On the participation of glycine receptors in the reconsolidation of spatial long-term memory in male rats.

The effects of intra-hippocampal manipulation of glycine receptors on the reconsolidation of recent and late long-term spatial memory were evaluated and assessed in the Morris water maze. The results obtained from the intra-hippocampal infusion of glycine and taurine demonstrated that taurine at a 100 nmol/side dose impaired the reconsolidation of recent and late long-term spatial memory. In comparison, at a dose of 10 nmol/side, it only affected the reconsolidation of late long-term spatial memory, reinforcing that there are differences between molecular mechanisms underlying recent and late long-term memory reconsolidation. On the other hand, glycine impaired the reconsolidation of early and late spatial memory when infused at a dose of 10 nmol/side, but not at a dose of 100 nmol/side, unless it is co-infused with an allosteric site antagonist of the NMDA receptor. Altogether these results show that glycine acting in situ in the hippocampal CA1 region exerts a pharmacological effect on U-curve, which can be explained by its concomitant action on its ionotropic receptor GlyR and on its NMDA receptor co-agonist site.

On the participation of adenosinergic receptors in the reconsolidation of spatial long-term memory in male rats.

To date, there is insufficient evidence to explain the role of adenosinergic receptors in the reconsolidation of long-term spatial memory. In this work, the role of the adenosinergic receptor family (A1, A2A, A2B, and A3) in this process has been elucidated. It was demonstrated that when infused bilaterally into the hippocampal CA1 region immediately after an early nonreinforced test session performed 24 h posttraining in the Morris water maze task, adenosine can cause anterograde amnesia for recent and late long-term spatial memory. This effect on spatial memory reconsolidation was blocked by A1 or A3 receptor antagonists and mimicked by A1 plus A3 receptor agonists, showing that this effect occurs through A1 and A3 receptors simultaneously. The A3 receptor alone participates only in the reconsolidation of late long-term spatial memory. When the memory to be reconsolidated was delayed (reactivation 5 d posttraining), the amnesic effect of adenosine became transient and did not occur in a test performed 5 d after the reactivation of the mnemonic trace. Finally, it has been shown that the amnesic effect of adenosine on spatial memory reconsolidation depends on the occurrence of protein degradation and that the amnesic effect of inhibition of protein synthesis on spatial memory reconsolidation is dependent on the activation of A3 receptors.

Factors associated with Alzheimer's disease prevalence and mortality in Brazil-An ecological study.

A few epidemiological studies are evaluating the prevalence and mortality rates of Alzheimer's disease, with no one using a nationwide sample of Brazilian elderlies. This study aims to calculate the prevalence of Alzheimer's disease and investigate possible associations with sociodemographic and lifestyle factors and the presence of diseases non-communicable, and the prevalence and mortality for all Brazilian state capitals. This is an ecological design study made with secondary public data provided by the Ministry of Health. Prevalence rates were calculated based on the analysis of the dispensing of Alzheimer's disease-specific drugs. Correlation analyzes were performed between rates and factors, and a multiple linear regression analysis was used to analyze possible associations between variables, controlled for each other. AD prevalence was 313/100,000. Prevalence rates were positively associated with primary health care coverage factors and negatively associated with ultra-processed food consumption and physical activity levels. AD mortality was 98/100,000. Mortality rates were positively associated with the proportion of obese elderly and elderly living on up to half the minimum wage and were inversely associated with the proportion of elderly with diabetes factors. We found positive and negative associations of sociodemographic, behavioral and diabetes indicators with Alzheimer's disease prevalence and mortality, which provide data that can be investigated by studies with different designs.

Confirmed Synergy Between the ɛ4 Allele of Apolipoprotein E and the Variant K of Butyrylcholinesterase as a Risk Factor for Alzheimer's Disease: A Systematic Review and Meta-Analysis.

Background: Alzheimer's disease (AD) has several risk factors. APOE4 is the main one, and it has been suggested that there may be a synergy between it and BCHE-K as a risk factor. Objective: To investigate the association between APOE4 and BCHE-K as a risk factor for AD. Methods: We searched PubMed, Web of Science, Embase, and Scopus on August 8, 2021 for studies that analyzed the association of APOE4 and BCHE-K with AD. The random effect model was performed in meta-analysis according to age group. A chi-square was performed with the meta-analysis data to verify if the effect found is not associated only with the E4 allele. Results: Twenty-one studies with 6,853 subjects (3,528 AD and 3,325 Controls) were included in the meta-analysis. The quality of the evidence is moderate. There is a positive E4-K association for subjects with AD as shown by the odds ratio of 3.43. The chi-square meta test, which measures the probability that the E4-K association is due to chance, has an odds ratio of 6.155, indicating that the E4-K association is not a random event. The odds ratio of an E4-K association in subjects with AD increases to OR 4.46 for the 65- to 75-year-old group and OR 4.15 for subjects older than 75 years. The probability that the E4-K association is due to chance is ruled out by chi-square meta test values of OR 8.638 and OR 9.558. Conclusion: The synergy between APOE4 and BCHE-K is a risk factor for late-onset AD.

