RESUMO
Synaptic dysfunction plays a crucial role in the pathogenesis of Alzheimer's disease (AD). α/ß-hydrolase domain-containing 6 (ABHD6) contributes to synaptic dysfunctions, and ABHD6 inhibition has shown potential therapeutic value in neurological disorders. However, the role of ABHD6 in AD has not been fully defined. In this study, we demonstrated that adeno-associated virus (AAV) mediated shRNA targeting ABHD6 in hippocampal neurons attenuated synaptic dysfunction and memory impairment of APPswe/PS1dE9 (APP/PS1) mice, while it didn't affect the amyloid-beta (Aß) levels and neuroinflammation in the brains. In addition, intraperitoneal injection of wwl70, a specific inhibitor of ABHD6, improved synaptic plasticity and memory function in APP/PS1 mice, which might attribute to the activation of endogenous cannabinoid signaling. Furthermore, wwl70 significantly decreased the Aß levels and neuroinflammation in the hippocampus of AD mice, and enhanced Aß phagocytized by microglia. In conclusion, for the first time our data have shown that ABHD6 inhibition might be a promising strategy for AD treatment, and wwl70 is a potential candidate for AD drug development pipeline.
Assuntos
Doença de Alzheimer , Hidrolases , Animais , Camundongos , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide , Modelos Animais de Doenças , Transtornos da Memória/tratamento farmacológico , Camundongos Transgênicos , Monoacilglicerol Lipases , Doenças NeuroinflamatóriasRESUMO
Blood-based biomarker assays of plasma ß-amyloid (Aß) and tau have the advantages of cost-effective and less invasive for the diagnosis of Alzheimer's disease (AD). We used two independent cohorts to cross-validate the clinical use of the nanoparticle-based immunomagnetic assay of plasma biomarkers to assist in the differential diagnosis of early AD. There were in total 160 subjects in the derivation cohort, and 242 in the validation cohort both containing controls, mild cognitive impairment due to AD and AD dementia diagnosed according to the 2011 NIA-AA guidelines. The cutoff value for plasma Aß1-42 (16.4 pg/ml) performed the best in differentiating between controls and patients with prodromal or clinical AD, with 92.5% for positive percent agreement (PPA), negative percent agreement (NPA), and overall rate of agreement (ORA). Aß1-42â¯×â¯tau (642.58) was useful for separating patients with dementia and prodromal states of AD, with 84.9% PPA, 78.8% NPA and 83% ORA.
Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Biomarcadores/sangue , Demência/sangue , Demência/diagnóstico , Imunoensaio/métodos , Nanopartículas/química , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/sangue , Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico , Estudos Transversais , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas tau/sangueRESUMO
The structure of the Aß(11-42) amyloid available in PDB makes possible the molecular analysis of the specificity of amyloid formation. This molecule (PDB ID 2MVX) is the object of analysis. This work presents the outcome of in silico experiments involving various alternative conformations of the Aß(11-42) sequence, providing clues as to the amylodogenecity of its constituent fragments. The reference structure (PDB) has been compared with folds generated using I-Tasser and Robetta-the strongest contenders in the CASP challenge. Additionally, a polypeptide which matches the Aß(11-42) sequence has been subjected to folding simulations based on the fuzzy oil drop model, which favors the production of a monocentric hydrophobic core. Computer simulations yielded 15 distinct structural forma (five per software package), which, when compared to the experimentally determined structure, allow us to study the role of structural elements which cause an otherwise globular protein to transform into an amyloid. The unusual positions of hydrophilic residues disrupting the expected hydrophobic core and propagating linearly along the long axis of fibril is recognized as the seed for amyloidogenic transformation in this polypeptide. This paper discusses the structure of the Aß(11-42) amyloid fibril, listed in PDB under ID 2MXU (fragment od Aß(1-42) amyloid).
