Deletion of MyD88 in astrocytes prevents ß-amyloid-induced neuropathology in mice.

As the understanding of immune responses in Alzheimer's disease (AD) is in its early phases, there remains an urgency to identify the cellular and molecular processes driving chronic inflammation. In AD, a subpopulation of astrocytes acquires a neurotoxic phenotype which prompts them to lose typical physiological features. While the underlying molecular mechanisms are still unknown, evidence suggests that myeloid differentiation primary response 88 (MyD88) adaptor protein may play a role in coordinating these cells' immune responses in AD. Herein, we combined studies in human postmortem samples with a conditional genetic knockout mouse model to investigate the link between MyD88 and astrocytes in AD. In silico analyses of bulk and cell-specific transcriptomic data from human postmortem brains demonstrated an upregulation of MyD88 expression in astrocytes in AD versus non-AD individuals. Proteomic studies revealed an increase in glial fibrillary acidic protein in multiple brain regions of AD subjects. These studies also showed that although overall MyD88 steady-state levels were unaffected by AD, this protein was enriched in astrocytes near amyloid plaques and neurofibrillary tangles. Functional studies in mice indicated that the deletion of astrocytic MyD88 protected animals from the acute synaptic toxicity and cognitive impairment caused by the intracerebroventricular administration of ß-amyloid (Aß). Lastly, unbiased proteomic analysis revealed that loss of astrocytic MyD88 resulted in altered astrocyte reactivity, lower levels of immune-related proteins, and higher expression of synaptic-related proteins in response to Aß. Our studies provide evidence of the pivotal role played by MyD88 in the regulation of astrocytes response to AD.

Retinal pathological features and proteome signatures of Alzheimer's disease.

Alzheimer's disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in the early stages of functional impairment, and how they relate to disease progression in the brain remain largely unknown. To better understand the pathological features of AD in the retina, we conducted an extensive histopathological and biochemical investigation of postmortem retina and brain tissues from 86 human donors. Quantitative examination of superior and inferior temporal retinas from mild cognitive impairment (MCI) and AD patients compared to those with normal cognition (NC) revealed significant increases in amyloid ß-protein (Aß42) forms and novel intraneuronal Aß oligomers (AßOi), which were closely associated with exacerbated retinal macrogliosis, microgliosis, and tissue atrophy. These pathologies were unevenly distributed across retinal layers and geometrical areas, with the inner layers and peripheral subregions exhibiting most pronounced accumulations in the MCI and AD versus NC retinas. While microgliosis was increased in the retina of these patients, the proportion of microglial cells engaging in Aß uptake was reduced. Female AD patients exhibited higher levels of retinal microgliosis than males. Notably, retinal Aß42, S100 calcium-binding protein B+ macrogliosis, and atrophy correlated with severity of brain Aß pathology, tauopathy, and atrophy, and most retinal pathologies reflected Braak staging. All retinal biomarkers correlated with the cognitive scores, with retinal Aß42, far-peripheral AßOi and microgliosis displaying the strongest correlations. Proteomic analysis of AD retinas revealed activation of specific inflammatory and neurodegenerative processes and inhibition of oxidative phosphorylation/mitochondrial, and photoreceptor-related pathways. This study identifies and maps retinopathy in MCI and AD patients, demonstrating the quantitative relationship with brain pathology and cognition, and may lead to reliable retinal biomarkers for noninvasive retinal screening and monitoring of AD.

Prevalence of self-reported symptoms of temporomandibular disorders and associated factors in the period of distance learning.

