Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Front Neurosci ; 13: 861, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474823

RESUMO

How endogenously produced soluble amyloid ß-protein (Aß) affects synaptic plasticity in vulnerable circuits should provide insight into early Alzheimer's disease pathophysiology. McGill-R-Thy1-APP transgenic rats, modeling Alzheimer's disease amyloidosis, exhibit an age-dependent soluble Aß-mediated impairment of the induction of long-term potentiation (LTP) by 200 Hz conditioning stimulation at apical CA3-to-CA1 synapses. Here, we investigated if synaptic weakening at these synapses in the form of activity-dependent persistent reversal (depotentiation) of LTP is also altered in pre-plaque rats in vivo. In freely behaving transgenic rats strong, 400 Hz, conditioning stimulation induced stable LTP that was NMDA receptor- and voltage-gated Ca2+ channel-dependent. Surprisingly, the ability of novelty exploration to induce depotentiation of 400 Hz-induced LTP was impaired in an Aß-dependent manner in the freely behaving transgenic rats. Moreover, at apical synapses, low frequency conditioning stimulation (1 Hz) did not trigger depotentiation in anaesthetized transgenic rats, with an age-dependence similar to the LTP deficit. In contrast, at basal synapses neither LTP, induced by 100 or 200 Hz, nor novelty exploration-induced depotentiation was impaired in the freely behaving transgenic rats. These findings indicate that activity-dependent weakening, as well as strengthening, is impaired in a synapse- and age-dependent manner in this model of early Alzheimer's disease amyloidosis.

2.
Neurobiol Dis ; 127: 582-590, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30910746

RESUMO

Soluble synaptotoxic aggregates of the main pathological proteins of Alzheimer's disease, amyloid ß-protein (Aß) and tau, have rapid and potent inhibitory effects on long-term potentiation (LTP). Although the promotion of synaptic weakening mechanisms, including long-term depression (LTD), is posited to mediate LTP inhibition by Aß, little is known regarding the action of exogenous tau on LTD. The present study examined the ability of different assemblies of full-length human tau to affect LTD in the dorsal hippocampus of the anaesthetized rat. Unlike Aß, intracerebroventricular injection of soluble aggregates of tau (SτAs), but not monomers or fibrils, potently increased the threshold for LTD induction in a manner that required cellular prion protein. However, MTEP, an antagonist of the putative prion protein coreceptor metabotropic glutamate receptor 5, did not prevent the disruption of synaptic plasticity by SτAs. In contrast, systemic treatment with Ro 25-6981, a selective antagonist at GluN2B subunit-containing NMDA receptors, reduced SτA-mediated inhibition of LTD, but not LTP. Intriguingly, SτAs completely blocked Aß-facilitated LTD, whereas a subthreshold dose of SτAs facilitated Aß-mediated inhibition of LTP. Overall, these findings support the importance of cellular prion protein in mediating a range of, sometimes opposing, actions of soluble Aß and tau aggregates with different effector mechanisms on synaptic plasticity.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Hipocampo/efeitos dos fármacos , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Agregados Proteicos/fisiologia , Proteínas tau/metabolismo , Animais , Hipocampo/metabolismo , Depressão Sináptica de Longo Prazo/fisiologia , Masculino , Piridinas/farmacologia , Ratos , Receptor de Glutamato Metabotrópico 5/agonistas , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Tiazóis/farmacologia
3.
J Neurosci ; 38(50): 10595-10606, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30355631

RESUMO

Intracellular neurofibrillary tangles (NFTs) composed of tau protein are a neuropathological hallmark of several neurodegenerative diseases, the most common of which is Alzheimer's disease (AD). For some time NFTs were considered the primary cause of synaptic dysfunction and neuronal death, however, more recent evidence suggests that soluble aggregates of tau are key drivers of disease. Here we investigated the effect of different tau species on synaptic plasticity in the male rat hippocampus in vivo Intracerebroventricular injection of soluble aggregates formed from either wild-type or P301S human recombinant tau potently inhibited hippocampal long-term potentiation (LTP) at CA3-to-CA1 synapses. In contrast, tau monomers and fibrils appeared inactive. Neither baseline synaptic transmission, paired-pulse facilitation nor burst response during high-frequency conditioning stimulation was affected by the soluble tau aggregates. Similarly, certain AD brain soluble extracts inhibited LTP in a tau-dependent manner that was abrogated by either immunodepletion with, or coinjection of, a mid-region anti-tau monoclonal antibody (mAb), Tau5. Importantly, this tau-mediated block of LTP was prevented by administration of mAbs selective for the prion protein (PrP). Specifically, mAbs to both the mid-region (6D11) and N-terminus (MI-0131) of PrP prevented inhibition of LTP by both recombinant and brain-derived tau. These findings indicate that PrP is a mediator of tau-induced synaptic dysfunction.SIGNIFICANCE STATEMENT Here we report that certain soluble forms of tau selectively disrupt synaptic plasticity in the live rat hippocampus. Further, we show that monoclonal antibodies to cellular prion protein abrogate the impairment of long-term potentiation caused both by recombinant and Alzheimer's disease brain-derived soluble tau. These findings support a critical role for cellular prion protein in the deleterious synaptic actions of extracellular soluble tau in tauopathies, including Alzheimer's disease. Thus, approaches targeting cellular prion protein, or downstream pathways, might provide an effective strategy for developing therapeutics.


