RESUMO
Background: Previous work from our group has shown that chronic exposure to Vanadium pentoxide (V2O5) causes cytoskeletal alterations suggesting that V2O5 can interact with cytoskeletal proteins through polymerization and tyrosine phosphatases inhibition, causing Alzheimer's disease (AD)-like hippocampal cell death. Objective: This work aims to characterize an innovative AD experimental model through chronic V2O5 inhalation, analyzing the spatial memory alterations and the presence of neurofibrillary tangles (NFTs), amyloid-ß (Aß) senile plaques, cerebral amyloid angiopathy, and dendritic spine loss in AD-related brain structures. Methods: 20 male Wistar rats were divided into control (deionized water) and experimental (0.02âM V2O5 1âh, 3/week for 6 months) groups (nâ=â10). The T-maze test was used to assess spatial memory once a month. After 6 months, histological alterations of the frontal and entorhinal cortices, CA1, subiculum, and amygdala were analyzed by performing Congo red, Bielschowsky, and Golgi impregnation. Results: Cognitive results in the T-maze showed memory impairment from the third month of V2O5 inhalation. We also noted NFTs, Aß plaque accumulation in the vascular endothelium and pyramidal neurons, dendritic spine, and neuronal loss in all the analyzed structures, CA1 being the most affected. Conclusions: This model characterizes neurodegenerative changes specific to AD. Our model is compatible with Braak AD stage IV, which represents a moment where it is feasible to propose therapies that have a positive impact on stopping neuronal damage.
Assuntos
Doença de Alzheimer , Encéfalo , Modelos Animais de Doenças , Memória Espacial , Compostos de Vanádio , Animais , Masculino , Administração por Inalação , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/patologia , Angiopatia Amiloide Cerebral/induzido quimicamente , Angiopatia Amiloide Cerebral/patologia , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Córtex Entorrinal/efeitos dos fármacos , Córtex Entorrinal/patologia , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/patologia , Aprendizagem em Labirinto/efeitos dos fármacos , Emaranhados Neurofibrilares/efeitos dos fármacos , Emaranhados Neurofibrilares/patologia , Placa Amiloide/induzido quimicamente , Placa Amiloide/patologia , Ratos Wistar , Memória Espacial/efeitos dos fármacos , Compostos de Vanádio/administração & dosagem , Compostos de Vanádio/toxicidadeRESUMO
BACKGROUND: There is an increasing concern about the neurotoxicity of engineered nanomaterials (NMs). To investigate the effects of subchronic oral exposures to SiO2 and CeO2 NMs on Alzheimer's disease (AD)-like pathology, 5xFAD transgenic mice and their C57BL/6J littermates were fed ad libitum for 3 or 14 weeks with control food pellets, or pellets dosed with these respective NMs at 0.1% or 1% (w/w). Behaviour effects were evaluated by X-maze, string suspension, balance beam and open field tests. Brains were analysed for plaque load, beta-amyloid peptide levels, markers of oxidative stress and neuroinflammation. RESULTS: No marked behavioural impairments were observed in the mice exposed to SiO2 or CeO2 and neither treatment resulted in accelerated plaque formation, increased oxidative stress or inflammation. In contrast, the 5xFAD mice exposed to 1% CeO2 for 14 weeks showed significantly lower hippocampal Aß plaque load and improved locomotor activity compared to the corresponding controls. CONCLUSIONS: The findings from the present study suggest that long-term oral exposure to SiO2 or CeO2 NMs has no neurotoxic and AD-promoting effects. The reduced plaque burden observed in the mice following dietary CeO2 exposure warrants further investigation to establish the underlying mechanism, given the easy applicability of this administration method.