Association between cognitive performance and sarcopenic obesity in older adults with Alzheimer's disease.

Sarcopenic obesity (SO), the co-occurrence of sarcopenia and obesity, is associated with functional loss, frailty, and incapacity in older adults. Recently, SO was associated with reduced cognitive performance in adults. However, no SO studies have been done with older adults with Alzheimer's disease (AD). Objective: The objective of this study was to verify the occurrence of SO and associated factors in 43 older adults with AD. Methods: We applied the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). SO was verified by using dual-emission X-ray absorptiometry. Results: We found five women with SO. Women had higher body fat and lower muscle mass compared with men. There was a significant relationship between body fat and cognitive performance only in men (r=0.65; p<0.01) adjusted by age and education. Men with obesity and aged >75 years had better cognitive performance compared with non-obese men aged <75 years (p=0.010) and women with obesity aged >75 years (p=0.033). Conclusions: Women with AD had higher body fat and lower muscle mass than men. SO occurs in older women with AD. Men with higher body fat showed better cognitive performance, independent of age and education.

A obesidade sarcopênica (SO), coocorrência de sarcopenia e obesidade, está associada à perda funcional, à fragilidade e à incapacidade em idosos. Recentemente, verificou-se que a SO está associada ao desempenho cognitivo reduzido em adultos. No entanto, não foram feitos estudos de SO em idosos com doença de Alzheimer (AD). Objetivo: Verificar a ocorrência de obesidade sarcopênica e fatores associados em 43 adultos idosos com doença de Alzheimer. Métodos: Aplicamos o miniexame do estado mental (MEEM) e a avaliação clínica da demência (CDR). A SO foi verificada utilizando a absorciometria de dupla emissão de raios X. Resultados: Foram classificadas cinco idosas com SO. As mulheres idosas tinham maior gordura corporal e menor massa muscular em comparação com os homens. Houve relação significativa, ajustada por idade e educação, entre gordura corporal e desempenho cognitivo apenas nos homens (r=0,65; p<0,01). Os homens com obesidade e com mais de 75 anos tiveram melhor desempenho cognitivo em comparação com os homens não obesos <75 anos (p=0,010) e com as mulheres com obesidade >75 anos (p=0,033). Conclusões: As mulheres com AD tinham maior gordura corporal e menor massa muscular do que os homens. A SO ocorreu em mulheres mais velhas com AD. Os homens com maior gordura corporal apresentaram melhor desempenho cognitivo, independentemente da idade e da educação.

Neuroprotective effects of strength training in a neuroinflammatory animal model.

BACKGROUND: The preventive role of muscular strength on diminishing neuroinflammation is yet unknown. In this study, the role of the prophylactic muscular strength exercise was investigated in order to verify whether it would diminish cognitive alterations and modify the antioxidant intracellular scenery in an animal neuroinflammatory model in of the CA1 region of the hippocampus. METHODS: The animals received muscular strength training (SE) three times a week for eight weeks. Subsequently, the stereotaxic surgery was performed with an intra-hippocampal infusion of either saline solution (SAL) or lipopolysaccharide (LPS). Next, we performed the behavioral tests: object recognition and social recognition. Then, the animals were euthanized, and their hippocampus and prefrontal cortex were collected. In another moment, we performed the dosage of the antioxidant activity and histological analysis. RESULTS: The results showed that the muscular strength exercises could show a beneficial prophylactic effect in the cognitive deficiencies caused by acute neuroinflammation. Regarding oxidative stress, there was an increase in catalase enzyme activity (CAT) in the group (SE + LPS) compared to the control groups (p < 0.05). As for the cognitive alterations, there were found in the (SE + LPS) group, diminishing the mnemonic hazard of the discriminative and social memories compared to the control groups (p < 0.05). CONCLUSION: We concluded, therefore, that the exercise performed prophylactically presents a protective effect capable of minimizing such mnemonic deficits and increasing catalase enzyme activity in rats that suffered a local neuroinflammatory process in the hippocampus.

Delta-Aminolevulinate dehydratase and glutathione peroxidase activity in Alzheimer's disease: a case-control study.