Assuntos
Hipocampo/metabolismo , Hipocampo/patologia , Plasticidade Neuronal/fisiologia , Proteínas PrPC/metabolismo , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Inibidores da Angiogênese/farmacologia , Animais , Feminino , Hipocampo/efeitos dos fármacos , Humanos , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Proteínas Priônicas/metabolismo , Ratos
4.
Cell Rep ; 23(7): 1932-1938, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29768194

RESUMO

The early stages of Alzheimer's disease are associated with synaptic dysfunction prior to overt loss of neurons. To identify extracellular molecules that impair synaptic plasticity in the brain, we studied the secretomes of human iPSC-derived neuronal models of Alzheimer's disease. When introduced into the rat brain, secretomes from human neurons with either a presenilin-1 mutation, amyloid precursor protein duplication, or trisomy of chromosome 21 all strongly inhibit hippocampal long-term potentiation. Synaptic dysfunction caused by presenilin-1 mutant and amyloid precusor protein duplication secretomes is mediated by Aß peptides, whereas trisomy of chromosome 21 (trisomy 21) neuronal secretomes induce dysfunction through extracellular tau. In all cases, synaptotoxicity is relieved by antibody blockade of cellular prion protein. These data indicate that human models of Alzheimer's disease generate distinct proteins that converge at the level of cellular prion protein to induce synaptic dysfunction in vivo.


Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Espaço Extracelular/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Modelos Biológicos , Plasticidade Neuronal , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Animais , Genótipo , Humanos , Potenciação de Longa Duração , Masculino , Neurônios/metabolismo , Presenilina-1/metabolismo , Ratos
5.
Neurobiol Dis ; 114: 24-30, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29477641

RESUMO

Pro-inflammatory mechanisms have recently emerged as an important component of early Alzheimer's disease (AD) pathogenesis. A particularly attractive therapeutic strategy is to selectively prevent the disruptive effects of activation of the innate immune system in the brain at an early transitional stage by reducing the production or directly neutralizing pro-inflammatory cytokines, in particular IL-1ß and TNF-α. Here we tested their in vivo effects on synaptic plasticity deficits, which provide sensitive and robust measures of synaptic failure, in a rat model of AD amyloidosis. Using electrophysiological techniques we longitudinally studied the effects of the NLRP3 inflammasome inhibitor Mcc950, the IL-1 receptor antagonist (anakinra) and an anti-TNF-α agent (etanercept) in awake freely moving transgenic rats overexpressing AD associated ß-amyloid precursor protein at a pre-plaque stage of amyloidosis. Repeated treatment with Mcc950 reversibly abrogated the inhibition of long-term potentiation. The IL-1 receptor antagonist and etanercept also had a similar beneficial effect on the deficit in synaptic plasticity. Our findings support the clinical development of Mcc950 and clinically available IL-1- and TNF-α-neutralizing agents in early AD.


Assuntos
Doença de Alzheimer/fisiopatologia , Amiloidose/fisiopatologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Plasticidade Neuronal/fisiologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Amiloidose/tratamento farmacológico , Amiloidose/genética , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Etanercepte/farmacologia , Etanercepte/uso terapêutico , Humanos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/agonistas , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Transgênicos
6.
Neuropharmacology ; 121: 231-246, 2017 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-28390893

RESUMO

Alzheimer's disease amyloid-ß (Aß) oligomers are synaptotoxic, inappropriately increasing extracellular glutamate concentration and glutamate receptor activation to thereby rapidly disrupt synaptic plasticity. Thus, acutely promoting brain glutamate homeostasis with a blood-based scavenging system, glutamate-oxaloacetate transaminase (GOT), and blocking metabotropic glutamate 5 (mGlu5) receptor or its co-receptor cellular prion protein (PrP), prevent the acute inhibition of long-term potentiation (LTP) by exogenous Aß. Here, we evaluated the time course of the effects of such interventions in the persistent disruptive effects of Aß oligomers, either exogenously injected in wild type rats or endogenously generated in transgenic rats that model Alzheimer's disease amyloidosis. We report that repeated, but not acute, systemic administration of recombinant GOT type 1, with or without the glutamate co-substrate oxaloacetate, reversed the persistent deleterious effect of exogenous Aß on synaptic plasticity. Moreover, similar repetitive treatment reversibly abrogated the inhibition of LTP monitored longitudinally in freely behaving transgenic rats. Remarkably, brief repeated treatment with an mGlu5 receptor antagonist, basimglurant, or an antibody that prevents Aß oligomer binding to PrP, ICSM35, also had similar reversible ameliorative effects in the transgenic rat model. Overall, the present findings support the ongoing development of therapeutics for early Alzheimer's disease based on these complementary approaches.