Assuntos
Doença de Alzheimer , Nanoestruturas , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Exposição Dietética , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nanoestruturas/toxicidade , Placa Amiloide/induzido quimicamente , Dióxido de Silício/toxicidadeRESUMO
Dystrophic neuronal processes harboring neuritic plaque (NP) tau pathology are found in association with Aß plaques in Alzheimer's disease (AD) brain. Microglia are also in proximity to these plaques and microglial gene variants are known risk factors in AD, including loss-of-function variants of TREM2. We have further investigated the role of Aß plaque-associated microglia in 5XFAD mice in which NP tau pathology forms after intracerebral injection of AD brain-derived pathologic tau (AD-tau), focusing on the consequences of reduced TREM2 expression and microglial depletion after treatment with the colony-stimulating factor 1 (CSFR1) inhibitor, PLX3397. Young 5XFAD mice treated with PLX3397 had a large reduction of brain microglia, including cortical plaque-associated microglia, with a significant reduction of Aß plaque burden in the cortex. A corresponding decrease in cortical APP-positive dystrophic processes and NP tau pathology were observed after intracerebral AD-tau injection in the PLX3397-treated 5XFAD mice. Consistent with prior reports, 5XFAD × TREM2-/- mice showed a significant reduction of plaque-associated microglial, whereas 5XFAD × TREM2+/- mice had significantly more plaque-associated microglia than 5XFAD × TREM2-/- mice. Nonetheless, AD-tau injected 5XFAD × TREM2+/- mice showed greatly increased AT8-positive NP tau relative to 5XFAD × TREM2+/+ mice. Expression profiling revealed that 5XFAD × TREM2+/- mice had a disease-associated microglial (DAM) gene expression profile in the brain that was generally intermediate between 5XFAD × TREM2+/+ and 5XFAD × TREM2-/- mice. Microarray analysis revealed significant differences in cortical and hippocampal gene expression between AD-tau injected 5XFAD × TREM2+/- and 5XFAD × TREM2-/- mice, including pathways linked to microglial function. These data suggest there is not a simple correlation between the extent of microglia plaque interaction and plaque-associated neuritic damage. Moreover, the differences in gene expression and microglial phenotype between TREM2+/- and TREM2-/- mice suggest that the former may better model the single copy TREM2 variants associated with AD risk.
Assuntos
Glicoproteínas de Membrana/deficiência , Microglia/metabolismo , Placa Amiloide/metabolismo , Receptores Imunológicos/deficiência , Proteínas tau/toxicidade , Animais , Feminino , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Placa Amiloide/induzido quimicamente , Placa Amiloide/genética , Receptores Imunológicos/genética , Proteínas tau/administração & dosagemRESUMO
Drug discovery and development for Alzheimer's disease (AD) are complex and challenging due to the higher failure rate in the drug development process. The overproduction and deposition of Aß senile plaque and intracellular neurofibrillary tangle (NFT) formation are well-recognized diagnostic hallmarks of AD. Numerous transgenic models of Alzheimer's disease have restrictions on cost-effectiveness and time in the preclinical setup. Zebrafish has emerged as an excellent complementary model for neurodegenerative research due to simpler organisms with robust, clearly visible behavior forms. Glutaminergic and cholinergic pathways responsible for learning and memory are present in zebrafish and actively participate in the transmission process. Therefore, it is imperative to study neurotoxic agents' mechanisms that induce dysfunction of memory, learning, and neurons in the zebrafish. This review illustrates the in-depth molecular mechanism of several neurotoxic agents such as okadaic acid, cigarette smoke extract, and metals to produce cognitive deficits or neurodegeneration similar to mammals. These updates would determine an ideal and effective neurotoxic agent for producing AD pathophysiology in the zebrafish brain for preclinical screening.
Assuntos
Doença de Alzheimer/induzido quimicamente , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Neurotoxinas/toxicidade , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Placa Amiloide/induzido quimicamente , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Peixe-Zebra , Proteínas tau/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum (G. lucidum, Lingzhi), also known as "immortality mushroom" has been broadly used to improve health and longevity for thousands of years in Asia. G. lucidum and its spores have been used to promote health, based on its broad pharmacological and therapeutic activity. This species is recorded in Chinese traditional formula as a nootropic and has been suggested to improve cognitive dysfunction in Alzheimer's disease. However, little is known about the nootropic effects and molecular mechanism of action of G. lucidum spores. AIM OF THE STUDY: The present study investigated the protective effects of sporoderm-deficient Ganoderma lucidum spores (RGLS) against learning and memory impairments and its mechanism of action. MATERIALS AND METHODS: In the Morris water maze, the