Assuntos
Peptídeos beta-Amiloides/química , Amiloide/química , Fragmentos de Peptídeos/química , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Amiloidose/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Fragmentos de Peptídeos/metabolismo , Conformação Proteica , Dobramento de ProteínaRESUMO
Neuroinflammation and excessive ß-amyloid1-42 (Aß1-42) generation contribute to the pathogenesis of Alzheimer's disease (AD). Emerging evidence has demonstrated that hydrogen sulfide (H2S), an endogenous gasotransmitter, produces therapeutic effects in AD; however, the underlying mechanisms remain largely elusive. In the present study, we investigated the effects of H2S on exogenous ATP-induced inflammation and Aß1-42 production in both BV-2 and primary cultured microglial cells and analyzed the potential mechanism(s) mediating these effects. Our results showed that NaHS, an H2S donor, inhibited exogenous ATP-stimulated inflammatory responses as manifested by the reduction of pro-inflammatory cytokines, ROS and activation of nuclear factor-κB (NF-κB) pathway. Furthermore, NaHS also suppressed the enhanced production of Aß1-42 induced by exogenous ATP, which is probably due to its inhibitory effect on exogenous ATP-boosted expression of amyloid precursor protein (APP) and activation of ß- and γ-secretase enzymes. Thereafter, we found that exogenous ATP-induced inflammation and Aß1-42 production requires the activation of signal transducer and activator of transcription 3 (STAT3) and cathepsin S (Cat S) as inhibition of the activity of either proteins attenuated the effect of exogenous ATP. Intriguingly, NaHS suppressed exogenous ATP-induced phosphorylation of STAT3 and the activation of Cat S. In addition, we observed that NaHS led to the persulfidation of Cat S at cysteine-25. Importantly, mutation of cysteine-25 into serine attenuated the activity of Cat S stimulated by exogenous ATP and subsequent inflammation and Aß1-42 production, indicating its involvement in H2S-mediated effect. Taken together, our data provide a novel understanding of H2S-mediated effect on neuroinflammation and Aß1-42 production by suppressing the activation of STAT3 and Cat S.
Assuntos
Sulfeto de Hidrogênio/farmacologia , Microglia/efeitos dos fármacos , Neuroimunomodulação/efeitos dos fármacos , Trifosfato de Adenosina/efeitos adversos , Trifosfato de Adenosina/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Animais , Catepsinas/efeitos dos fármacos , Catepsinas/fisiologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Células HEK293 , Humanos , Sulfeto de Hidrogênio/metabolismo , Inflamação , Camundongos , Fragmentos de Peptídeos/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Fosforilação , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/efeitos dos fármacos , Sulfetos/farmacologiaRESUMO
Increasing evidence demonstrates that the neurotoxicity of amyloid-beta (Aß) deposition plays a causative role in Alzheimer's disease (AD). Herein, we evaluated the neuroprotective effects of 6α-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777), a specific G-protein coupled bile acid receptor 1 (TGR5) agonist, in the Aß1-42-treated mouse model of acute neurotoxicity. Single intracerebroventricular (i.c.v.) injection of aggregated Aß1-42 (410â¯pmol/mouse; 5⯵l) into the mouse brain induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction. In contrast, INT-777 (1.5 or 3.0⯵g/mouse, i.c.v.) significantly improved Aß1-42-induced cognitive impairment, as reflected by better performance in memory tests. Importantly, INT-777 treatment reversed Aß1-42-induced TGR5 down-regulation, suppressed the increase of nuclear NF-κB p65, and mitigated neuroinflammation, as evidenced by lower proinflammatory cytokines and less Iba1-positive cells in the hippocampus and frontal cortex. INT-777 treatment also pronouncedly suppressed apoptosis through the reduction of TUNEL-positive cells, decreased caspase-3 activation, increased the ratio of Bcl-2/Bax, and ameliorated synaptic dysfunction by promoting dendritic spine generation with the upregulation of postsynaptic and presynaptic proteins (PSD95 and synaptophysin) in Aß1-42-treated mice. Our results indicate that INT-777 has potent neuroprotective effects against Aß1-42-induced neurotoxicity. Taken together, these findings suggest that the activation of TGR5 could be a novel and promising strategy for the treatment of AD.