Assuntos
Amiloidose/patologia , Amiloidose/fisiopatologia , Região CA1 Hipocampal/fisiologia , Potenciação de Longa Duração/efeitos dos fármacos , Proteínas Priônicas/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Peptídeos beta-Amiloides/imunologia , Peptídeos beta-Amiloides/farmacologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Amiloidose/sangue , Amiloidose/genética , Animais , Anticorpos/farmacologia , Aspartato Aminotransferase Citoplasmática/farmacologia , Região CA1 Hipocampal/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Imidazóis/farmacologia , Potenciação de Longa Duração/genética , Masculino , Mutação/genética , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/farmacologia , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Piridinas/farmacologia , Ratos , Ratos Transgênicos , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Vigília
7.
J Biol Chem ; 290(47): 28343-52, 2015 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-26221033

RESUMO

Despite significant advances, the molecular identity of the cytotoxic species populated during in vivo amyloid formation crucial for the understanding of neurodegenerative disorders is yet to be revealed. In this study lysozyme prefibrillar oligomers and fibrils in both mature and sonicated states have been isolated through an optimized ultrafiltration/ultracentrifugation method and characterized with various optical spectroscopic techniques, atomic force microscopy, and transmission electron microscopy. We examined their level and mode of toxicity on rat pheochromocytoma (PC12) cells in both differentiated and undifferentiated states. We find that oligomers and fibrils display cytotoxic capabilities toward cultured cells in vitro, with oligomers producing elevated levels of cellular injury toward undifferentiated PC12 cells (PC12(undiff)). Furthermore, dual flow cytometry staining experiments demonstrate that the oligomers and mature fibrils induce divergent cellular death pathways (apoptosis and secondary necrosis, respectively) in these PC12 cells. We have also shown that oligomers but not sonicated mature fibrils inhibit hippocampal long term potentiation, a form of synaptic plasticity implicated in learning and memory, in vivo. We conclude that our in vitro and in vivo findings confer a level of resistance toward amyloid fibrils, and that the PC 12-based comparative cytotoxicity assay can provide insights into toxicity differences between differently aggregated protein species.


Assuntos
Amiloide/metabolismo , Biopolímeros/metabolismo , Morte Celular , Amiloide/química , Animais , Biopolímeros/química , Células PC12 , Ratos
8.
Acta Neuropathol Commun ; 2: 175, 2014 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-25540024

RESUMO

Long before synaptic loss occurs in Alzheimer's disease significant harbingers of disease may be detected at the functional level. Here we examined if synaptic long-term potentiation is selectively disrupted prior to extracellular deposition of Aß in a very complete model of Alzheimer's disease amyloidosis, the McGill-R-Thy1-APP transgenic rat. Longitudinal studies in freely behaving animals revealed an age-dependent, relatively rapid-onset and persistent inhibition of long-term potentiation without a change in baseline synaptic transmission in the CA1 area of the hippocampus. Thus the ability of a standard 200 Hz conditioning protocol to induce significant NMDA receptor-dependent short- and long-term potentiation was lost at about 3.5 months of age and this deficit persisted for at least another 2-3 months, when plaques start to appear. Consistent with in vitro evidence for a causal role of a selective reduction in NMDA receptor-mediated synaptic currents, the deficit in synaptic plasticity in vivo was associated with a reduction in the synaptic burst response to the conditioning stimulation and was overcome using stronger 400 Hz stimulation. Moreover, intracerebroventricular treatment for 3 days with an N-terminally directed monoclonal anti- human Aß antibody, McSA1, transiently reversed the impairment of synaptic plasticity. Similar brief treatment with the BACE1 inhibitor LY2886721 or the γ-secretase inhibitor MRK-560 was found to have a comparable short-lived ameliorative effect when tracked in individual rats. These findings provide strong evidence that endogenously generated human Aß selectively disrupts the induction of long-term potentiation in a manner that enables potential therapeutic options to be assessed longitudinally at the pre-plaque stage of Alzheimer's disease amyloidosis.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Hipocampo/fisiopatologia , Potenciação de Longa Duração/fisiologia , Transmissão Sináptica/fisiologia , Fatores Etários , Doença de Alzheimer/fisiopatologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/imunologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/imunologia , Animais , Anticorpos/farmacologia , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Compostos Heterocíclicos com 2 Anéis/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Ácidos Picolínicos/farmacologia , Ratos , Ratos Transgênicos , Ratos Wistar , Sulfonamidas/farmacologia , Transmissão Sináptica/efeitos dos fármacos
9.
J Neurosci ; 34(18): 6140-5, 2014 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-24790184