effects of RGLS on learning and memory impairments were evaluated in a rat model of sporadic Alzheimer's disease that was induced by an intracerebroventricular injection of streptozotocin (STZ). Changes in amyloid ß (Aß) expression, Tau expression and phosphorylation, brain-derived neurotrophic factor (BDNF), and the BDNF receptor tropomyosin-related kinase B (TrkB) in the hippocampus were evaluated by Western blot. RESULTS: Treatment with RGLS (360 and 720 mg/kg) significantly enhanced memory in the rat model of STZ-induced sporadic Alzheimer's disease and reversed the STZ-induced increases in Aß expression and Tau protein expression and phosphorylation at Ser199, Ser202, and Ser396. The STZ-induced decreases in neurotrophic factors, including BDNF, TrkB and TrkB phosphorylation at Tyr816, were reversed by treatment with RGLS. CONCLUSION: These findings indicate that RGLS prevented learning and memory impairments in the present rat model of STZ-induced sporadic Alzheimer's disease, and these effects depended on a decrease in Aß expression and Tau hyperphosphorylation and the modulation of BDNF-TrkB signaling in the hippocampus.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Transtornos da Memória/prevenção & controle , Reishi/química , Esporos Fúngicos/química , Doença de Alzheimer/induzido quimicamente , Peptídeos beta-Amiloides/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/uso terapêutico , Hipocampo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Fosforilação/efeitos dos fármacos , Placa Amiloide/induzido quimicamente , Placa Amiloide/prevenção & controle , Ratos Sprague-Dawley , Receptor trkB/efeitos dos fármacos , Receptor trkB/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/toxicidade , Proteínas tau/efeitos dos fármacos , Proteínas tau/metabolismoRESUMO
The protein misfolded structure called amyloids is related with extensive range of pathologies like local amyloidosis and neurodegenerative diseases. Several studies have reported the potential of insulin to generate local amyloidosis under certain state. Reports also showed that fibrils of insulin generated local amyloid mass due to continuous subcutaneous injection in mouse as well as rat. The present study was designed to examine the consequence of insulin fibril injections in rats, as well as the ability of enzymes, Lumbrokinase (LK) and Serratiopeptidase (SP) in diminishing this amyloid mass progression. The results showed that insulin fibrils generated amyloid masses in rats after subcutaneous injection for two weeks which was significantly condensed in size for the groups injected with insulin fibrils combined with LK or SP. At higher doses of LK and SP, the absence of amyloid structure was observed in histopathological studies. Light microscopy, polarized microscopy as well as Lumia live in vivo imaging system was used to analyze the results. In conclusion, the overall outcome of this study showed the anti-amyloid potential of enzyme LK and SP in the attenuation of local amyloidosis.
Assuntos
Endopeptidases/farmacologia , Insulina/efeitos adversos , Peptídeo Hidrolases/farmacologia , Placa Amiloide/metabolismo , Placa Amiloide/prevenção & controle , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/prevenção & controle , Animais , Benzotiazóis/química , Vermelho Congo/química , Modelos Animais de Doenças , Reação no Local da Injeção/patologia , Reação no Local da Injeção/prevenção & controle , Injeções Subcutâneas , Insulina/administração & dosagem , Masculino , Microscopia de Fluorescência , Microscopia de Polarização , Placa Amiloide/induzido quimicamente , Placa Amiloide/patologia , Agregação Patológica de Proteínas/induzido quimicamente , Agregação Patológica de Proteínas/patologia , Ratos , Ratos Wistar , Tela Subcutânea/efeitos dos fármacos , Tela Subcutânea/patologiaRESUMO
Excess of Aß42 peptide is considered a hallmark of the disease. Here we express the human Aß42 peptide to assay the neuroprotective effects of PI3K in adult Drosophila melanogaster. The neuronal expression of the human peptide elicits progressive toxicity in the adult fly. The pathological traits include reduced axonal transport, synapse loss, defective climbing ability and olfactory perception, as well as lifespan reduction. The Aß42-dependent synapse decay does not involve transcriptional changes in the core synaptic protein encoding genes bruchpilot, liprin and synaptobrevin. All toxicity features, however, are suppressed by the coexpression of PI3K. Moreover, PI3K activation induces a significant increase of 6E10 and thioflavin-positive amyloid deposits. Mechanistically, we suggest that Aß42-Ser26 could be a candidate residue for direct or indirect phosphorylation by PI3K. Along with these in vivo experiments, we further analyze Aß42 toxicity and its suppression by PI3K activation in in vitro assays with SH-SY5Y human neuroblastoma cell cultures, where Aß42 aggregation into large insoluble deposits is reproduced. Finally, we show that the Aß42 toxicity syndrome includes the transcriptional shut down of PI3K expression. Taken together, these results uncover a potential novel pharmacological strategy against this disease through the restoration of PI3K activity.
Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/farmacologia , Drosophila melanogaster/genética , Longevidade/efeitos dos fármacos , Percepção Olfatória/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Fosfatidilinositol 3-Quinases/genética , Placa Amiloide/genética , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Animais , Animais Geneticamente Modificados , Transporte Axonal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fragmentos de Peptídeos/química , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Placa Amiloide/induzido quimicamente , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Agregados Proteicos , Proteínas R-SNARE/genética , Proteínas R-SNARE/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismoRESUMO
BACKGROUND: Formaldehyde (FA) has been implicated in Alzheimer's disease (AD) pathology as an age-related factor and as a protein cross-linker known to aggregate Amyloid-Beta (Aß) and tau protein in vitro. Higher levels of FA have also been found in patients with greater cognitive impairment and in AD patient brains. OBJECTIVE: To directly evaluate the effect of chronically elevated FA levels on the primate brain with respect to AD pathological markers. METHOD: Young rhesus macaques (5-8 yrs, without AD related mutations) were given chronic intracerebroventricular (i.c.v.) injections of FA or vehicle over a 12-month period. Monkeys were monitored for changes in cognitive ability and evaluated post-mortem for common AD pathological markers. RESULTS: Monkeys injected with FA were found to have significant spatial working memory impairments. Histopathological analysis revealed the presence of amyloid-ß+ neuritic-like plaques, neurofibrillary tangle-like formations, increased tau protein phosphorylation, neuronal loss and reactive gliosis in three memory (and AD) related brain areas (the hippocampus, entorhinal cortex and prefrontal cortex (PFC)) of monkeys receiving i.c.v. injections of FA. ELISA assays revealed that the amounts of pT181 and Aß42 were markedly higher in the PFC and hippocampus of FA treated monkeys. CONCLUSION: FA was found to induce major AD-like pathological markers and cognitive impairments in young rhesus monkeys independent of genetic predispositions. This suggests FA may play a significant role in the initiation and progression of the disease.
Assuntos
Doença de Alzheimer/induzido quimicamente , Transtornos Cognitivos/induzido quimicamente , Modelos Animais de Doenças , Desinfetantes/toxicidade , Formaldeído/toxicidade , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Transtornos Cognitivos/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/induzido quimicamente , Macaca mulatta , Masculino , Memória de Curto Prazo/fisiologia , Rememoração Mental/fisiologia , Fosfopiruvato Hidratase/metabolismo , Placa Amiloide/induzido quimicamente , Placa Amiloide/patologia , Quinolinas/metabolismo , Processamento Espacial/fisiologia , Proteínas tau/metabolismoRESUMO
RATIONALE: Alzheimer's disease (AD) is the most common form of dementia characterized by a progressive decline in cognitive function. The serotonergic system via the 5-HT1A receptor and 5-HT2A receptor is proposed to affect the cognitive process. OBJECTIVE: In the present study, the effects of NAD-299 (5-HT1AR antagonist) and TCB-2 (5-HT2AR agonist) on learning and memory processes, hippocampal brain-derived neurotrophic factor (BDNF) levels, neuronal necrosis, and Aß plaque production have been investigated on the intracerebroventricular (icv) injection of streptozotocin (STZ)-induced memory deficits in rats. METHODS: Fifty-four adult male Wistar rats (250-300 g) were divided into six groups (n = 9 in each group): control, sham-operated, AD (icv-STZ (3 mg/kg, 10 µl)), AD+NAD-299 (5 µg/1 µl icv for 30 days), AD+TCB-2 (5 µg/1 µl icv for 30 days), and AD+NAD-299 + TCB-2 (NAD-299 (5 µg/0.5 µl icv) and TCB-2 (5 µg/0.5 µl icv) for 30 days). Following the treatment period, rats were subjected to behavioral tests of learning and memory. Then, hippocampal BDNF, amyloid-beta (Aß) plaque, and neuronal loss were determined by ELISA Kit, Congo red staining, and Nissl staining, respectively. RESULTS: The results of behavioral tests showed that icv-STZ injection decreased the discrimination index in the novel object recognition (NOR) test. In the passive avoidance learning (PAL) task, icv-STZ injection significantly decreased step-through latency (STLr) and increased time spent in dark compartment (TDC). Treatment with NAD-299, TCB-2, and NAD-299 + TCB-2 attenuated the STZ-induced memory impairment in both NOR and PAL tasks. icv-STZ induced a decrease in hippocampal BDNF levels and increased Aß plaques production in the brain, whereas treatment with NAD-299, TCB-2, and NAD-299 + TCB-2 reduced Aß plaques in the brain and increased the hippocampal BDNF level. Results of Nissl staining showed that icv-STZ injection increased neuronal loss in the hippocampus, while treatment with NAD-299, TCB-2, and NAD-299 + TCB-2 reduced hippocampal neurodegeneration. CONCLUSION: These findings suggest that 5-HT1AR blockade by NAD-299 and 5-HT2AR activation by TCB-2 improve cognitive dysfunction in icv-STZ-treated rats, and these drugs may potentially prevent the progression of AD.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Benzopiranos/uso terapêutico , Compostos Bicíclicos com Pontes/uso terapêutico , Hipocampo/metabolismo , Transtornos da Memória/metabolismo , Metilaminas/uso terapêutico , Placa Amiloide/metabolismo , Animais , Aprendizagem da Esquiva/fisiologia , Benzopiranos/farmacologia , Fator Neurotrófico Derivado do Encéfalo , Compostos Bicíclicos com Pontes/farmacologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Metilaminas/farmacologia , Placa Amiloide/induzido quimicamente , Placa Amiloide/tratamento farmacológico , Distribuição Aleatória , Ratos , Ratos Wistar , Receptor 5-HT2A de Serotonina/metabolismo , Estreptozocina/toxicidadeRESUMO