OBJECTIVE: Assess the prevalence of self-reported TMD symptoms and anxiety and check the quality of sleep and life during the distance learning period in university students at the University of Brasilia (UnB). MATERIALS AND METHODS: The participants were students from the Health Sciences College and Medicine College at UnB. Self-administered questionnaires were used to evaluate symptoms of TMD, quality of life, and sleep quality. One-way analysis of variance, followed by Bonferroni test, and Kruskal-Wallis test, followed by Dunn's test, were performed (P < 0.05). For qualitative data analysis, the chi-square test was applied (P < 0.05). RESULTS: Total 156 students were included; prevalence of TMD, anxiety, sleep disturbance, and poor sleep quality was 73.1%, 84%, 12.8%, and 62.8%, respectively. A greater prevalence of painful TMD was observed in students with severe anxiety (P = 0.007). Students with symptoms of painful TMD, severe anxiety, and sleep disorders had statistically worse quality of life. CONCLUSIONS: The implementation of distance learning in health courses to replace classroom teaching during the COVID-19 pandemic has impacted TMD prevalence, anxiety, quality of life, and sleep quality. CLINICAL RELEVANCE: Psychological factors are directly associated with TMD symptoms and quality of life, TMD conditions are related to quality of life as well. COVID-19 pandemic and the distance learning in health courses are new situations that can lead to a great impact on mental health and in consequence to TMD conditions and quality of life.

Amyloid-beta impairs TOM1-mediated IL-1R1 signaling.

Defects in interleukin-1ß (IL-1ß)-mediated cellular responses contribute to Alzheimer's disease (AD). To decipher the mechanism associated with its pathogenesis, we investigated the molecular events associated with the termination of IL-1ß inflammatory responses by focusing on the role played by the target of Myb1 (TOM1), a negative regulator of the interleukin-1ß receptor-1 (IL-1R1). We first show that TOM1 steady-state levels are reduced in human AD hippocampi and in the brain of an AD mouse model versus respective controls. Experimentally reducing TOM1 affected microglia activity, substantially increased amyloid-beta levels, and impaired cognition, whereas enhancing its levels was therapeutic. These data show that reparation of the TOM1-signaling pathway represents a therapeutic target for brain inflammatory disorders such as AD. A better understanding of the age-related changes in the immune system will allow us to craft therapies to limit detrimental aspects of inflammation, with the broader purpose of sharply reducing the number of people afflicted by AD.

Land-use and land-cover change shape the sustainability and impacts of protected areas.

Protected areas (PAs) remain the dominant policy to protect biodiversity and ecosystem services but have been shown to have limited impact when development interests force them to locations with lower deforestation pressure. Far less known is that such interests also cause widespread tempering, reduction, or removal of protection [i.e., PA downgrading, downsizing, and degazettement (PADDD)]. We inform responses to PADDD by proposing and testing a bargaining explanation for PADDD risks and deforestation impacts. We examine recent degazettements for hydropower development and rural settlements in the state of Rondônia in the Brazilian Amazon. Results support two hypotheses: (i) ineffective PAs (i.e., those where internal deforestation was similar to nearby rates) were more likely to be degazetted and (ii) degazettement of ineffective PAs caused limited, if any, additional deforestation. We also report on cases in which ineffective portions were upgraded. Overall our results suggest that enhancing PAs' ecological impacts enhances their legal durability.

Evaluation of the level of cortisol, capillary blood glucose, and blood pressure in response to anxiety of patients rehabilitated with complete dentures.

BACKGROUND: The aim was to analyze the levels of stress of edentulous patients through the state-trait anxiety inventory (STAI) and salivary flow through the visual analogue scale (VAS) xerostomia questionnaire, as well as analyze the levels of cortisol, capillary blood glucose, and blood pressure (BP) before and after the installation of complete dentures. METHODS: Fifty patients were evaluated. The STAI and VAS xerostomia questionnaire were applied before the installation of the prosthesis, on the day of its installation, and 1 month after the last recall visit. The BP measurement, as well as salivary and blood collections, were performed before the installation of the prothesis, and 1 month after the last recall visit. Data from the VAS xerostomia questionnaire and cortisol levels were submitted to ANOVA and the Tukey test (P = .05). Data from the STAI, as well as blood glucose and BP levels, were submitted to the Chi-square test (P = .05). The correlation between cortisol and blood glucose and between cortisol levels and BP was analyzed. RESULTS: There was no statistically significant association between the questions of the VAS xerostomia questionnaire, STAI-state and STAI-trait scores, or the periods analyzed. However, the cortisol level collected in the morning decreased after the installation of the prosthesis. There was a correlation between cortisol and blood glucose and BP levels. CONCLUSIONS: The installation of complete dentures was beneficial for patients since it was probably responsible for the cortisol level reduction.