Assuntos
Ácidos Cólicos/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/efeitos adversos , Peptídeos beta-Amiloides/metabolismo , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Caspase 3/metabolismo , Ácidos Cólicos/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Neuroimunomodulação/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/metabolismoRESUMO
Alzheimer's disease (AD) is a common form of dementia mainly characterized by the deposition of neurofibrillary tangles and ß-amyloid (Aß) peptides in the brain. Additionally, increasing evidence demonstrates that a neuro-inflammatory state plays a key role in the development of this disease. Beside synthetic drugs, the use of natural compounds represents an alternative for the development of new potential drugs for the treatment of AD. Among these, the root of Salvia miltiorhiza Bunge (also known as Danshen) used for the treatment of cardiovascular, cerebrovascular disease and CNS functional decline in Chinese traditional medicine is one of the most representative examples. We therefore evaluated the effects of tanshinone IIA (TIIA) and cryptotanshinone (CRY) (the two major lipophilic compounds of Danshen) in a non-genetic mouse model of ß-amyloid (Aß)-induced AD, which is mainly characterized by reactive gliosis and neuro-inflammation in the brain. To this aim, mice were injected intracerebroventricularly (i.c.v.) with Aß1-42 peptide (3µg/3µl) and after with TIIA and CRY (1, 3, or 10mg/kg) intraperitoneally (i.p.) 3 times weekly for 21days following the induction of experimental AD. Spatial working memory was assessed as a measure of short-term memory in mice, whereas the level of GFAP, S100ß, COX-2, iNOS and NF-kBp65 monitored by western blot and ELISA assay, were selected as markers of reactive gliosis and neuro-inflammation. Finally, by docking studies, the modulation of key pro-inflammatory enzymes and pathways involved in the AD-related neuro-inflammation were also investigated. Results indicate that TIIA and CRY alleviate memory decline in Aß1-42-injected mice, in a dose dependent manner. Moreover, the analysis of gliosis-related and neuro-inflammatory markers in the hippocampal tissues reveal a remarkable reduction in the expression of GFAP, S100ß, COX-2, iNOS and NF-kBp65 after CRY (10mg/kg) treatment. These effects were less evident, but still significant, after TIIA (10mg/kg). Finally, in silico analysis also revealed that both compounds were able to interact with the binding sites of NF-kBp65 endorsing the data from biochemical analysis. We conclude that TIIA and CRY display anti-inflammatory and neuroprotective effect in a non-genetic mouse model of AD, thus playing a role in slowing down the course and onset of AD.
Assuntos
Abietanos/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Fenantrenos/uso terapêutico , Peptídeos beta-Amiloides , Animais , Modelos Animais de Doenças , Masculino , Memória/efeitos dos fármacos , Camundongos , Fragmentos de PeptídeosRESUMO
Four new dihydrobenzofuran neolignans 1a/1b and 2a/2b were isolated from the fruit of Rubus ideaus. 1a/1b and 2a/2b as two pairs of enantiomers were separated on a chiral chromatographic column. Their structures were determined using a suite of techniques including 1D and 2D NMR, HRESIMS, together with theoretical electronic circular dichroism (ECD) calculation. All compounds were evaluated for their inhibition of self-induced Aß1-42 aggregation. Compounds 1b and 2a exhibited optimal Aß1-42 aggregation inhibition capability, with an inhibition potency of 81.6% and 83.4% at 20⯵M, respectively. Additionally, molecular docking was performed to identify the possible factor responsible for the enantioselectivity in the anti-Aß1-42 aggregation activity.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Benzofuranos/química , Lignanas/química , Fragmentos de Peptídeos/metabolismo , Rubus/química , Peptídeos beta-Amiloides/antagonistas & inibidores , Sítios de Ligação , Dicroísmo Circular , Frutas/química , Frutas/metabolismo , Lignanas/isolamento & purificação , Lignanas/metabolismo , Espectroscopia de Ressonância Magnética , Conformação Molecular , Simulação de Acoplamento Molecular , Fragmentos de Peptídeos/antagonistas & inibidores , Extratos Vegetais/química , Estrutura Terciária de Proteína , Rubus/metabolismo , EstereoisomerismoRESUMO