Lead exposure has been evidenced as a risk factor for Alzheimer's disease (AD), mainly affecting the ageing. However, the early manifestation and mechanisms of AD-like pathology induced by lead exposure remains to be elucidated. Considering the fact that impaired cholesterol metabolism is associated with many neurodegenerative disorders including AD, in this study we focused on the role of cholesterol metabolism in lead induced premature AD-like pathology. We treated weaning rats with lead at different concentrations for 4 weeks. We found that developmental lead exposure increased amyloid-beta (Aß) accumulation and amyloid plaque deposition in the cortex and hippocampus. Lead exposure increased amyloid precursor protein (APP) expression and activated the sterol regulatory element binding protein 2 (SREBP2)-beta secretase (BACE1) pathway. In addition, we found that lead exposure decreased cholesterol levels by upregulating the expression of liver X receptor-a (LXR-a) and ATP-binding cassette transporter protein family member A1 (ABCA1) and decreasing the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CR) and low density lipoprotein receptor (LDL-R) in young rat brain tissues. Taken together, our data demonstrated that developmental lead exposure induced early manifestation of AD-like pathology and disturbed cholesterol metabolism in young rat brains.
Assuntos
Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Encéfalo/patologia , Colesterol/metabolismo , Intoxicação do Sistema Nervoso por Chumbo/patologia , Chumbo/toxicidade , Secretases da Proteína Precursora do Amiloide/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Encefálica/efeitos dos fármacos , Chumbo/sangue , Masculino , Tamanho do Órgão/efeitos dos fármacos , Placa Amiloide/induzido quimicamente , Placa Amiloide/patologia , Ratos , Ratos Sprague-Dawley , Receptores de LDL/efeitos dos fármacos , Receptores de LDL/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas de Ligação a Elemento Regulador de Esterol/efeitos dos fármacosRESUMO
Alzheimer's disease (AD) is the most common type of dementia, mainly encompassing cognitive decline in subjects aged ≥65 years. Further, AD is characterized by selective synaptic and neuronal degeneration, vascular dysfunction, and two histopathological features: extracellular amyloid plaques composed of amyloid beta peptide (Aß) and neurofibrillary tangles formed by hyperphosphorylated tau protein. Dementia and AD are chronic neurodegenerative conditions with a complex physiopathology involving both genetic and environmental factors. Recent clinical studies have shown that proton pump inhibitors (PPIs) are associated with risk of dementia, including AD. However, a recent case-control study reported decreased risk of dementia. PPIs are a widely indicated class of drugs for gastric acid-related disorders, although most older adult users are not treated for the correct indication. Although neurological side effects secondary to PPIs are rare, several preclinical reports indicate that PPIs might increase Aß levels, interact with tau protein, and affect the neuronal microenvironment through several mechanisms. Considering the controversy between PPI use and dementia risk, as well as both cognitive and neuroprotective effects, the aim of this review is to examine the relationship between PPI use and brain effects from a neurobiological and clinical perspective.
Assuntos
Demência/induzido quimicamente , Demência/metabolismo , Inibidores da Bomba de Prótons/metabolismo , Inibidores da Bomba de Prótons/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Estudos de Casos e Controles , Demência/tratamento farmacológico , Humanos , Emaranhados Neurofibrilares/efeitos dos fármacos , Emaranhados Neurofibrilares/metabolismo , Placa Amiloide/induzido quimicamente , Placa Amiloide/tratamento farmacológico , Placa Amiloide/metabolismo , Inibidores da Bomba de Prótons/efeitos adversos , Proteínas tau/metabolismoRESUMO
BACKGROUND: There is increasing interest in whether anesthetic agents affect the risk or progression of Alzheimer's disease (AD). To mitigate many of the methodological issues encountered in human retrospective cohort studies we have used a transgenic model of AD to investigate the effect of propofol on AD pathology. METHODS: Six month-old amyloid precursor protein/presenilin 1 (APP/PS1) transgenic AD mice and control mice were exposed to 3 doses of propofol (200 mg/kg) or vehicle, delivered at monthly intervals. RESULTS: There was no difference in the extent of ß-amyloid (Aß) immunolabeled plaque deposition in APP/PS1 mice in vehicle versus propofol treatment groups. We also detected no difference in plaque-associated synapse loss in APP/PS1 mice following repeat propofol exposure relative to vehicle. Western blotting indicated that there was no difference in post-synaptic density protein 95, synaptophysin or glutamic acid decarboxylase 65/67 expression in control or APP/PS1 mice subjected to repeat propofol treatment relative to vehicle. CONCLUSIONS: These data suggest that repeat propofol anesthesia may not exacerbate plaque deposition or associated synapse loss in AD. Interestingly, this data also provides some of the first evidence suggesting that repeat propofol exposure in adult wild-type mice does not result in robust long-term alterations in the levels of key excitatory and inhibitory synaptic markers.
