles concentrate more mercury, corroborating what has been predicted by the adsorption processes.

Cation recognition controlled by protonation or chemical reduction: a computational study.

To control biochemical processes, non-covalent interactions involving cations are activated by protons or electrons. In the present study, the bonding situation between: (i) carboxylic acid or (ii) ferrocene-functionalized crown ether derivatives and cations (Li+, Na+ or K+) has been elucidated and, mainly, tuned by the substitution of hydrogen atoms by electron donor (-NH2) or acceptor (-NO2) groups. The deprotonation of the carboxyl groups improves the interaction with the cations through more favorable electrostatic O⋯cation interactions. Reducing the ferrocene structures favors cationic recognition supported by a less unfavorable iron⋯cation binding. The receptors preferably interact with smaller cations because of more attractive electrostatic and orbital (σ or π) O⋯cation interactions. The presence of electron donor or acceptor groups in the carboxylic acid-functionalized crown ethers promotes less attractive interactions with the cations, mainly due to the less favorable electrostatic O⋯Na+ interactions. The -H → -NH2 substitution in the ferrocene framework favors the cationic recognition. It is based on the strengthening of the electrostatic and σ O⋯Na+ and H2N⋯Na+ bonds. The (i) absence of repulsive electrostatic iron⋯cation interactions, or (ii) the presence of oxygen atoms with large electron density, ensures carboxylic acid-functionalized crown ethers have more favorable interactions with cations than ferrocene compounds. Therefore, this work has demonstrated how cation recognition can be improved by structural changes in carboxylic acid- or ferrocene-functionalized crown ethers and has shown that the carboxylic acid molecules appear to be better candidates for cation recognition than ferrocene derivatives.

Synthesis and Application of a New Polymer with Imprinted Ions for the Preconcentration of Uranium in Natural Water Samples and Determination by Digital Imaging.

This work proposes the synthesis of a new polymer with imprinted ions (IIP) for the pre-concentration of uranium in natural waters using digital imaging as a detection technique. The polymer was synthesized using 2-(5-bromo-2-pyridylazo)-5-diethylaminophenol (Br-PADAP) for complex formation, ethylene glycol dimethacrylate (EGDMA) as a crosslinking reagent, methacrylic acid (AMA) as functional monomer, and 2,2'-azobisisobutyronitrile as a radical initiator. The IIP was characterized by Fourier transform infrared spectroscopy and scanning electron microscopy (FTIR). Uranium determination was performed using digital imaging (ID), and some experimental conditions (sample pH, eluent concentration, and sampling flow rate) were optimized using a two-level full factorial design and Doelhert response surface methodology. Thus, using the optimized conditions, the system allowed the determination of uranium with detection and quantification limits of 2.55 and 8.51 µg L-1, respectively, and a pre-concentration factor of 8.2. All parameters were determined using a 25 mL sample volume. The precision expressed as relative deviation (RSD%) was 3.5% for a solution with a concentration of 50 µg L-1. Given this, the proposed method was used for the determination of uranium in four samples of natural waters collected in the city of Caetité, Bahia, Brazil. The concentrations obtained ranged from 35 to 75.4 µg L-1. The accuracy was evaluated by the addition/recovery test, and the values found ranged between 91 and 109%.

Alzheimer's disease brain-derived extracellular vesicles reveal altered synapse-related proteome and induce cognitive impairment in mice.

INTRODUCTION: Extracellular vesicles (EVs) have been implicated in the spread of neuropathology in Alzheimer's disease (AD), but their involvement in behavioral outcomes linked to AD remains to be determined. METHODS: EVs isolated from post mortem brain tissue from control, AD, or frontotemporal dementia (FTD) donors, as well as from APP/PS1 mice, were injected into the hippocampi of wild-type (WT) or a humanized Tau mouse model (hTau/mTauKO). Memory tests were carried out. Differentially expressed proteins in EVs were assessed by proteomics. RESULTS: Both AD-EVs and APP/PS1-EVs trigger memory impairment in WT mice. We further demonstrate that AD-EVs and FTD-EVs carry Tau protein, present altered protein composition associated with synapse regulation and transmission, and trigger memory impairment in hTau/mTauKO mice. DISCUSSION: Results demonstrate that AD-EVs and FTD-EVs have negative impacts on memory in mice and suggest that, in addition to spreading pathology, EVs may contribute to memory impairment in AD and FTD. HIGHLIGHTS: Aß was detected in EVs from post mortem AD brain tissue and APP/PS1 mice. Tau was enriched in EVs from post mortem AD, PSP and FTD brain tissue. AD-derived EVs and APP/PS1-EVs induce cognitive impairment in wild-type (WT) mice. AD- and FTD-derived EVs induce cognitive impairment in humanized Tau mice. Proteomics findings associate EVs with synapse dysregulation in tauopathies.