Alzheimer's disease (AD) is a neurodegenerative pathology that affects elderly people all over the world. Several studies have demonstrated that oxidative stress is an aggravating factor for AD development and progression. Therefore, this study aimed to evaluate the activity of two oxidative stress markers, glutathione peroxidase (GPx) and δ-aminolevulinate dehydratase (δ-ALA-D), as well as correlate them with blood metal levels and AD progression. For this purpose, 88 elderly individuals were divided in two groups: AD group (34 patients diagnosed with AD) and control group (34 subjects paired by age with the AD group). The Mini-Mental State Examination and the Clinical Dementia Rating (CDR) were used as tools to classify the AD progression. GPx and δ-ALA-D activities were measured in all subjects through blood tests. Both enzymes' activities were decreased in AD patients when compared to the age-matched control group, regardless of the CDR. Moreover, GPx activity was positively correlated with selenium levels in the blood; and the δ-ALA-D activity was negatively correlated with blood copper levels. Taken together, our results indicated that, for the first time, blood δ-ALA-D activity was significantly inhibited in AD patients. While literature reports conflicting data regarding GPx activity in AD patients, the δ-ALA-D activity seems to be a more consistent tool to be applied as an earlier AD marker.

Supplementation with different teas from Camellia sinensis prevents memory deficits and hippocampus oxidative stress in ischemia-reperfusion.

Memory and cognition impairments resultant of ischemic stroke could be minimized or avoided by antioxidant supplementation. In this regard, the neuroprotective potential of Green tea from Camellia sinensis has been investigated. However, there is a lack of information regarding the neuroprotective potential of others teas processed from the Camellia sinensis. Here we investigate the neuroprotective role of green, red, white and black tea on memory deficits and brain oxidative stress in a model of ischemic stroke in rats. Our findings show that green and red teas prevent deficits in object and social recognition memories, but only green tea protects against deficits in spatial memory and avoids hippocampal oxidative status and intense necrosis and others alterations in the brain tissue. In summary, green tea shows better neuroprotection in ischemic stroke than the others teas from Camellia sinensis.

Effects of l-arginine and creatine administration on spatial memory in rats subjected to a chronic variable stress model.

CONTEXT: Chronic stress results from repeated exposure to one or more types of stressors over a period, ranging from days to months, and can be associated with physical, behavioral, and neuropsychiatric manifestations. Some physiological alterations resulting from chronic stress can potentially cause deficits on spatial learning and memory. OBJECTIVE: This study investigated the effects of chronic variable stress (CVS) and administration of l-arginine and creatine on spatial memory in rats. Furthermore, body, heart, adrenal weight, and plasma glucose and corticosterone levels were analyzed. MATERIAL AND METHODS: Male Wistar rats were subjected to a CVS model for 40 days and evaluated for spatial memory after the stress period. Chronically stressed animals were treated daily by gavage with: 0.5% carboxymethylcellulose (Group Cs), 500 mg/kg l-arginine (Group Cs/La), 300 mg/kg creatine (Group Cs/Cr); and 500 mg/kg l-arginine and 300 mg/kg creatine (Group Cs/La + Cr) during the entire experimental period. RESULTS: Our results showed that animals in the Cs/Cr and Cs/La + Cr groups presented significantly decreased corticosterone levels compared to group Cs (p < 0.05); animals in group Cs/Cr were more efficient in finding the platform, in the working memory task, compared to all other groups (p < 0.01); and animals in group Cs/La + Cr significantly improved in reference memory retention compared to controls (p < 0.05). DISCUSSION AND CONCLUSION: Overall, these results demonstrated that a single administration of creatine improves working memory efficiency, and, when co-administrated with l-arginine, improves reference memory retention, a phenomenon that is possibly associated with increased creatine/phosphocreatine levels and l-arginine-derived NO synthesis.

Memory reconsolidation and its maintenance depend on L-voltage-dependent calcium channels and CaMKII functions regulating protein turnover in the hippocampus.