Can Nonthermal Plasma Improve the Adhesion between Acrylic Resin for Ocular Prostheses and Silicone-Based Relining Material?

PURPOSE: To investigate the influence of nonthermal plasma (NTP) treatment on the tensile bond strength between heat-polymerized acrylic resin for ocular prostheses and silicone reliner, with and without the use of an adhesive primer. MATERIALS AND METHODS: One-hundred and sixty-four acrylic resin specimens were fabricated and randomly distributed into four groups according to the type of surface treatment: Sofreliner Primer, NTP, Sofreliner Primer + NTP, and NTP + Sofreliner Primer. Two specimens interposed with relining material (Sofreliner) formed one test sample to perform the tensile bond strength tests, before (initial) and after storage (final) in saline solution (37°C, 90 days, n = 10). Surface characterization was performed by scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS). The failure type was classified as cohesive, adhesive, or mixed. The data were analyzed statistically using the two-way ANOVA and Tukey test, as well as the chi-squared test (α = 0.05), Bonferroni correction (α = 0.005), and Spearman correlation coefficient (α = 0.05). RESULTS: The SEM and EDS analyses showed the presence of a thin, homogenous organic film in the groups treated with NTP. The NTP + Sofreliner Primer group presented the largest bond strength mean values in the initial period (p < 0.05). Sofreliner Primer and NTP + Sofreliner Primer groups presented the first and second largest tensile bond strength mean values in the final period (p < 0.05), respectively. NTP + Sofreliner Primer group also had the largest number of cohesive (70%, initial) and mixed (90%, final) failures. CONCLUSIONS: The NTP treatment performed before the primer application enhanced the bond between the acrylic resin ocular prosthesis and the Sofreliner silicone-based reliner, even after 90 days of immersion in saline solution.

Inflammation: the link between comorbidities, genetics, and Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder, most cases of which lack a clear causative event. This has made the disease difficult to characterize and, thus, diagnose. Although some cases are genetically linked, there are many diseases and lifestyle factors that can lead to an increased risk of developing AD, including traumatic brain injury, diabetes, hypertension, obesity, and other metabolic syndromes, in addition to aging. Identifying common factors and trends between these conditions could enhance our understanding of AD and lead to the development of more effective treatments. Although the immune system is one of the body's key defense mechanisms, chronic inflammation has been increasingly linked with several age-related diseases. Moreover, it is now well accepted that chronic inflammation has an important role in the onset and progression of AD. In this review, the different inflammatory signals associated with AD and its risk factors will be outlined to demonstrate how chronic inflammation may be influencing individual susceptibility to AD. Our goal is to bring attention to potential shared signals presented by the immune system during different conditions that could lead to the development of successful treatments.

Effect of nonthermal plasma on the properties of a resinous liner submitted to aging.

STATEMENT OF PROBLEM: The properties, such as softness and viscoelasticity, of a resinous reliner can deteriorate and extrinsic elements can become incorporated, making surface protection of the reliner material essential. PURPOSE: The purpose of this in vitro study was to evaluate the effect of low temperature plasma on Coe-Soft resinous reliner, submitted to aging in artificial saliva for up to 180 days. Sorption, solubility, Shore A hardness, surface energy, and topographic characteristics were analyzed by scanning electronic microscopy (SEM) and energy-dispersive spectroscopy (EDS). MATERIAL AND METHODS: Forty-four specimens were fabricated and distributed in 2 groups: nonplasma reliner (control group) and reliner with plasma (plasma group). The plasma was applied with a mixture of 70% hexamethyldisiloxane, 20% O, and 10% Ar. Total work pressure was maintained at a constant 20 Pa for 30 minutes of deposition. The specimens were analyzed before and after aging in an incubator with immersion in artificial saliva for 30, 90, and 180 days. The quantitative data were submitted to 2-way ANOVA and the Tukey test (α=.05), while qualitative data were compared visually. RESULTS: The control group presented lower Shore A hardness values only in the initial period, and surface energy increased with aging for both groups until 90 days. Greater sorption percentage values were encountered at 180 days in the plasma group. Greater solubility values were encountered in the control group in all periods. CONCLUSIONS: Plasma is an option for the protection of the material studied because the deposited film remained on the surface of the reliner material after aging.