Assuntos
Doença de Alzheimer/patologia , Anestésicos Intravenosos/farmacologia , Encéfalo/efeitos dos fármacos , Placa Amiloide/patologia , Propofol/farmacologia , Sinapses/efeitos dos fármacos , Doença de Alzheimer/induzido quimicamente , Anestésicos Intravenosos/administração & dosagem , Animais , Western Blotting , Encéfalo/patologia , Encéfalo/ultraestrutura , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Transgênicos , Placa Amiloide/induzido quimicamente , Propofol/administração & dosagem , Sinapses/patologiaRESUMO
OBJECTIVE: The purpose of this study was to describe the imaging characteristics of subcutaneous amyloid deposits occurring at sites of insulin injection, commonly known as "insulin balls," in diabetic patients on ultrasound, CT, and MRI with pathologic correlation. MATERIALS AND METHODS: We retrospectively reviewed the radiographic findings of 14 lesions in 9 patients diagnosed with subcutaneous amyloid deposits at our institution between 2005-2015. Three board-certified radiologists analyzed the following: (1) the shape, size, margin, morphologic characteristics, and blood flow on US using the color Doppler signal, (2) shape, size, margin, attenuation, and presence or absence of contrast enhancement on CT, and (3) shape, size, margin, signal intensity, and presence or absence of contrast enhancement on MRI. RESULTS: All lesions showed ill-defined hypovascular subcutaneous nodules with irregular margins. The median diameter of lesions was 50.4 mm on US, 46.8 mm on CT, and 51.4 mm on MRI. The internal echogenicity of subcutaneous amyloid deposits was hypoechoic and heterogeneous on US. All lesions showed isodensity compared to muscle with irregular margins and minimal contrast enhancement on CT. Both T1- and T2-weighted MR images showed low signal intensity compared with subcutaneous fat. Normal diffusion and minimal contrast enhancement were seen. CONCLUSIONS: Subcutaneous amyloid deposits which cause insulin resistance are typically ill-defined and heterogeneous hypovascular subcutaneous nodules with irregular margins on imaging that correspond to insulin injection sites. It is also characteristic that T2WI shows low intensity compared with fat on MRI, reflective of the amyloid content.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Placa Amiloide/induzido quimicamente , Placa Amiloide/diagnóstico por imagem , Adulto , Idoso , Meios de Contraste , Feminino , Humanos , Injeções Subcutâneas , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Amyloidosis is a heterogeneous group of protein deposition diseases with more than 40 known clinical presentations. Localized amyloidosis occurs when the protein deposits exist in a singular location. Patients with diabetes mellitus who inject insulin at the same site can develop localized insulin-derived amyloidosis (AIns) at the injection site, which can be confused clinically with lipoma, lipohyperplasia, lipoatrophy, and fat necrosis. Histologic examination is performed to confirm localized AIns. We report a case of a patient with a long history of type 2 diabetes who presented with a subcutaneous mass in the abdomen at a preferred insulin injection site. Examination by light microscopy revealed diffuse deposition of eosinophilic material. Two of the tissue fragments contained numerous 30-40 µm spherical bodies within the eosinophilic material. The bodies had dark centers with peripheral eosinophilic material. Polarized sections stained with Congo red showed apple green birefringence, a characteristic of amyloid. Immunohistochemistry was positive for insulin antibodies in the dark spherules and the surrounding matrix. Proteomic analysis by mass spectrometry showed that the Congo red-positive material was insulin. Electron microscopy showed a background matrix consisting of nonbranching protein fibrils measuring 8.8-16.1 nm, consistent with amyloid; the spherules contained dark globular proteins in the center surrounded by nonbranching fibrillary proteins. Because these spherules were positive for insulin by immunohistochemistry and showed amyloid ultrastructurally, we refer to them as amyloid insulin bodies. The identification of AIns, specifically with amyloid insulin bodies, is important for diagnosis and treatment and may further our understanding of amyloidogenesis.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Placa Amiloide/induzido quimicamente , Abdome/patologia , Idoso , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Injeções Subcutâneas , Insulina/administração & dosagem , Placa Amiloide/patologiaRESUMO
