RESUMO
BACKGROUND: Exercise training promotes brain plasticity and is associated with protection against cognitive impairment and Alzheimer's disease (AD). These beneficial effects may be partly mediated by blood-borne factors. Here we used an in vitro model of AD to investigate effects of blood plasma from exercise-trained donors on neuronal viability, and an in vivo rat model of AD to test whether such plasma impacts cognitive function, amyloid pathology, and neurogenesis. METHODS: Mouse hippocampal neuronal cells were exposed to AD-like stress using amyloid-ß and treated with plasma collected from human male donors 3 h after a single bout of high-intensity exercise. For in vivo studies, blood was collected from exercise-trained young male Wistar rats (high-intensity intervals 5 days/week for 6 weeks). Transgenic AD rats (McGill-R-Thy1-APP) were injected 5 times/fortnight for 6 weeks at 2 months or 5 months of age with either (a) plasma from the exercise-trained rats, (b) plasma from sedentary rats, or (c) saline. Cognitive function, amyloid plaque pathology, and neurogenesis were assessed. The plasma used for the treatment was analyzed for 23 cytokines. RESULTS: Plasma from exercised donors enhanced cell viability by 44.1% (pâ¯=â¯0.032) and reduced atrophy by 50.0% (p < 0.001) in amyloid-ß-treated cells. In vivo exercised plasma treatment did not alter cognitive function or amyloid plaque pathology but did increase hippocampal neurogenesis by â¼3 fold, regardless of pathological stage, when compared to saline-treated rats. Concentrations of 7 cytokines were significantly reduced in exercised plasma compared to sedentary plasma. CONCLUSION: Our proof-of-concept study demonstrates that plasma from exercise-trained donors can protect neuronal cells in culture and promote adult hippocampal neurogenesis in the AD rat brain. This effect may be partly due to reduced pro-inflammatory signaling molecules in exercised plasma.
Assuntos
Doença de Alzheimer , Ratos , Masculino , Camundongos , Animais , Humanos , Placa Amiloide/patologia , Placa Amiloide/prevenção & controle , Ratos Wistar , Hipocampo/patologia , Peptídeos beta-Amiloides/metabolismo , Neurogênese/fisiologia , Citocinas , Plasma/metabolismoAssuntos
Doença de Alzheimer , Placa Amiloide , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Doença de Alzheimer/prevenção & controle , Amiloide , Peptídeos beta-Amiloides , Amiloidose , Sistemas de Liberação de Medicamentos , Humanos , Placa Amiloide/tratamento farmacológico , Placa Amiloide/prevenção & controleRESUMO
Amyloid beta (Aß) plaque is a defining pathologic feature of Alzheimer disease (AD). Aducanumab, a monoclonal IgG1 that selectively binds aggregated species of Aß, has been shown by amyloid positron emission tomography (Amyloid PET) to reduce Aß plaques in patients with prodromal and mild AD. This is the first autopsy report of the AD neuropathology in a patient previously treated with aducanumab. The patient was an 84-year-old woman who was randomized to the placebo arm of the PRIME Phase 1b study (221AD103). The patient progressed to moderate dementia (MMSE = 14/30), beyond the targeted early AD treatment stage, before receiving aducanumab in the long-term extension (LTE). The patient then received 32 monthly doses of aducanumab, titrated up to 6 mg/kg, for a cumulative dose of 186 mg/kg. In the LTE, Amyloid PET scans demonstrated robust Aß plaque reduction, from a composite standard uptake value ratio (SUVR) of 1.5 at screening to < 1.1 at 56 weeks post-aducanumab dosing. MRI examinations were negative for amyloid-related imaging abnormalities (ARIA). She passed away in hospice care 4 months after her last dose of aducanumab. The postmortem neuropathologic examination confirmed AD neuropathologic changes. Aß and IBA1 immunohistochemistry assays demonstrated sparse residual Aß plaque engaged by amoeboid reactive microglia. Phospho-Tau (pTau) immunohistochemistry demonstrated neocortical neurofibrillary degeneration (Braak stage V, NIA/AA Stage B3). However, the density of pTau neuropathology, including neuritic plaque pTau (NP-Tau), appeared lower in the PRIME LTE Patient compared to a reference cohort of untreated Braak stage V-VI, NIA/AA Stage B3 AD cases. Taken together, this case report is the first to provide Amyloid PET and neuropathologic evidence substantiating the impact of aducanumab to reduce Aß plaque neuropathology in a patient with AD. Furthermore, this report underscores the critical importance of autopsy neuropathology studies to augment our understanding of aducanumab's mechanism of action and impact on AD biomarkers.