BACKGROUND: Alzheimer's disease is the most common neurodegenerative disease associated with aggregation of Aß peptides. Aß toxicity is mostly related to the capacity of intermediate oligomers to disrupt membrane integrity. We previously expressed Aß1-42 in a eukaryotic cellular system and selected synthetic variants on their sole toxicity. The most toxic mutant G37C forms stable oligomers. METHODS: Different biophysical methods (Fluorescence spectroscopy, cross-linking, mass spectrometry (MS), Small Angle X-ray Scattering (SAXS), Atomic Force Microscopy (AFM), Transmission Electron Microscopy (TEM), calcein leakage) were used. RESULTS: The oligomers are mostly populated by a 14mers resulting from the packing of homodimers. These homodimers come from the formation of a disulfide bridge between two monomers. This link stabilizes the multimers and prevents the assembly into amyloid fibrils. These oligomers affect the membrane integrity. The reduction of disulfide bonds leads to a rearrangement and redirects assembly of Aß amyloid fibrils. CONCLUSION: The toxic synthetic AßG37C mutant can assemble into an amyloid of unusual morphology through the formation of anti-parallel ß-sheets. This pathway involves the formation of oligomers resulting from the arrangement of Aß dimers linked by covalent di-sulfide link, being these oligomers harmful for the membranes. GENERAL SIGNIFICANCE: The capacity to produce large amount of stable oligomers without additional detergents or extrinsic cross-linkers allow further structural and biophysical studies to understand their capacity to assemble and disrupt the membranes, a key event in Alzheimer's disease.
Assuntos
Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Amiloide/química , Amiloide/metabolismo , Humanos , Microscopia de Força Atômica/métodos , Microscopia Eletrônica de Transmissão/métodos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Dobramento de Proteína , Espalhamento a Baixo Ângulo , Espectrometria de Fluorescência/métodos , Difração de Raios X/métodosRESUMO
A series of salicyladimine derivatives were designed, synthesized and evaluated as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some derivatives possessed significant inhibitory activities against amyloid-ß (Aß) aggregation and human monoamine oxidase B (hMAO-B) as well as remarkable antioxidant effects and low cell toxicity. The optimal compound, 5, exhibited excellent potency for inhibition of self-induced Aß1-42 aggregation (91.3±2.1%, 25µM), inhibition of hMAO-B (IC50, 1.73±0.39µM), antioxidant effects (43.4±2.6µM of IC50 by DPPH method, 0.67±0.06 trolox equivalent by ABTS method), metal chelation and BBB penetration. Furthermore, compound 5 had neuroprotective effects against ROS generation, H2O2-induced apoptosis, 6-OHDA-induced cell injury, and a significant in vitro anti-inflammatory activity. Collectively, these findings highlighted that compound 5 was a potential balanced multifunctional neuroprotective agent for the development of anti-AD drugs.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Desenho de Fármacos , Iminas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Salicilatos/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Peróxido de Hidrogênio/farmacologia , Iminas/síntese química , Iminas/química , Ligantes , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Células PC12 , Fragmentos de Peptídeos/antagonistas & inibidores , Agregados Proteicos/efeitos dos fármacos , Ratos , Salicilatos/síntese química , Salicilatos/química , Relação Estrutura-AtividadeRESUMO
By fusing donepezil and curcumin, a novel series of compounds were obtained as multitarget-directed ligands against Alzheimer's disease. Among them, compound 11b displayed potent acetylcholinesterase (AChE) inhibition (IC50=187nM) and the highest BuChE/AChE selectivity (66.3). Compound 11b also inhibited 45.3% Aß1-42 self-aggregation at 20µM and displayed remarkable antioxidant effects. The metal-chelating property of compound 11b was elucidated by determining the 1:1 stoichiometry for the 11b-Cu(II) complex. The excellent blood-brain barrier permeability of 11b also indicated the potential for the compound to penetrate the central nervous system.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Inibidores da Colinesterase/farmacologia , Curcumina/farmacologia , Indanos/farmacologia , Fragmentos de Peptídeos/metabolismo , Piperidinas/farmacologia , Agregados Proteicos/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacocinética , Curcumina/análogos & derivados , Curcumina/farmacocinética , Donepezila , Desenho de Fármacos , Electrophorus , Humanos , Indanos/química , Indanos/farmacocinética , Ligantes , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Piperidinas/química , Piperidinas/farmacocinética , SuínosRESUMO