Brain FNDC5/Irisin Expression in Patients and Mouse Models of Major Depression.

Major depressive disorder (MDD) is a major cause of disability in adults. MDD is both a comorbidity and a risk factor for Alzheimer's disease (AD), and regular physical exercise has been associated with reduced incidence and severity of MDD and AD. Irisin is an exercise-induced myokine derived from proteolytic processing of fibronectin type III domain-containing protein 5 (FNDC5). FNDC5/irisin is reduced in the brains of AD patients and mouse models. However, whether brain FNDC5/irisin expression is altered in depression remains elusive. Here, we investigate changes in fndc5 expression in postmortem brain tissue from MDD individuals and mouse models of depression. We found decreased fndc5 expression in the MDD prefrontal cortex, both with and without psychotic traits. We further demonstrate that the induction of depressive-like behavior in male mice by lipopolysaccharide decreased fndc5 expression in the frontal cortex, but not in the hippocampus. Conversely, chronic corticosterone administration increased fndc5 expression in the frontal cortex, but not in the hippocampus. Social isolation in mice did not result in altered fndc5 expression in either frontal cortex or hippocampus. Finally, fluoxetine, but not other antidepressants, increased fndc5 gene expression in the mouse frontal cortex. Results indicate a region-specific modulation of fndc5 in depressive-like behavior and by antidepressant in mice. Our finding of decreased prefrontal cortex fndc5 expression in MDD individuals differs from results in mice, highlighting the importance of carefully interpreting observations in mice. The reduction in fndc5 mRNA suggests that decreased central FNDC5/irisin could comprise a shared pathologic mechanism between MDD and AD.

Cerebrospinal fluid irisin and lipoxin A4 are reduced in elderly Brazilian individuals with depression: Insight into shared mechanisms between depression and dementia.

INTRODUCTION: Depression is frequent among older adults and is a risk factor for dementia. Identifying molecular links between depression and dementia is necessary to shed light on shared disease mechanisms. Reduced brain-derived neurotrophic factor (BDNF) and neuroinflammation are implicated in the pathophysiology of depression and dementia. The exercise-induced hormone, irisin, increases BDNF and improves cognition in animal models of Alzheimer's disease. Lipoxin A4 is a lipid mediator with anti-inflammatory activity. However, the roles of irisin and lipoxin A4 in depression remain to be determined. METHODS: In the present study, blood and CSF were collected from 61 elderly subjects, including individuals with and without cognitive impairment. Screening for symptoms of depression was performed using the 15-item Geriatric Depression Scale (GDS-15). RESULTS: CSF irisin and lipoxin A4 were positively correlated and reduced, along with a trend of BDNF reduction, in elderly individuals with depression, similar to previous observations in patients with dementia. DISCUSSION: Our findings provide novel insight into shared molecular signatures connecting depression and dementia.

Long-term impact of patients' compliance to peri-implant maintenance therapy on the incidence of peri-implant diseases: An 11-year prospective follow-up clinical study.

OBJECTIVE: To prospectively evaluate the incidence of peri-implant diseases and the associated risk factors during 11 years of peri-implant maintenance therapy (PIMT). MATERIAL AND METHODS: A sample of 80 partially edentulous individuals rehabilitated with dental implants was invited to participate in a PIMT program (T1-prior to entering the PIMT program). After 11 years, 51 individuals remained regularly or irregularly adherent to PIMT (T2-last recall after 11 years) and were classified as regular (RC; n = 27) or irregular (IC; n = 24) compliers. Data of interest were analyzed using univariate and multivariate logistic regression analyses. RESULTS: The incidence of peri-implant mucositis and peri-implantitis observed at T2 in the IC group (70.8% and 37.5%, respectively) were significantly higher than those observed in the RC group (37.0% and 11.1%, respectively). The incidence of peri-implant diseases was mostly attributable to potentially modifiable risk factors, as such: RC group-PM (p = 0.013); IC group-high plaque index (p < 0.001), irregular compliance (p < 0.001), the presence of PM (p = 0.015) and periodontitis (p < 0.039). CONCLUSION: Regular compliance during PIMT had a strong effect in minimizing the incidence of peri-implant diseases. Increasing regular dental visits and improving oral hygiene would provide benefits for preventing peri-implant diseases.

Lack of molecular evidence of fecal-borne viruses in capybaras from São Paulo state, Brazil, 2018-2020: a minor public health issue.