Assuntos
Doença de Alzheimer , Anticorpos Monoclonais Humanizados , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Feminino , Humanos , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia , Placa Amiloide/prevenção & controle , Tomografia por Emissão de Pósitrons , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Deposition of amyloid-ß (Aß) in the brain is one of the important histopathological features of Alzheimer's disease (AD). Previously, we reported a correlation between cell adhesion molecule L1 (L1) expression and the occurrence of AD, but its relationship was unclear. Here, we report that the expression of L1 and a 70 kDa cleavage product of L1 (L1-70) was reduced in the hippocampus of AD (APPswe) mice. Interestingly, upregulation of L1-70 expression in the hippocampus of 18-month-old APPswe mice, by parabiosis involving the joining of the circulatory system of an 18-month-old APPswe mouse with a 2-month-old wild-type C57BL/6 mouse, reduced amyloid plaque deposition. Furthermore, the reduction was accompanied by the appearance of a high number of activated microglia. Mechanistically, we observed that L1-70 could combine with topoisomerase 1 (Top1) to form a complex, L1-70/Top1, that was able to regulate expression of macrophage migration inhibitory factor (MIF), resulting in the activation of microglia and reduction of Aß plaques. Also, transforming growth factor ß1 (TGFß-1) transferred from the blood of young wild-type C57BL/6 mice to the aged AD mice, was identified as a circulating factor that induces full-length L1 and L1-70 expression. All together, these findings suggest that L1-70 contributes to the clearance of Aß in AD, thereby adding a novel perspective in understanding AD pathogenesis.
Assuntos
Doença de Alzheimer/prevenção & controle , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/prevenção & controle , Envelhecimento , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , DNA Topoisomerases Tipo I/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/patologia , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Camundongos , Microglia/metabolismo , Neurônios/metabolismo , Parabiose , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Utilizing the pathology and microbiology found in tissue from patients with documented Alzheimer's disease (AD), the pathogenesis of this fateful disorder has been made clear. Borrelia burgdorferi and Treponema denticola spirochetes enter the brain, mostly via neuronal pathways and the entorhinal circulation. These organisms easily pass through the blood-brain barrier and have an affinity for neural tissue. Once in the brain, the spirochetes make intra- and extracellular biofilms, and it is the biofilms that create the pathology. Specifically, it is the intracellular biofilms that are ultimately responsible for neurofibrillary tangles and dendritic disintegration. The extracellular biofilms are responsible for the inflammation that initially is generated by the first responder, Toll-like receptor 2. The hypothesis that arises from this work is two-pronged: one is related to prevention; the other to treatment. Regarding prevention, it is very likely possible that AD could be prevented by periodic administration of penicillin (PCN), which would kill the spirochetes before they made biofilms; this would prevent the disease and would not allow any of the above deleterious changes generated by the biofilms to occur. As regards treatment, it may be possible to slow or prevent further decline in early AD by administration of PCN together with a biofilm disperser. The disperser would disrupt the biofilm coating and enable the PCN to kill the spirochetes. This protocol could be administered in a trial with the control arm utilizing the current treatment. The progress of the treatment could be evaluated by one of the current blood tests that is semi-quantitative. The specific protocols are listed.