Immediate postretrieval bilateral blockade of long-acting voltage-dependent calcium channels (L-VDCCs), but not of glutamatergic NMDA receptors, in the dorsal CA1 region of the hippocampus hinders retention of long-term spatial memory in the Morris water maze. Immediate postretrieval bilateral inhibition of calcium/calmodulin-dependent protein kinase (CaMK) II in dorsal CA1 does not affect retention of this task 24 h later but does hinder it 5 d later. These two distinct amnesic effects are abolished if protein degradation by proteasomes is inhibited concomitantly. These results indicate that spatial memory reconsolidation depends on the functionality of L-VDCC in dorsal CA1, that maintenance of subsequent reconsolidated memory trace depends on CaMKII, and these results also suggest that the role played by both L-VDCC and CaMKII is to promote the retrieval-dependent, synaptically localized enhancement of protein synthesis necessary to counteract a retrieval-dependent, synaptic-localized enhancement of protein degradation, which has been described as underlying the characteristic labilization of the memory trace triggered by retrieval. Thus, conceivably, L-VDCC and CaMKII would enhance activity-dependent localized protein renewal, which may account for the improvement of the long-term efficiency of the synapses responsible for the maintenance of reactivated long-term spatial memory.

Histamine reverses a memory deficit induced in rats by early postnatal maternal deprivation.

Early partial maternal deprivation causes long-lasting neurochemical, behavioral and brain structural effects. In rats, it causes a deficit in memory consolidation visible in adult life. Some of these deficits can be reversed by donepezil and galantamine, which suggests that they may result from an impairment of brain cholinergic transmission. One such deficit, representative of all others, is an impairment of memory consolidation, clearly observable in a one-trial inhibitory avoidance task. Recent data suggest a role of brain histaminergic systems in the regulation of behavior, particularly inhibitory avoidance learning. Here we investigate whether histamine itself, its analog SKF-91844, or various receptor-selective histamine agonists and antagonists given into the CA1 region of the hippocampus immediately post-training can affect retention of one-trial inhibitory avoidance in rats submitted to early postnatal maternal deprivation. We found that histamine, SKF-91844 and the H2 receptor agonist, dimaprit enhance consolidation on their own and reverse the consolidation deficit induced by maternal deprivation. The enhancing effect of histamine was blocked by the H2 receptor antagonist, ranitidine, but not by the H1 receptor antagonist pyrilamine or by the H3 antagonist thioperamide given into CA1 at doses known to have other behavioral actions, without altering locomotor and exploratory activity or the anxiety state of the animals. The present results suggest that the memory deficit induced by early postnatal maternal deprivation in rats may in part be due to an impairment of histamine mediated mechanisms in the CA1 region of the rat hippocampus.

Histaminergic mechanisms for modulation of memory systems.

Encoding for several memory types requires neural changes and the activity of distinct regions across the brain. These areas receive broad projections originating in nuclei located in the brainstem which are capable of modulating the activity of a particular area. The histaminergic system is one of the major modulatory systems, and it regulates basic homeostatic and higher functions including arousal, circadian, and feeding rhythms, and cognition. There is now evidence that histamine can modulate learning in different types of behavioral tasks, but the exact course of modulation and its mechanisms are controversial. In the present paper we review the involvement of the histaminergic system and the effects histaminergic receptor agonists/antagonists have on the performance of tasks associated with the main memory types as well as evidence provided by studies with knockout models. Thus, we aim to summarize the possible effects histamine has on modulation of circuits involved in memory formation.

Histamine facilitates consolidation of fear extinction.

Non-reinforced retrieval induces memory extinction, a phenomenon characterized by a decrease in the intensity of the learned response. This attribute has been used to develop extinction-based therapies to treat anxiety and post-traumatic stress disorders. Histamine modulates memory and anxiety but its role on fear extinction has not yet been evaluated. Therefore, using male Wistar rats, we determined the effect of the intra-hippocampal administration of different histaminergic agents on the extinction of step-down inhibitory avoidance (IA), a form of aversive learning. We found that intra-CA1 infusion of histamine immediately after non-reinforced retrieval facilitated consolidation of IA extinction in a dose-dependent manner. This facilitation was mimicked by the histamine N-methyltransferase inhibitor SKF91488 and the H2 receptor agonist dimaprit, reversed by the H2 receptor antagonist ranitidine, and unaffected by the H1 antagonist pyrilamine, the H3 antagonist thioperamide and the antagonist at the NMDA receptor (NMDAR) polyamine-binding site ifenprodil. Neither the H1 agonist 2-2-pyridylethylamine nor the NMDAR polyamine-binding site agonist spermidine affected the consolidation of extinction while the H3 receptor agonist imetit hampered it. Extinction induced the phosphorylation of ERK1 in dorsal CA1 while intra-CA1 infusion of the MEK inhibitor U0126 blocked extinction of the avoidance response. The extinction-induced phosphorylation of ERK1 was enhanced by histamine and dimaprit and blocked by ranitidine administered to dorsal CA1 after non-reinforced retrieval. Taken together, our data indicate that the hippocampal histaminergic system modulates the consolidation of fear extinction through a mechanism involving the H2-dependent activation of ERK signalling.