Tamoxifen (TMX) is a selective estrogen receptor modulator (SERM) used in the treatment of breast cancer. Earlier studies show its neuroprotection via regulating apoptosis, microglial functions, and synaptic plasticity. TMX also showed memory enhancement in ovariectomized mice, and protection from amyloid induced damage in hippocampal cell line. These reports encouraged us to explore the role of TMX in relevance to Alzheimer's disease (AD). We report here, the effect of TMX treatment a) on memory, and b) levels of neurotransmitters (acetylcholine (ACh) and dopamine (DA)) in breeding-retired-female mice injected with beta amyloid1-42 (Aß1-42). Mice were treated with TMX (10mg/kg, i.p.) for 15 days. In Morris water maze test, the TMX treated mice escape latency decreased during training trials. They also spent longer time in the platform quadrant on probe trial, compared to controls. In Passive avoidance test, TMX treated mice avoided stepping on the shock chamber. This suggests that TMX protects memory from Aß induced toxicity. In frontal cortex, ACh was moderately increased, with TMX treatment. In striatum, dopamine was significantly increased, 3,4-dihydroxyphenylacetic acid (DOPAC) level and DOPAC/DA ratio was decreased post TMX treatment. Therefore, TMX enhances spatial and contextual memory by reducing dopamine metabolism and increasing ACh level in Aß1-42 injected-breeding-retired-female mice.
Assuntos
Doença de Alzheimer/patologia , Amiloidose/patologia , Memória/efeitos dos fármacos , Tamoxifeno/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/farmacologia , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides , Amiloidose/induzido quimicamente , Amiloidose/psicologia , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Modelos Animais de Doenças , Dopamina/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Neostriado/patologia , Moduladores Seletivos de Receptor Estrogênico/farmacologiaRESUMO
A series of new cyanopyridine-triazine hybrids were designed, synthesized and screened as multitargeted anti-Alzheimer's agents. These molecules were designed while using computational techniques and were synthesized via a feasible concurrent synthetic route. Inhibition potencies of synthetic compounds 4a-4h against cholinesterases, Aß1-42 disaggregation, oxidative stress, cytotoxicity, and neuroprotection against Aß1-42-induced toxicity of the synthesized compounds were evaluated. Compounds 4d and 4h showed promising inhibitory activity on acetylcholinesterase (AChE) with IC50 values 0.059 and 0.080µM, respectively, along with good inhibition selectivity against AChE over butyrylcholinesterase (BuChE). Molecular modelling studies revealed that these compounds interacted simultaneously with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The mixed type inhibition of compound 4d further confirmed their dual binding nature in kinetic studies. Furthermore, the results from neuroprotection studies of most potent compounds 4d and 4h indicate that these derivatives can reduce neuronal death induced by H2O2-mediated oxidative stress and Aß1-42 induced cytotoxicity. In addition, in silico analysis of absorption, distribution, metabolism and excretion (ADME) profile of best compounds 4d and 4h revealed that they have drug like properties. Overall, these cyanopyridine-triazine hybrids can be considered as a candidate with potential impact for further pharmacological development in Alzheimer's therapy.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Piridinas/farmacologia , Triazinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/química , Butirilcolinesterase/metabolismo , Linhagem Celular , Inibidores da Colinesterase/química , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Piridinas/química , Triazinas/químicaRESUMO