Assuntos
Doença de Alzheimer , Encéfalo , Neurônios/metabolismo , Placa Amiloide , Proteínas tau , Doença de Alzheimer/microbiologia , Doença de Alzheimer/patologia , Biofilmes , Borrelia burgdorferi/isolamento & purificação , Encéfalo/microbiologia , Encéfalo/patologia , Humanos , Inflamação , Penicilinas/uso terapêutico , Placa Amiloide/patologia , Placa Amiloide/prevenção & controle , Treponema denticola/isolamento & purificação , Proteínas tau/metabolismoRESUMO
Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Preventive therapies for AD are not yet available, and potential disease-modifying therapies targeting amyloid-ß plaques in symptomatic stages of AD have only just been approved in the United States. Small-molecule inhibitors of ß-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1; also known as ß-secretase 1) reduce the production of amyloid-ß peptide and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment that was associated with all but one inhibitor; preliminary results suggest that the cognitive effects are non-progressive and reversible. These discontinuations have raised questions regarding the suitability of BACE1 as a drug target for AD. In this Perspective, we discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors and related secretase modulators as preventative therapies. We also propose a series of experiments that should be performed to inform 'go-no-go' decisions in future trials with BACE inhibitors and consider the possibility that low levels of BACE1 inhibition could avoid adverse effects while achieving efficacy for AD prevention.
Assuntos
Doença de Alzheimer/prevenção & controle , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Secretases da Proteína Precursora do Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Ácido Aspártico Endopeptidases/genética , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placa Amiloide/prevenção & controle , Projetos de PesquisaRESUMO
AIMS: Alzheimer's disease (AD) is the most common irreversible chronic neurodegenerative disease. It is characterized by the abnormal accumulation of ß-amyloid protein (Aß), which triggers homeostatic breakage in several physiological systems. However, the effect of chronic exercise on the formation of Aß as an alternative therapy has been investigated. This systematic review examines the antiamyloid effect of different types and intensities of exercise, seeking to elucidate its neuroprotective mechanisms. MAIN METHODS: The research was conducted in the electronic databases Pubmed, Embase, Scopus and Web of Science, using the following descriptors: "amyloid beta" (OR senile plaque OR amyloid plaque) and "exercise" (OR physical activity OR training). The risk of bias was evaluated through SYRCLE's Risk of Bias for experimental studies. KEY FINDINGS: 2268 articles were found, being 36 included in the study. A higher frequency of use of mice with genetic alterations was identified for the Alzheimer's disease (AD) model (n = 29). It was used as chronic training: treadmill running (n = 24), voluntary running wheel (n = 7), swimming (n = 4) and climbing (n = 2). The hippocampus and the cortex were the most investigated regions. However, physiological changes accompanied by the reduction of Aß and associated with AD progression were verified. It is concluded that exercise reduces the production of Aß in models of animals with AD. SIGNIFICANCE: Nevertheless, this effect contributes to the improvement of several physiological aspects related to Aß and that contribute to neurological impairment in AD.