Stress Distribution in an Implant-Supported Mandibular Complete Denture Using Different Cantilever Lengths and Occlusal Coating Materials.

PURPOSE: The aim of this study was to assess stress distribution in the bone-implant interface of a mandibular implant-supported prosthesis with different cantilever lengths, aesthetic coating materials, and implant abutments. MATERIALS AND METHODS: A photoelastic model of an edentulous mandible, containing 5 external hexagon implants, was constructed. Experimental models were divided into 6 groups: group 1-UCLA component and metal bar; group 2-UCLA component and acrylic resin coating; group 3-UCLA component and porcelain coating; group 4-abutment and metal bar; group 5-abutment and acrylic resin coating; and group 6-abutment and porcelain coating. Forces were applied to the most anterior implant, the most posterior implant, and different cantilever lengths. RESULTS: The results showed a higher number of high-stress fringes as the cantilever length increased. Fringes were better distributed in groups with prostheses composed of acrylic resin and in groups that contained an abutment. CONCLUSION: The stress distribution in the bone-implant interface is improved when the cantilever is eliminated and when abutments in an acrylic resin prosthesis are used.

A photoelastic and strain gauge comparison of two attachments for obturator prostheses.

STATEMENT OF PROBLEM: The rehabilitation of patients after a maxillectomy involves the use of an obturator to seal oral-nasal-sinus communication and to facilitate mastication, swallowing, and speech. PURPOSE: The purpose of this in vitro study was to evaluate different attachment systems used for implant-retained obturators at dissipation loads and under shear forces. MATERIAL AND METHODS: Photoelastic models were fabricated with 3 external hexagon implants at the incisor, canine, and first molar regions. Subsequently, overdentures were made, and metal hooks were placed at the incisor and first molar regions to displace the prostheses in the vertical, anterior, and posterior directions, with a constant speed of 50 mm/min. A photoelastic model with an O-ring or bar-clip system was placed in a circular polariscope, and tested with a universal testing machine. The images were recorded and high-intensity fringes were counted using software. For strain gauge analysis, each strain gauge was placed horizontally at the mesial and distal sides of the implants. The registered strains were submitted to 2-way ANOVA (α=.05). RESULTS: The O-ring showed the lowest number of high-intensity fringes in photoelastic imaging, while the strain gauge analysis showed the lowest stress values in the bar-clip group (P=.007). CONCLUSIONS: The stress around titanium implant necks was more damaging to surrounding bone, while the bar-clip attachment system had a better biomechanical performance. The bar-clip presented the lowest strain values around the dental implants and few high-intensity fringes.

AF710B, a Novel M1/σ1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer's Disease.