Capybara (Hydrochoerus hydrochaeris) is the world's largest rodent species distributed throughout South America. These animals are incredibly tolerant to anthropogenic environments and are occupying large urban centers. Capybaras are known to carry potentially zoonotic agents, including R. rickettsia, Leishmania spp., Leptospira spp., Trypanosoma spp., Salmonella spp., Toxoplasma gondii, and rabies virus. Focusing on the importance of monitoring potential sources of emerging zoonotic viruses and new viral reservoirs, the aim of the present study was to assess the presence of fecal-borne viruses in the feces of capybaras living in urban parks in São Paulo state, Brazil. A total of 337 fecal samples were collected between 2018 and 2020 and screened for the following: (i) Rotavirus group A (RVA) by ELISA; (ii) non-RVA species and Picobirnavirus (PBV) using PAGE; (iii) Human Bocaparvovirus (HBoV), Bufavirus (BuV), Tusavirus (TuV), and Cutavirus (CuV) qPCR; (iv) Human Enterovirus (EV), Norovirus GII (NoV), and Hantavirus by in houses RT-qPCR; (v) SARS-CoV-2 via commercial RT-qPCR kit assay; and (vi) Astrovirus (AstV) and Adenovirus (AdV) using conventional nested (RT)-PCRs. All fecal samples tested were negative for fecal-borne viruses. This study adds further evidence that the fecal-borne viruses is a minor public health issue in Brazilian capybaras, at least during the surveillance period and surveyed areas. Continuous monitoring of sylvatic animals is essential to prevent and control the emergence or re-emergence of newly discovered virus as well as viruses with known zoonotic potential.

Memory recovery through gene therapy with a single chain antibody fragment selective for Aß oligomers in a model of Alzheimer's disease in rats / Recuperación de la memoria mediante terapia génica con un fragmento de anticuerpo selectivo para oligómeros de Aß en un modelo de Alzheimer en ratas

Strong evidence supports the hypothesis that synapse damage and memory impairment in early Alzheimer Disease (AD) might be due to synaptic failure caused by amyloid beta oligomers (AßOs). The preclinical efficacy of a single-chain variable fragment (scFv) antibody NUsc1 that selectively targets a subpopulation of AßOs has been demonstrated; NUsc1 prevented inhibition of AßO-inducedlong-term potentiation in hippocampal slices and short-term memory impairment in mice. Since specific targeting of AßOs by NUsc1 can be a substantial improvement in target engagement and efficacy of AD therapy, an adeno-associated virus (AAV) vector was developed to drive neuronal expression of NUsc1 within the brain. AAV-NUsc1 rescued Short-Term Memory (STM) for objectand conspecific interaction in mouse models of AD. In the McGill-R-Thy1-APP (Tg+/­) heterozygous transgenic McGill-R-Thy1-APP (Tg+/­) rat model of AD, progressive amyloid pathology is ac-companied by cognitive impairment involving long-term memory (LTM) decline. LTM in a Novel-Object-Recognition (NOR) task was impaired in 4-month-old (Tg+/­) male rats, suggesting that they are unable to form/evoke such discriminative memories. Hence, it was investigated if AAV-NUsc1 treatment could rescued this memory. 10-12 weeks-old either Tg or wild type male rats were i.c.v. infused with AAV-NUsc1. Two months later, short-term exploratory behavior, habituation to an Open Field (OF), object discrimination and LTM for objects were assessed. AAV-NUsc1 treated Tg rats were able to successfully perform the task 24 h after training, denoting recovery of LT discrimination capacity and LTM formation. Wild type rats successfully performed the task either treated or not with AAV-NUsc1. In addition, exploration and short-term habituation to an open field was preserved in Tg+/­ rats either treated or not. Our present and previous results suggest that AAV-NUsc1 represents a significant advance in gene therapy, supporting the feasibility of immunotherapy using viral vector-mediated NUsc1 gene delivery as a potential therapeutic approach in AD.