Assuntos
Doença de Alzheimer/prevenção & controle , Condicionamento Físico Animal , Placa Amiloide/prevenção & controle , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Animais , Encéfalo/patologia , Camundongos , Placa Amiloide/patologia , Placa Amiloide/terapiaRESUMO
Alzheimer's disease (AD), the most common cause of dementia and neurodegeneration in the elderly, is characterized by deterioration of memory and executive and motor functions. Neuropathologic hallmarks of AD include neurofibrillary tangles (NFTs), paired helical filaments, and amyloid plaques. Mutations in the microtubule-associated protein Tau, a major component of the NFTs, cause its hyperphosphorylation in AD. We have shown that signaling by the gaseous molecule hydrogen sulfide (H2S) is dysregulated during aging. H2S signals via a posttranslational modification termed sulfhydration/persulfidation, which participates in diverse cellular processes. Here we show that cystathionine γ-lyase (CSE), the biosynthetic enzyme for H2S, binds wild type Tau, which enhances its catalytic activity. By contrast, CSE fails to bind Tau P301L, a mutant that is present in the 3xTg-AD mouse model of AD. We further show that CSE is depleted in 3xTg-AD mice as well as in human AD brains, and that H2S prevents hyperphosphorylation of Tau by sulfhydrating its kinase, glycogen synthase kinase 3ß (GSK3ß). Finally, we demonstrate that sulfhydration is diminished in AD, while administering the H2S donor sodium GYY4137 (NaGYY) to 3xTg-AD mice ameliorates motor and cognitive deficits in AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Cistationina gama-Liase/genética , Glicogênio Sintase Quinase 3 beta/genética , Sulfeto de Hidrogênio/farmacologia , Morfolinas/farmacologia , Fármacos Neuroprotetores/farmacologia , Compostos Organotiofosforados/farmacologia , Proteínas tau/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Cistationina gama-Liase/metabolismo , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HEK293 , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Emaranhados Neurofibrilares/efeitos dos fármacos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fosforilação , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Placa Amiloide/prevenção & controle , Ligação Proteica , Processamento de Proteína Pós-Traducional , Sulfatos/metabolismo , 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
We examined the evidence for intermittent fasting (IF) as a preventative tool to influence ß-amyloid in animal models of Alzheimer's disease (AD). A Scopus, Ovid, PubMed, and Web of Science (WoS), search yielded 29 results using the keywords "amyloid beta", "intermittent fasting", "intermittent caloric restriction", "alternate day fasting", "modified alternate-day fasting", "time-restricted feeding", "Ramadan fast", "intermittent calori* restriction", "intermittent restrictive diet", and "Alzheimer*". Five research articles addressed directly the effects of intermittent fasting on ß-amyloid levels in animal models of AD: alternate day fasting (ADF) and time-restricted feeding (TRF) methods were incorporated in these studies. The study designs were found to be heterogeneous. Variations in the levels of ß-amyloid peptides or plaque in either the hippocampus, cortical areas, or both in animals following dietary intervention were observed as compared to the ad libitum group. Non-significant changes were observed in three studies, while two studies interestingly demonstrated amelioration and reduction in ß-amyloid levels. Given the conflicting results obtained from this study, significant care has to be taken into consideration before the protocol can be applied as a preventative approach to treat Alzheimer's disease. Longitudinal research is warranted to fully grasp how dietary habits can help alleviate the disease either through upstream or downstream of AD pathology.
Assuntos
Doença de Alzheimer/dietoterapia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Jejum , Placa Amiloide/dietoterapia , Doença de Alzheimer/patologia , Animais , Comportamento Animal , Restrição Calórica , Cognição , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Placa Amiloide/prevenção & controle , RatosRESUMO
Alzheimer's disease (AD) is proposed to be induced by abnormal aggregation of amyloidß in the brain. Here, we designed a brain-permeable peptide nanofiber drug from a fragment of heat shock protein to suppress aggregation of the pathogenic proteins. To facilitate delivery of the nanofiber into the brain, a protein transduction domain from Drosophila Antennapedia was incorporated into the peptide sequence. The resulting nanofiber efficiently suppressed the cytotoxicity of amyloid ßby trapping amyloid ß onto its hydrophobic nanofiber surface. Moreover, the intravenously or intranasally injected nanofiber was delivered into the mouse brain, and improved the cognitive function of an Alzheimer transgenic mouse model. These results demonstrate the potential therapeutic utility of nanofibers for the treatment of AD.