We previously developed orthosteric M1 muscarinic agonists (e.g. AF102B, AF267B and AF292), which act as cognitive enhancers and potential disease modifiers. We now report on a novel compound, AF710B, a highly potent and selective allosteric M1 muscarinic and σ1 receptor agonist. AF710B exhibits an allosteric agonistic profile on the M1 muscarinic receptor; very low concentrations of AF710B significantly potentiated the binding and efficacy of carbachol on M1 receptors and their downstream effects (p-ERK1/2, p-CREB). AF710B (1-30 µg/kg, p.o.) was a potent and safe cognitive enhancer in rats treated with the M1 antagonist trihexyphenidyl (passive avoidance impairment). These effects of AF710B involve σ1 receptor activation. In agreement with its antiamnesic properties, AF710B (at 30 nM), via activation of M1 and a possible involvement of σ1 receptors, rescued mushroom synapse loss in PS1-KI and APP-KI neuronal cultures, while AF267B (1 µM) was less potent in PS1-KI and ineffective in APP-KI models, respectively. In female 3xTg-AD mice, AF710B (10 µg/kg, i.p./daily/2 months) (i) mitigated cognitive impairments in the Morris water maze; (ii) decreased BACE1, GSK3ß activity, p25/CDK5, neuroinflammation, soluble and insoluble Aß40, Aß42, plaques and tau pathologies. AF710B differs from conventional σ1 and M1 muscarinic (orthosteric, allosteric or bitopic) agonists. These results highlight AF710B as a potential treatment for Alzheimer's disease (e.g. improving cognitive deficits, synaptic loss, amyloid and tau pathologies, and neuroinflammation) with a superior profile over a plethora of other therapeutic strategies.

Evaluation of marginal bone loss of dental implants with internal or external connections and its association with other variables: A systematic review.

STATEMENT OF PROBLEM: Different factors can influence marginal bone loss around dental implants, including the type of internal and external connection between the implant and the abutment. The evidence needed to evaluate these factors is unclear. PURPOSE: The purpose of this systematic review was to evaluate marginal bone loss by radiographic analysis around dental implants with internal or external connections. MATERIAL AND METHODS: A systematic review was conducted following the criteria defined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Initially, a population, intervention, comparison, and outcome(s) (PICO) question was defined: does the connection type (internal or external) influence marginal bone loss in patients undergoing implantation? An electronic search of PubMed/MEDLINE and Scopus databases was performed for studies in English language published between January 2000 and December 2014 by 2 independent reviewers, who analyzed the marginal bone loss of dental implants with an internal and/or external connection. RESULTS: From an initial screening yield of 595 references and after considering inclusion and exclusion criteria, 17 articles were selected for this review. Among them, 10 studies compared groups of implants with internal and external connections; 1 study evaluated external connections; and 6 studies analyzed internal connections. A total of 2708 implants were placed in 864 patients. Regarding the connection type, 2347 implants had internal connections, and 361 implants had external connections. Most studies showed lower marginal bone loss values for internal connection implants than for external connection implants. CONCLUSIONS: Osseointegrated dental implants with internal connections exhibited lower marginal bone loss than implants with external connections. This finding is mainly the result of the platform switching concept, which is more frequently found in implants with internal connections.

Higher Dental Caries Prevalence and Its Association with Dietary Habits and Physical Limitation in Epidermolysis Bullosa Patients: A Case Control Study.

AIM: Epidermolysis bullosa (EB) represents a highly rare subgroup of skin diseases that affects skin and mucous membrane. The aim of the present study was to assess caries prevalence and its associated factors in EB subjects. Salivary status was also assessed. MATERIALS AND METHODS: Ten subjects with EB who were under supervision were selected (cases) and matched by age and gender with unaffected individuals (controls). Dental caries were recorded using the World Health Organization (WHO) criteria. Oral hygiene and dietary habits were investigated by clinical examination and questionnaires. Both nonstimulated and stimulated saliva were collected and salivary pH, buffering capacity and mouth opening were evaluated. RESULTS: The results showed that the median decay-missing-filled teeth was significantly higher (p = 0.0094) in EB cases 5 (3.9-20.3) than in controls 3 (2-3.25). The groups also differed when food consistency was analyzed. Individuals with EB have a higher intake of soft food. In addition, the median mouth-opening values from cases (0.84-2.84 cm) and controls (4.3-4.9 cm) have shown to be statistically different (p = 0.007). Considering the salivary parameters, none of them showed significant differences among groups. CONCLUSION: Epidermolysis bullosa subjects present higher caries scores and might be related to their physical condition and dietary habits. CLINICAL SIGNIFICANCE: There is a lack of information about oral status in EB subjects. Hence, our findings add useful information regarding the relationship between caries prevalence and associated risk factors in EB subjects.