As the resident macrophage of the central nervous system, microglia are thought to contribute to Alzheimer's disease (AD) pathology through lack of neuroprotection. The role of immune dysfunction in AD may be due to disruption of regulatory signals for the activation of microglia that may occur early in development. We hypothesized that early toxicant exposure would systematically activate microglia, possibly reversing the pathological severity of AD. Offspring of a triple transgenic murine model for AD (3×TgAD) were exposed to a model neurotoxicant, lead acetate, from postnatal days (PND) 5-10. Our results indicated that female mice exposed to Pb had a greater and earlier incidence of amyloid burden within the hippocampus, coinciding with decreased markers of microglial activation at PND 50. Pb-exposed males had increased microglial activation at PND 50, as evidence by CD11b expression and microglial abundance, with no significant increase in amyloid burden at that time. There was greater amyloid burden at PND 90 and 180 in both male and female mice exposed to Pb compared with control. Together, these data suggest that activated microglia are neuroprotective against amyloid accumulation early in AD pathology, and that early exposure to Pb could increase susceptibility to later-life neurodegeneration. Likewise, females may be more susceptible to early-life microglial damage, and, subsequently, AD. Further investigation into the sex biased mechanisms by which microglial activation is altered by an early-life immune insult will provide critical insight into the temporal susceptibility of the developing neuroimmune system and its potential role in AD etiopathology.
Assuntos
Doença de Alzheimer/metabolismo , Modelos Animais de Doenças , Chumbo/toxicidade , Microglia/metabolismo , Placa Amiloide/metabolismo , Caracteres Sexuais , Fatores Etários , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Animais , Feminino , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/patologia , Placa Amiloide/induzido quimicamente , Placa Amiloide/patologia , GravidezRESUMO
Previous phytochemical investigations of Akebiae Caulis resulted in the isolation of triterpenes, triterpene glycosides, phenylethanoid glycosides and megastigmane glycoside. Amyloid beta (Aß), the main component of the senile plaques detected in Alzheimer's disease, induces cell death. However, only a limited number of studies have addressed the biological and pharmacological effects of Akebiae Caulis. In particular, the inhibitory activity of Akebiae Caulis against Aß42 fibrillogenesis remains unclear. Herein, a new triterpene glycoside, akequintoside F (1), along with nine known compounds pulsatilla saponin A (2), collinsonidin (3), akebonic acid (4), hederagenin (5), 1-(3',4'-dihydroxycinnamoyl) cyclopentane-2,3-diol (6), asperosaponin C (7), leontoside A (8), quinatic acid (9), and quinatoside A (10) were isolated from Akebiae Caulis using repeated column chromatography with silica gel, LiChroprep RP-18, and MCI gel. The chemical structures of compounds 1-10 were illustrated based on 1D and 2D NMR spectroscopy, including 1H-1H COSY, HSQC, HMBC and NOESY spectroscopic analyses. Compound 1 a novel compound and known compounds 6 and 7 were isolated for the first time from this plant. Among these compounds, 1, 3, 4, 5 and 7 displayed significant inhibitory effects on Aß42 induced fibrillogenesis. We present the first report of new compound 1 and the inhibitory effects of components from Akebiae Caulis on Aß42 fibrillogenesis.
Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Emaranhados Neurofibrilares/patologia , Ácido Oleanólico/análogos & derivados , Fragmentos de Peptídeos/antagonistas & inibidores , Plantas Medicinais/química , Placa Amiloide/prevenção & controle , Triterpenos/farmacologia , Modelos Moleculares , Ácido Oleanólico/farmacologia , Raízes de Plantas/química , Caules de Planta/química , Placa Amiloide/induzido quimicamente , Espectrofotometria InfravermelhoRESUMO
Alzheimer's disease (AD) is a complex, progressive neurological disorder characterized by the formation of extracellular amyloid plaques composed of ß-amyloid protein (Aß), the key component in pathogenesis of AD. Peripheral administration of enoxaparin (ENO) reportedly reduces the level of Aß and the amyloid plaques in the cortex of amyloid precursor protein (APP) transgenic mice. However, the exact mechanism of these effects is unclear. Our previous studies indicated that ENO can inhibit APP processing to Aß in primary cortical cells from Tg2576 mice by downregulating BACE1 levels. This study examines whether ENO-induced reduction of amyloid load is due to the decreased APP processing to Aß in Tg2576 mice. Surprisingly, our results indicated that ENO significantly increases the Aß42/Aß40 ratio in cortex and enhances the amyloid plaque load in both cortex and hippocampus, although overall APP processing was not influenced by ENO. Moreover, ENO stimulated the aggregation of both Aß40 and Aß42 in vitro. Although ENO has been reported to improve cognition in vivo and has potential as a therapeutic agent for AD, the results from our study suggest that ENO can exacerbate the amyloid pathology, and the strategy of using ENO for the treatment of AD may require further assessment. © 2016 Wiley Periodicals, Inc.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Encéfalo/efeitos dos fármacos , Enoxaparina/toxicidade , Fibrinolíticos/toxicidade , Placa Amiloide/induzido quimicamente , Proteína ADAM10/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Mutação/genética , Placa Amiloide/genética , Agregados Proteicos/efeitos dos fármacos , Agregados Proteicos/genéticaRESUMO
AIM: Streptozotocin (STZ) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/Aß pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of Alzheimer's disease (AD). In this study, we constructed a cell-based platform using STZ to induce stress conditions mimicking the complicated pathologies of AD in vitro, and evaluated the anti-amyloid effects of a small molecule, N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) in the amelioration of cognitive deficits in AD model mice. METHODS: Cell-based assays for screening anti-amyloid compounds were established by assessing Aß accumulation in HEK293-APPsw and CHO-APP cells, and Aß clearance in primary astrocytes and SH-SY5Y cells after the cells were treated with STZ in the presence of the test compounds. Autophagic flux was observed using confocal laser scanning microscopy. APP/PS1 transgenic mice were administered LX2343 (10 mg·kg-1·d-1, ip) for 100 d. After LX2343 administration, cognitive ability of the mice was evaluated using Morris water maze test, and senile plaques in the brains were detected using Thioflavine S staining. ELISA assay was used to evaluate Aß and sAPPß levels, while Western blot analysis was used to measure the signaling proteins in both cell and animal brains. RESULTS: LX2343 (5-20 µmol/L) dose-dependently decreased Aß accumulation in HEK293-APPsw and CHO-APP cells, and promoted Aß clearance in SH-SY5Y cells and primary astrocytes. The anti-amyloid effects of LX2343 were attributed to suppressing JNK-mediated APPThr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC50 value of 11.43±0.36 µmol/L, on the other hand. Furthermore, LX2343 acted as a non-ATP competitive PI3K inhibitor to negatively regulate AKT/mTOR signaling, thus promoting autophagy, and increasing Aß clearance. Administration of LX2343 in APP/PS1 transgenic mice significantly ameliorated cognitive deficits and markedly ameliorated the Aß pathology in their brains. CONCLUSION: LX2343 ameliorates cognitive dysfunction in APP/PS1 transgenic mice via both Aß production inhibition and clearance promotion, which highlights the potential of LX2343 in the treatment of AD.
Assuntos
Acetamidas/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Nootrópicos/uso terapêutico , Placa Amiloide/tratamento farmacológico , Sulfonamidas/uso terapêutico , Acetamidas/farmacologia , Animais , Células CHO , Cricetulus , Drosophila melanogaster , Células HEK293 , Humanos , Camundongos , Camundongos Transgênicos , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Placa Amiloide/induzido quimicamente , Estreptozocina , Sulfonamidas/farmacologiaRESUMO
MDMA is one of the most used drugs by adolescents and its consumption has been associated with many psychobiological problems, among them psychomotor problems. Moreover, some authors described that early exposure to MDMA may render the dopaminergic neurons more vulnerable to the effects of future neurotoxic insults. Alzheimer disease (AD) is the main cause of dementia in the elderly and a percentage of the patients have predisposition to suffer nigrostriatal alterations, developing extrapyramidal signs. Nigrostriatal dysfunction in the brain of aged APPswe/PS1dE9 (APP/PS1), a mouse model of familiar AD (FAD), has also been described. The aim of the present study was to investigate the consequences of adolescent exposure to MDMA in APP/PS1 mice, on nigrostriatal function on early adulthood. We used a MDMA schedule simulating weekend binge abuse of this substance. Our MDMA schedule produced a genotype-independent decrease in dopaminergic neurons in the substantia nigra that remained at least 3months. Shortly after the injury, wild-type animals showed a decrease in the locomotor activity and apparent DA depletion in striatum, however in the APP/PS1 mice neither the locomotor activity nor the DA levels were modified, but a reduction in dopamine transporter (DAT) expression and a higher levels of oxidative stress were observed. We found that these disturbances are age-related characteristics that this APP/PS1 mice develops spontaneously much later. Therefore, MDMA administration seems to anticipate the striatal dopaminergic dysfunction in this FAD model. The most important outcome lies in a potentiation, by MDMA, of the amyloid beta deposition in the striatum.