Assuntos
Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/administração & dosagem , Encéfalo/metabolismo , Modelos Animais de Doenças , Transtornos da Memória/prevenção & controle , Nanofibras/administração & dosagem , Placa Amiloide/prevenção & controle , Administração Intranasal , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Animais , Encéfalo/efeitos dos fármacos , Feminino , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Camundongos , Camundongos Transgênicos , Nanofibras/química , Placa Amiloide/etiologia , Placa Amiloide/patologiaRESUMO
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
Constant exposure to light is prevalent in modern society where light noise, shift work, and jet lag is common. Constant light exposure disrupts circadian rhythm, induces stress and thus influences memory performance. We subjected adult male Wistar rats to a two-month exposure to constant light (LL), constant dark or normal light-dark cycles. Significant cognitive impairment and oxidative stress were observed in LL rats without a significant elevation in soluble Aß1-42 levels. Next, we examined whether long-term exposure to constant light may accelerate dementia in a sub-pathological Aß model of rats. Normal control rats received ACSF, AD rats received 440 pmol, and sub-pathological Aß rats (Aß(s)) received 220 pmol of human Aß42 peptide in a single unilateral ICV administration. Sub-pathological Aß rats exposed to constant light (LL + Aß(s)) show significant memory deficits and oxidative damage, although not significantly different from LL rats. Additionally, constant light promoted aggregation of exogenous Aß42 in LL + Aß(s) rats shown by the presence of congophilic plaques. Furthermore, chronic fluoxetine treatment (5 mg/kg/day) rescued rats from the behavioral deficits, oxidative damage and amyloid aggregation. Whereas, rifampicin treatment (20 mg/kg/day) did not reverse the behavioral deficits or oxidative stress but rescued rats from amyloid plaque formation. It was concluded that constant light for two months induces behavioral deficits, oxidative stress, and accelerates aggregation of sub-pathological concentrations of human-Aß42 peptides in Wistar rats, which is reversed by daily fluoxetine administration.
Assuntos
Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/farmacologia , Luz/efeitos adversos , Estresse Oxidativo/efeitos da radiação , Agregação Patológica de Proteínas/etiologia , Doença de Alzheimer/tratamento farmacológico , Animais , Ritmo Circadiano/efeitos dos fármacos , Modelos Animais de Doenças , Fluoxetina/administração & dosagem , Humanos , Masculino , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Placa Amiloide/prevenção & controle , Agregação Patológica de Proteínas/tratamento farmacológico , Ratos , Ratos Wistar , Rifampina/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: In the amyloid hypothesis of Alzheimer's disease (AD), the dysregulation of amyloid-ß protein (Aß) production and clearance leads to amyloid deposits, tau tangles, neuronal loss, and cognitive dysfunction. Thus far, therapies targeting the enzymes responsible for Aß production have been found ineffective or having significant side effects. OBJECTIVE: To test whether a γ-secretase modulator, BPN-15606, is an effective disease-modifying or preventative treatment in the PSAPP mouse model of AD. METHODS: We treated pre-plaque (3-month-old) and post-plaque (6-month-old) PSAPP AD transgenic mice for 3 months and examined behavioral, biochemical, and pathological end points. RESULTS: BPN-15606 attenuated cognitive impairment and reduced amyloid plaque load, microgliosis, and astrogliosis associated with the AD phenotype of PSAPP mice when administered to pre-plaque (3-month-old) but was ineffective when administered to post-plaque (6-month-old) mice. No treatment-related toxicity was observed. CONCLUSION: BPN-15606 appears efficacious when administered prior to significant pathology.