Short-term modern life-like stress exacerbates Aß-pathology and synapse loss in 3xTg-AD mice.

Alzheimer's disease (AD) is a progressive neurological disorder that impairs memory and other cognitive functions in the elderly. The social and financial impacts of AD are overwhelming and are escalating exponentially as a result of population aging. Therefore, identifying AD-related risk factors and the development of more efficacious therapeutic approaches are critical to cure this neurological disorder. Current epidemiological evidence indicates that life experiences, including chronic stress, are a risk for AD. However, it is unknown if short-term stress, lasting for hours, influences the onset or progression of AD. Here, we determined the effect of short-term, multi-modal 'modern life-like' stress on AD pathogenesis and synaptic plasticity in mice bearing three AD mutations (the 3xTg-AD mouse model). We found that combined emotional and physical stress lasting 5 h severely impaired memory in wild-type mice and tended to impact it in already low-performing 3xTg-AD mice. This stress reduced the number of synapse-bearing dendritic spines in 3xTg-AD mice and increased Aß levels by augmenting AßPP processing. Thus, short-term stress simulating modern-life conditions may exacerbate cognitive deficits in preclinical AD by accelerating amyloid pathology and reducing synapse numbers. Epidemiological evidence indicates that life experiences, including chronic stress, are a risk for Alzheimer disease (AD). However, it is unknown if short stress in the range of hours influences the onset or progression of AD. Here, we determined the effect of short, multi-modal 'modern-lifelike'stress on AD pathogenesis and synaptic plasticity in mice bearing three AD mutations (the 3xTg-AD mouse model). We found that combined emotional and physical stress lasting 5 h severely impaired memory in wild-type mice and tended to impact it in already low-performing 3xTg-AD mice. This stress reduced the number of synapse-bearing dendritic spines in 3xTg-AD mice and increased Aß levels by augmenting AßPP processing. Thus, short stress simulating modern-life conditions may exacerbate cognitive deficits in preclinical AD by accelerating amyloid pathology and reducing synapse numbers.

Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice.

BACKGROUND: Microglia are dependent upon colony-stimulating factor 1 receptor (CSF1R) signaling for their survival in the adult brain, with administration of the dual CSF1R/c-kit inhibitor PLX3397 leading to the near-complete elimination of all microglia brainwide. Here, we determined the dose-dependent effects of a specific CSF1R inhibitor (PLX5622) on microglia in both wild-type and the 3xTg-AD mouse model of Alzheimer's disease. METHODS: Wild-type mice were treated with PLX5622 for up to 21 days, and the effects on microglial numbers were assessed. 3xTg-AD mice were treated with PLX5622 for 6 or 12 weeks and effects on microglial numbers and pathology subsequently assessed. RESULTS: High doses of CSF1R inhibitor eliminate most microglia from the brain, but a 75% lower-dose results in sustained elimination of ~30 of microglia in both wild-type and 3xTg-AD mice. No behavioral or cognitive deficits were found in mice either depleted of microglia or treated with lower CSF1R inhibitor concentrations. Aged 3xTg-AD mice treated for 6 or 12 weeks with lower levels of PLX5622 resulted in improved learning and memory. Aß levels and plaque loads were not altered, but microglia in treated mice no longer associated with plaques, revealing a role for the CSF1R in the microglial reaction to plaques, as well as in mediating cognitive deficits. CONCLUSIONS: We find that inhibition of CSF1R alone is sufficient to eliminate microglia and that sustained microglial elimination is concentration-dependent. Inhibition of the CSF1R at lower levels in 3xTg-AD mice prevents microglial association with plaques and improves cognition.

Genetic ablation of tau mitigates cognitive impairment induced by type 1 diabetes.