Kisspeptin (KP), the endogenous ligand of GPR54, is a recently discovered neuropeptide shown to be involved in regulating reproductive system, anxiety-related behavior, locomotion, food intake, and suppression of metastasis across a range of cancers. KP is transcribed within the hippocampus, and GPR54 has been found in the amygdala and hippocampus, suggesting that KP might be involved in mediating learning and memory. However, the role of KP in cognition was largely unclear. Here, we investigated the role of KP-13, one of the endogenous active isoforms, in memory processes, and determined whether KP-13 could mitigate memory impairment induced by Aß1-42 in mice, using novel object recognition (NOR) and object location recognition (OLR) tasks. Intracerebroventricular (i.c.v.) infusion of KP-13 (2µg) immediately after training not only facilitated memory formation, but also prolonged memory retention in both tasks. The memory-improving effects of KP-13 could be blocked by the GPR54 receptor antagonist, kisspeptin-234 (234), and GnRH receptors antagonist, Cetrorelix, suggesting pharmacological specificity. Then the memory-enhancing effects were also presented after infusion of KP-13 into the hippocampus. Moreover, we found that i.c.v. injection of KP-13 was able to reverse the memory impairment induced by Aß1-42, which was inhibited by 234. To sum up, the results of our work indicate that KP-13 could facilitate memory formation and prolong memory retention through activation of the GPR54 and GnRH receptors, and suppress memory-impairing effect of Aß1-42 through activation of the GPR54, suggesting that KP-13 may be a potential drug for enhancing memory and treating Alzheimer's disease.
Assuntos
Peptídeos beta-Amiloides/farmacologia , Hipocampo/metabolismo , Kisspeptinas/farmacologia , Transtornos da Memória/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores LHRH/metabolismo , Memória Espacial/efeitos dos fármacos , Animais , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/farmacologia , Hipocampo/efeitos dos fármacos , Antagonistas de Hormônios/farmacologia , Infusões Intraventriculares , Kisspeptinas/administração & dosagem , Masculino , Transtornos da Memória/induzido quimicamente , Camundongos , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Kisspeptina-1 , Receptores LHRH/antagonistas & inibidores , Reconhecimento Psicológico/efeitos dos fármacos , Retenção Psicológica/efeitos dos fármacosRESUMO
A series of 5,6,7-trimethoxyflavone-6-chlorotacrine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that the target compounds exhibited good acetylcholinesterase (AChE) inhibitory potencies, high selectivity toward AChE over butyrylcholinesterase (BuChE), potential antioxidant activities and significant inhibitory potencies of self-induced beta-amyloid peptide (Aß) aggregation. In particular, compound 14c had the strongest AChE inhibitory activity with IC50 value of 12.8 nM, potent inhibition of self-induced Aß1-42 aggregation with inhibition ratio of 33.8% at 25 µM. Moreover, compound 14c acted as an antioxidant, as well as a neuroprotectant. Furthermore, 14c could cross the blood-brain barrier (BBB) in vitro. The results showed that compound 14c might be a potential multifunctional candidate for the treatment of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Flavonas/farmacologia , Tacrina/análogos & derivados , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Butirilcolinesterase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Equidae , Flavonas/síntese química , Flavonas/química , Estrutura Molecular , Células PC12 , Ratos , Relação Estrutura-Atividade , Tacrina/síntese química , Tacrina/química , Tacrina/farmacologiaRESUMO
INTRODUCTION: We describe Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core progress including: the Biobank; cerebrospinal fluid (CSF) amyloid beta (Aß1-42), t-tau, and p-tau181 analytical performance, definition of Alzheimer's disease (AD) profile for plaque, and tangle burden detection and increased risk for progression to AD; AD disease heterogeneity; progress in standardization; and new studies using ADNI biofluids. METHODS: Review publications authored or coauthored by ADNI Biomarker core faculty and selected non-ADNI studies to deepen the understanding and interpretation of CSF Aß1-42, t-tau, and p-tau181 data. RESULTS: CSF AD biomarker measurements with the qualified AlzBio3 immunoassay detects neuropathologic AD hallmarks in preclinical and prodromal disease stages, based on CSF studies in non-ADNI living subjects followed by the autopsy confirmation of AD. Collaboration across ADNI cores generated the temporal ordering model of AD biomarkers varying across individuals because of genetic/environmental factors that increase/decrease resilience to AD pathologies. DISCUSSION: Further studies will refine this model and enable the use of biomarkers studied in ADNI clinically and in disease-modifying therapeutic trials.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Bases de Dados Bibliográficas/estatística & dados numéricos , HumanosRESUMO