Assuntos
Doença de Alzheimer/prevenção & controle , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Fenetilaminas/uso terapêutico , Piridazinas/uso terapêutico , Doença de Alzheimer/psicologia , Precursor de Proteína beta-Amiloide/genética , Animais , Comportamento Animal/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Disfunção Cognitiva/psicologia , Gliose , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Fenetilaminas/efeitos adversos , Placa Amiloide/genética , Placa Amiloide/prevenção & controle , Equilíbrio Postural/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Piridazinas/efeitos adversosRESUMO
Epidemiological studies have found that habitual coffee consumption may reduce the risk of Alzheimer's disease. Coffee contains numerous phenolic compounds (coffee polyphenols) such as chlorogenic acids. However, evidence demonstrating the contribution of chlorogenic acids to the prevention of cognitive dysfunction induced by Alzheimer's disease is limited. The present study investigated the effect of chlorogenic acids on the prevention of cognitive dysfunction in APP/PS2 transgenic mouse model of Alzheimer's disease. Five-week-old APP/PS2 mice were administered a diet supplemented with coffee polyphenols daily for 5 months. The memory and cognitive function of mice was determined using the novel object recognition test, Morris water maze test, and the step-through passive avoidance test. Immunohistochemical analysis revealed that chronic treatment with coffee polyphenols prevented cognitive dysfunction and significantly reduced the amount of amyloid ß (Aß) plaques in the hippocampus. Furthermore, we determined that 5-caffeoylquinic acid, one of the primary coffee polyphenols, did not inhibit Aß fibrillation; however, degraded Aß fibrils. In conclusion, our results demonstrate that coffee polyphenols prevent cognitive deficits and reduce Aß plaque deposition via disaggregation of Aß in the APP/PS2 mouse.
Assuntos
Doença de Alzheimer/prevenção & controle , Ácido Clorogênico/farmacologia , Café/química , Disfunção Cognitiva/prevenção & controle , Placa Amiloide/prevenção & controle , Polifenóis/farmacologia , Doença de Alzheimer/metabolismo , Amiloide/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Córtex Cerebral/efeitos dos fármacos , Ácido Clorogênico/metabolismo , Café/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Memória , Camundongos , Camundongos Transgênicos , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Teste de Campo Aberto/efeitos dos fármacos , Placa Amiloide/metabolismo , Polifenóis/metabolismo , Ácido Quínico/análogos & derivados , Ácido Quínico/química , Aprendizagem Espacial/efeitos dos fármacosRESUMO
Epidemiological, preclinical, and clinical studies have suggested a role for microdose lithium in reducing Alzheimer's disease (AD) risk by modulating key mechanisms associated with AD pathology. The novel microdose lithium formulation, NP03, has disease-modifying effects in the McGill-R-Thy1-APP transgenic rat model of AD-like amyloidosis at pre-plaque stages, before frank amyloid-ß (Aß) plaque deposition, during which Aß is primarily intraneuronal. Here, we are interested in determining whether the positive effects of microdose lithium extend into early Aß post-plaque stages. We administered NP03 (40µg Li/kg; 1 ml/kg body weight) to McGill-R-Thy1-APP transgenic rats for 12 weeks spanning the transition phase from plaque-free to plaque-bearing. The effect of NP03 on remote working memory was assessed using the novel object recognition task. Levels of human Aß38, Aß40, and Aß42 as well as levels of pro-inflammatory mediators were measured in brain-extracts and plasma using electrochemiluminescent assays. Mature Aß plaques were visualized with a thioflavin-S staining. Vesicular acetylcholine transporter (VAChT) bouton density and levels of chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-6 (IL-6), and 4-hydroxynonenal (4-HNE) were probed using quantitative immunohistochemistry. During the early Aß post-plaque stage, we find that NP03 rescues functional deficits in object recognition, reduces loss of cholinergic boutons in the hippocampus, reduces levels of soluble and insoluble cortical Aß42 and reduces hippocampal Aß plaque number. In addition, NP03 reduces markers of neuroinflammation and cellular oxidative stress. Together these results indicate that microdose lithium NP03 is effective at later stages of amyloid pathology, after appearance of Aß plaques.
Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/prevenção & controle , Citratos/uso terapêutico , Compostos de Lítio/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Placa Amiloide/patologia , Placa Amiloide/prevenção & controle , Aldeídos/metabolismo , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Quimiocinas/metabolismo , Composição de Medicamentos , Encefalite/metabolismo , Encefalite/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Interleucina-6/metabolismo , Memória de Curto Prazo/efeitos dos fármacos , Terminações Pré-Sinápticas/patologia , Ratos , Ratos Transgênicos , Reconhecimento Psicológico , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismoRESUMO
Alzheimer's disease (AD) is the most common form of dementia, characterized by amyloid-ß peptide (Aß) aggregates, phosphorylated tau protein (p-tau), and progressive neurodegeneration. Amyloid-ß peptide 42 (Aß42) is considered an early trigger of AD pathogenesis. We have previously reported that Aß N-terminus monoclonal antibody (mAb) A8 alleviated cognitive dysfunction and reduced the abundance of soluble Aß in the brains of the senescence-accelerated mouse prone 8 (SAMP8) mouse model. To confirm the efficacy of mAb A8 in the double-transgenic APPswe/PS1ΔE9 (APP/PS1) mice, here we reported the related findings. The Morris water maze (MWM) data showed that the A8 treatment group had a shorter escape latency than the control groups in the place navigation test and the probe trial (pâ<â0.05). Moreover, immunohistochemistry showed decreased levels of both Aß and p-tau in the brains of APP/PS1 mice. Regarding Aß levels, western blot results showed that Aß42 oligomer (pâ<â0.01) but not Aß40 levels were diminished in brains of A8-treated APP/PS1 mice. Western blot results showed that phospho-tau (pSer231) (pâ<â0.01) but not tau levels were reduced in A8-treated mouse brains. Furthermore, transmission electron microscopy images indicated ultrastructural improvements, including an increased (pâ<â0.01) density of synapses and a reduction of abnormally enlarged mitochondria (pâ<â0.01), in the brains of A8-treated mice. Taken together, our data showed that mAb A8 is highly efficacious in APP/PS1 mice as a treatment for AD, and the underlying mechanism may target synaptic pathology by inhibiting the amyloid cascade.
Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/imunologia , Precursor de Proteína beta-Amiloide/genética , Anticorpos Bloqueadores/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/imunologia , Presenilina-1/genética , Sinapses/patologia , Animais , Encéfalo/patologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/psicologia , Feminino , Humanos , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosforilação/efeitos dos fármacos , Placa Amiloide/genética , Placa Amiloide/patologia , Placa Amiloide/prevenção & controle , Sinapses/ultraestrutura , Proteínas tau/metabolismoRESUMO
In Alzheimer's disease, BACE1 protease initiates the amyloidogenic processing of amyloid precursor protein (APP) that eventually results in synthesis of ß-amyloid (Aß) peptide. Aß deposition in turn causes accumulation of BACE1 in plaque-associated dystrophic neurites, thereby potentiating progressive Aß deposition once initiated. Since systemic pharmacological BACE inhibition causes adverse effects in humans, it is important to identify strategies that specifically normalize overt BACE1 activity around plaques. The microtubule-associated protein tau regulates axonal transport of proteins, and tau deletion rescues Aß-induced transport deficits in vitro. In the current study, long-term in vivo two-photon microscopy and immunohistochemistry were performed in tau-deficient APPPS1 mice. Tau deletion reduced plaque-associated axonal pathology and BACE1 accumulation without affecting physiological BACE1 expression distant from plaques. Thereby, tau deletion effectively decelerated formation of new plaques and reduced plaque compactness. The data revealed that tau reinforces Aß deposition, presumably by contributing to accumulation of BACE1 in plaque-associated dystrophies. Targeting tau-dependent mechanisms could become a suitable strategy to specifically reduce overt BACE1 activity around plaques, thereby avoiding adverse effects of systemic BACE inhibition.