Patients affected by diabetes show an increased risk of developing Alzheimer disease (AD). Similarly, patients with AD show impaired insulin function and glucose metabolism. However, the underlying molecular mechanisms connecting these two disorders are still not well understood. Herein, we investigated the microtubule-associated protein tau as a new link between AD and diabetes. To determine whether diabetes causes cognitive decline by a tau-dependent mechanism, we treated non-transgenic (Ntg) and tau-knockout mice with streptozotocin, causing type 1 diabetes-like disease (T1D). Interestingly, although induction of T1D in Ntg mice led to cellular and behavioral deficits, it did not do so in tau-knockout mice. Thus, data suggest that tau is a fundamental mediator of the induction of cognitive impairments in T1D. Tau dysregulation, which causes a reduction in synaptic protein levels, may be responsible for the cognitive decline observed in Ntg streptozotocin-treated mice. Concomitantly, we demonstrate the novel finding that depletion of endogenous tau mitigates behavioral impairment and synaptic deficits induced in T1D-like mice. Overall, our data reveal that tau is a key molecular factor responsible for the induction of cognitive deficits observed in T1D and represents a potential therapeutic target for diabetes and patients with AD.

α7 Nicotinic receptor agonist enhances cognition in aged 3xTg-AD mice with robust plaques and tangles.

Alzheimer disease (AD) is a progressive neurodegenerative disorder with associated memory loss, spatial disorientation, and other psychiatric problems. Cholinergic system dysfunction is an early and salient feature of AD, and enhancing cholinergic signaling with acetylcholinesterase inhibitors is currently the primary strategy for improving cognition. The beneficial effects of acetylcholinesterase inhibitors, however, are typically short-lived and accompanied by adverse effects. Recent evidence suggests that activating α7 nicotinic acetylcholine receptors (α7 nAChR) may facilitate the specific modulation of brain cholinergic signaling, leading to cognitive enhancement and possibly to amelioration of AD pathologic findings. In the present study, we determined the effect of long-term treatment with the selective α7 nAChR agonist A-582941 in aged 3xTg-AD mice with robust AD-like pathology, which is particularly significant not only because this is the only mouse model that co-develops amyloid plaques and neurofibrillary tangles but also because it enabled us to explore whether A-582941 is able to restore brain function after the severe damage associated with AD. Analysis of ß-amyloid deposits, tau phosphorylation, and inflammatory cells revealed that, overall, pathologic findings were unchanged. Rather, α7 nAChR activation induced expression of c-Fos and brain-derived neurotrophic factor and phosphorylation of cyclic adenosine monophosphate response element binding and neurotrophic tyrosine receptor kinase type 2. More important, A-582941 completely restored cognition in aged 3xTg-AD mice to the level of that in age-matched nontransgenic mice. These novel findings indicate that activating α7 nAChR is a promising treatment for cognitive impairment in AD.

Surface degradation of lithium disilicate ceramic after immersion in acid and fluoride solutions.

PURPOSE: To analyze whether immersion in sodium fluoride (NaF) solutions and/or common acidic beverages (test solutions) would affect the surface roughness or topography of lithium disilicate ceramic. METHODS: 220 ceramic discs were divided into four groups, each of which was subdivided into five subgroups (n = 11). Control group discs were immersed in one of four test beverages for 4 hours daily or in artificial saliva for 21 days. Discs in the experimental groups were continuously immersed in 0.05% NaF, 0.2% NaF, or 1.23% acidulated phosphate fluoride (APF) gel for 12, 73, and 48 hours, respectively, followed by immersion in one of the four test beverages or artificial saliva. Vickers microhardness, surface roughness, scanning electron microscopy (SEM) associated with energy dispersive spectroscopy, and atomic force microscopy (AFM) assessments were made. Data were analyzed by nested analysis of variance (ANOVA) and Tukey's test (α = 0.05). RESULTS: Immersion in the test solutions diminished the microhardness and increased the surface roughness of the discs. The test beverages promoted a significant reduction in the Vickers microhardness in the 0.05% and 0.2% NaF groups. The highest surface roughness results were observed in the 0.2% NaF and 1.23% APF groups, with similar findings by SEM and AFM. Acidic beverages affected the surface topography of lithium disilicate ceramic. Fluoride treatments may render the ceramic surface more susceptible to the chelating effect of acidic solutions.