INTRODUCTION: The ability to identify individuals at increased genetic risk for Alzheimer's disease (AD) may streamline biomarker and drug trials and aid clinical and personal decision making. METHODS: We evaluated the discriminative ability of a genetic risk score (GRS) covering 22 published genetic risk loci for AD in 1162 Flanders-Belgian AD patients and 1019 controls and assessed correlations with family history, onset age, and cerebrospinal fluid (CSF) biomarkers (Aß1-42, T-Tau, P-Tau181P). RESULTS: A GRS including all single nucleotide polymorphisms (SNPs) and age-specific APOE ε4 weights reached area under the curve (AUC) 0.70, which increased to AUC 0.78 for patients with familial predisposition. Risk of AD increased with GRS (odds ratio, 2.32 (95% confidence interval 2.08-2.58 per unit; P < 1.0e(-15)). Onset age and CSF Aß1-42 decreased with increasing GRS (Ponset_age = 9.0e(-11); PAß = 8.9e(-7)). DISCUSSION: The discriminative ability of this 22-SNP GRS is still limited, but these data illustrate that incorporation of age-specific weights improves discriminative ability. GRS-phenotype correlations highlight the feasibility of identifying individuals at highest susceptibility.
Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Idade de Início , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/genética , Bélgica , Biomarcadores/líquido cefalorraquidiano , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/genética , Fenótipo , Fatores de Risco , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/genéticaRESUMO
The synthetic ~5 kDa ABP (amyloid-ß binding peptide) consists of a region of the 228 kDa human pericentrioloar material-1 (PCM-1) protein that selectively and avidly binds in vitro Aß1-42 oligomers, believed to be key co-drivers of Alzheimer's disease (AD), but not monomers (Chakravarthy et al., (2013) [3]). ABP also prevents Aß1-42 from triggering the apoptotic death of cultured human SHSY5Y neuroblasts, likely by sequestering Aß oligomers, suggesting that it might be a potential AD therapeutic. Here we support this possibility by showing that ABP also recognizes and binds Aß1-42 aggregates in sections of cortices and hippocampi from brains of AD transgenic mice and human AD patients. More importantly, ABP targets Aß1-42 aggregates when microinjected into the hippocampi of the brains of live AD transgenic mice.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Autoantígenos/química , Autoantígenos/farmacologia , Encéfalo/metabolismo , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Peptídeos/química , Peptídeos/farmacologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Peptídeos beta-Amiloides/metabolismo , Animais , Autoantígenos/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Proteínas de Ciclo Celular/administração & dosagem , Linhagem Celular , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fragmentos de Peptídeos/metabolismo , Peptídeos/administração & dosagem , Ligação ProteicaRESUMO
Alzheimer's disease (AD) is a neurodegenerative brain disorder that progressively impairs long-term and working memory. The function and mechanism of PA(Patchouli alcohol) in improving AD in the external treatment of encephalopathy remain unclear. This study aimed to investigate the therapeutic effect of PA on AD using an Aß1-42 induced AD mouse model with LPS(Lipopolysaccharide) stimulation of BV2 microglial cells. Additionally, we aimed to explore the potential mechanism of PA in enhancing autophagy and reducing neuroinflammation through the AMPK (AMP-activated protein kinase)/mTOR (Mammaliam target of rapamycin) signaling pathway. The Morris water maze was used to assess cognitive function, and cortical and hippocampal tissues were collected for further analysis of the corresponding signaling pathways and inflammatory changes through biological experiments. Our research findings demonstrate that PA has a significant positive impact on cognitive and memory impairments in mice that have been induced with Aß1-42-induced AD. Additionally, PA was also found to revert the activation of microglia induced by LPS. These effects may be attributed to the reduction of neuroinflammation and enhancement of the AMPK/mTOR autophagy pathway. Therefore, PA may serve as an effective therapeutic option to prevent or delay the progression of AD-associated memory dysfunction.