Assuntos
Doença de Alzheimer/prevenção & controle , Secretases da Proteína Precursora do Amiloide/fisiologia , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Regulação da Expressão Gênica , Placa Amiloide/prevenção & controle , Proteínas tau/antagonistas & inibidores , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Placa Amiloide/etiologia , Placa Amiloide/metabolismo , Placa Amiloide/patologiaRESUMO
Hippocampal lesions including synaptic injury, neuroinflammation, and impaired neurogenesis are featured pathology closely associated with neuronal stress and cognitive impairment in Alzheimer's disease (AD). Previous studies suggest that ghrelin and its receptor, growth hormone secretagogue receptor 1α (GHSR1α), promote hippocampal synaptic function and neurogenesis. GHSR1α activation thus holds the potential to be a therapeutic avenue for the treatment of hippocampal pathology in AD; however, a comprehensive study on the preventive effect of MK0677 on hippocampal lesions in AD-related conditions is still lacking. In this study, we treated a transgenic mouse model of AD-like amyloidosis (5xFAD mice) at the asymptomatic stage with MK0677, a potent ghrelin mimetic. We found that MK0677 fostered hippocampal neurogenesis in 5xFAD mice but observed little preventive function with regards to the development of hippocampal amyloid-ß (Aß) deposition, synaptic loss, microglial activation, or cognitive impairment. Furthermore, MK0677 at a dose of 3âmg/kg significantly increased 5xFAD mouse mortality. Despite enhanced hippocampal neurogenesis, MK0677 treatment has little beneficial effect to prevent hippocampal lesions or cognitive deficits against Aß toxicity. This study, together with a failed large-scale clinical trial, suggests the ineffectiveness of MK0677 alone for AD prevention and treatment.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Grelina , Hipocampo/patologia , Indóis/farmacologia , Indóis/uso terapêutico , Neurogênese/efeitos dos fármacos , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Amiloidose/genética , Amiloidose/patologia , Animais , Comportamento Animal , Biomimética , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/prevenção & controle , Transtornos Cognitivos/psicologia , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Microglia/patologia , Placa Amiloide/patologia , Placa Amiloide/prevenção & controle , Sinapses/patologiaRESUMO
Alzheimer's disease (AD) is associated with the cleavage of the amyloid precursor protein (APP) to produce the toxic amyloid-ß (Aß) peptide. Accumulation of Aß, together with the concomitant inflammatory response, ultimately leads to neuronal death and cognitive decline. Despite AD progression being underpinned by both neuronal and immunological components, therapeutic strategies based on dual targeting of these systems remains unexplored. Here, we report that inactivation of the p110δ isoform of phosphoinositide 3-kinase (PI3K) reduces anterograde axonal trafficking of APP in hippocampal neurons and dampens secretion of the inflammatory cytokine tumor necrosis factor-alpha by microglial cells in the familial AD APPswe/PS1ΔE9 (APP/PS1) mouse model. Moreover, APP/PS1 mice with kinase-inactive PI3Kδ (δD910A) had reduced Aß peptides levels and plaques in the brain and an abrogated inflammatory response compared with APP/PS1 littermates. Mechanistic investigations reveal that PI3Kδ inhibition decreases the axonal transport of APP by eliciting the formation of highly elongated tubular-shaped APP-containing carriers, reducing the levels of secreted Aß peptide. Importantly, APP/PS1/δD910A mice exhibited no spatial learning or memory deficits. Our data highlight inhibition of PI3Kδ as a new approach to protect against AD pathology due to its dual action of dampening microglial-dependent neuroinflammation and reducing plaque burden by inhibition of neuronal APP trafficking and processing.SIGNIFICANCE STATEMENT During Alzheimer's disease (AD), the accumulation of the toxic amyloid-ß (Aß) peptide in plaques is associated with a chronic excessive inflammatory response. Uncovering new drug targets that simultaneously reduce both Aß plaque load and neuroinflammation holds therapeutic promise. Using a combination of genetic and pharmacological approaches, we found that the p110δ isoform of phosphoinositide 3-kinase (PI3K) is involved in anterograde trafficking of the amyloid precursor protein in neurons and in the secretion of tumor necrosis factor-alpha from microglial cells. Genetic inactivation of PI3Kδ reduces Aß plaque deposition and abrogates the inflammatory response, resulting in a complete rescue of the life span and spatial memory performance. We conclude that inhibiting PI3Kδ represents a novel therapeutic approach to ameliorate AD pathology by dampening plaque accumulation and microglial-dependent neuroinflammation.