Evidencias conspicuas respaldan la hipótesis de que la presencia de oligómeros beta-amiloides (AßO) ocasiona un deterioro sináptico y de la memoria en etapas tempranas de la Enfermedad de Alzheimer (AD). Se ha demostrado que el anticuerpo de cadena única y Fragmento variable (scFv) NUsc1, que une selectivamente una subpoblación de AßO, evitó el deterioro de la memoria a corto plazo, inducido por AßO en ratones. Dado que la selectividad de NUsc1 mejora sustancialmente la detección del AßO, y consecuentemente su eficacia terapéutica para AD, se ha desarrollado un vector derivado de Virus Adenoasociado para expresar NUsc1 (AAV-NUsc1) en el cerebro. AAV-NUsc1 rescató la Memoria de Corto Plazo (STM) para el reconocimiento de objetos e interacción con congéneres en ratones modelo de AD. La rata McGill-R-Thy1-APP transgénica heterocigota (Tg+/­) modelo de AD, sufre una patología amiloide progresiva acompañada de deterioro cognitivo, que afecta la Memoria de Largo Plazo (LTM) de Reconocimiento de Objetos (NOR) evitando su formación/evocación. Evaluando si el tratamiento con AAV-NUsc1 podría rescatar la LTM de reconocimien-to en ratas macho (Tg+/­) de 4 meses. Ratas macho Tg y de genotipo salvaje (Wt) de 10-12 semanas fueron infundidas i.c.v con AAV-NUsc1. Dos meses más tarde, se evaluaron: el comportamiento exploratorio a corto plazo, la habituación a un Campo Abierto (OF), la discriminación y LTM para objetos. 24 h después del entrenamiento se observó que las ratas Tg tratadas con AAV-NUsc1 recuperaron la capacidad de expresar una LTM y de reconocer objetos novedosos. De manera similar, las ratas Wt tratadas con AAV-NUsc1 y las del grupo control, realizaron la tarea con éxito.La exploración y habituación al OF fueron similares para ratas Tg+/­ y Wt, tratadas y control. Nuestros resultados sugieren que AAV-NUsc1 representa un avance significativo en terapia génica, respaldando la viabilidad de la inmunoterapia mediada por vectores virales aportando el gen de NUsc1 como posible enfoque terapéutico para AD.

Lung inflammation induced by silica particles triggers hippocampal inflammation, synapse damage and memory impairment in mice.

BACKGROUND: Considerable evidence indicates that a signaling crosstalk between the brain and periphery plays important roles in neurological disorders, and that both acute and chronic peripheral inflammation can produce brain changes leading to cognitive impairments. Recent clinical and epidemiological studies have revealed an increased risk of cognitive impairment and dementia in individuals with impaired pulmonary function. However, the mechanistic underpinnings of this association remain unknown. Exposure to SiO2 (silica) particles triggers lung inflammation, including infiltration by peripheral immune cells and upregulation of pro-inflammatory cytokines. We here utilized a mouse model of lung silicosis to investigate the crosstalk between lung inflammation and memory. METHODS: Silicosis was induced by intratracheal administration of a single dose of 2.5 mg SiO2/kg in mice. Molecular and behavioral measurements were conducted 24 h and 15 days after silica administration. Lung and hippocampal inflammation were investigated by histological analysis and by determination of pro-inflammatory cytokines. Hippocampal synapse damage, amyloid-ß (Aß) peptide content and phosphorylation of Akt, a proxy of hippocampal insulin signaling, were investigated by Western blotting and ELISA. Memory was assessed using the open field and novel object recognition tests. RESULTS: Administration of silica induced alveolar collapse, lung infiltration by polymorphonuclear (PMN) cells, and increased lung pro-inflammatory cytokines. Lung inflammation was followed by upregulation of hippocampal pro-inflammatory cytokines, synapse damage, accumulation of the Aß peptide, and memory impairment in mice. CONCLUSION: The current study identified a crosstalk between lung and brain inflammatory responses leading to hippocampal synapse damage and memory impairment after exposure to a single low dose of silica in mice.

Age-linked suppression of lipoxin A4 associates with cognitive deficits in mice and humans.

Age increases the risk for cognitive impairment and is the single major risk factor for Alzheimer's disease (AD), the most prevalent form of dementia in the elderly. The pathophysiological processes triggered by aging that render the brain vulnerable to dementia involve, at least in part, changes in inflammatory mediators. Here we show that lipoxin A4 (LXA4), a lipid mediator of inflammation resolution known to stimulate endocannabinoid signaling in the brain, is reduced in the aging central nervous system. We demonstrate that genetic suppression of 5-lipoxygenase (5-LOX), the enzyme mediating LXA4 synthesis, promotes learning impairment in mice. Conversely, administration of exogenous LXA4 attenuated cytokine production and memory loss induced by inflammation in mice. We further show that cerebrospinal fluid LXA4 is reduced in patients with dementia and positively associated with cognitive performance, brain-derived neurotrophic factor (BDNF), and AD-linked amyloid-ß. Our findings suggest that reduced LXA4 levels may lead to vulnerability to age-related cognitive disorders and that promoting LXA4 signaling may comprise an effective strategy to prevent early cognitive decline in AD.