Assuntos
Proteínas Quinases Ativadas por AMP , Doença de Alzheimer , Peptídeos beta-Amiloides , Disfunção Cognitiva , Microglia , Fragmentos de Peptídeos , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Peptídeos beta-Amiloides/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/toxicidade , Proteínas Quinases Ativadas por AMP/metabolismo , Transdução de Sinais/efeitos dos fármacos , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Modelos Animais de DoençasRESUMO
Alzheimer's disease (AD) is a global medical challenge. Studies have shown that neurotoxicity caused by pathological aggregation of ß-amyloid (Aß) is an important factor leading to AD. Therefore, inhibiting the pathological aggregation of Aß is the key to treating AD. The recombinant human HspB5-ACD structural domain protein (AHspB5) prepared by our group in the previous period has been shown to have anti-amyloid aggregation effects, but its inability to penetrate biological membranes has limited its development. In this study, we prepared a recombinant fusion protein (T-AHspB5) of TAT and AHspB5. In vitro experiments showed that T-AHspB5 inhibited the formation of Aß1-42 protofibrils and had the ability to penetrate the blood-brain barrier; in cellular experiments, T-AHspB5 prevented Aß1-42-induced oxidative stress damage, apoptosis, and inflammatory responses in neuronal cells, and its mechanism of action was related to microglia activation and mitochondria-dependent apoptotic pathway. In animal experiments, T-AHspB5 improved memory and cognitive dysfunction and inhibited pathological changes of AD in APP/PS1 mice. In conclusion, this paper is expected to reveal the intervention mechanism and biological effect of T-AHspB5 on pathological aggregation of Aß1-42, provide a new pathway for the treatment of AD, and lay the foundation for the future development and application of T-AHspB5.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Peptídeos beta-Amiloides/metabolismo , Animais , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Camundongos , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Camundongos Transgênicos , Cadeia B de alfa-Cristalina/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Masculino , Proteínas Recombinantes/farmacologia , Domínios Proteicos , Agregação Patológica de Proteínas/tratamento farmacológico , Agregação Patológica de Proteínas/metabolismoRESUMO
The frequent intake of ultra-processed, heat-processed, and fat-enriched foods rich in dietary advanced lipoxidation end-products (ALEs) has been correlated with cognitive decline; however, the underlying mechanisms of action remain unexplored. This study investigated the impact of a 12-month dietary exposure to ALEs on learning, memory, and Aß1-42 accumulation in mice, with a focus on the AMPK/SIRT1 signaling pathway and ADAM10 expression. The gut microbiota and metabolomic profiles revealed ALEs-induced gut dysbiosis and cognitive impairment, highlighting modulation through the microbiota-gut-brain axis. Key findings include increased pathogenic bacteria and decreased beneficial bacteria, linked to metabolite profile changes that affect neurotoxic Aß1-42 peptide accumulation. This long-term comprehensive study underscores the need for dietary guidelines to reduce ALE intake and mitigate neurodegenerative disease risk, highlighting the intricate interplay between diet, gut microbiota, and cognitive health.