RESUMO

Alzheimer's disease (AD) is associated with pathological assembly states of amyloid-ß protein (Aß). Aß-related synaptotoxicity can be blocked by anti-prion protein (PrP) antibodies, potentially allowing therapeutic targeting of this aspect of AD neuropathogenesis. Here, we show that intravascular administration of a high-affinity humanized anti-PrP antibody to rats can prevent the plasticity-disrupting effects induced by exposure to soluble AD brain extract. These results provide an in vivo proof of principle for such a therapeutic strategy.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/farmacologia , Anticorpos Monoclonais/administração & dosagem , Região CA1 Hipocampal/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Príons/imunologia , Idoso de 80 Anos ou mais , Análise de Variância , Animais , Biofísica , Vias de Administração de Medicamentos , Estimulação Elétrica , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Príons/metabolismo , Ratos , Ratos Wistar , Lobo Temporal/química , Lobo Temporal/metabolismo
10.
Biochemistry ; 53(24): 3908-21, 2014 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-24840308

RESUMO

Evidence for a central role of amyloid ß-protein (Aß) in the genesis of Alzheimer's disease (AD) has led to advanced human trials of Aß-lowering agents. The "amyloid hypothesis" of AD postulates deleterious effects of small, soluble forms of Aß on synaptic form and function. Because selectively targeting synaptotoxic forms of soluble Aß could be therapeutically advantageous, it is important to understand the full range of soluble Aß derivatives. We previously described a Chinese hamster ovary (CHO) cell line (7PA2 cells) that stably expresses mutant human amyloid precursor protein (APP). Here, we extend this work by purifying an sodium dodecyl sulfate (SDS)-stable, ∼8 kDa Aß species from the 7PA2 medium. Mass spectrometry confirmed its identity as a noncovalently bonded Aß40 homodimer that impaired hippocampal long-term potentiation (LTP) in vivo. We further report the detection of Aß-containing fragments of APP in the 7PA2 medium that extend N-terminal from Asp1 of Aß. These N-terminally extended Aß-containing monomeric fragments are distinct from soluble Aß oligomers formed from Aß1-40/42 monomers and are bioactive synaptotoxins secreted by 7PA2 cells. Importantly, decreasing ß-secretase processing of APP elevated these alternative synaptotoxic APP fragments. We conclude that certain synaptotoxic Aß-containing species can arise from APP processing events N-terminal to the classical ß-secretase cleavage site.


Assuntos
Peptídeos beta-Amiloides/fisiologia , Precursor de Proteína beta-Amiloide/metabolismo , Plasticidade Neuronal , Sinapses/efeitos dos fármacos , Doença de Alzheimer/fisiopatologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/isolamento & purificação , Peptídeos beta-Amiloides/farmacologia , Peptídeos beta-Amiloides/toxicidade , Animais , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Meios de Cultivo Condicionados , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Fragmentos de Peptídeos , Ratos
11.
Philos Trans R Soc Lond B Biol Sci ; 369(1633): 20130147, 2014 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-24298149

RESUMO

Many endogenous factors influence the time course and extent of the detrimental effects of amyloid ß-protein (Aß) on synaptic function. Here, we assessed the impact of varying endogenous glutamatergic and cholinergic transmission by pharmacological means on the disruption of plasticity at hippocampal CA3-to-CA1 synapses in the anaesthetized rat. NMDA receptors (NMDARs) are considered critical in mediating Aß-induced inhibition of long-term potentiation (LTP). However, intracerebroventricular injection of Aß1-42 inhibited not only NMDAR-dependent LTP but also voltage-activated Ca(2+)-dependent LTP induced by strong conditioning stimulation during NMDAR blockade. On the other hand, another form of NMDAR-independent synaptic plasticity, endogenous acetylcholine-induced muscarinic receptor-dependent long-term enhancement, was not hindered by Aß1-42. Interestingly, augmenting endogenous acetylcholine activation of nicotinic receptors prior to the injection of Aß1-42 prevented the inhibition of NMDAR-dependent LTP, whereas the same intervention when introduced after the infusion of Aß was ineffective. We also examined the duration of action of Aß, including water soluble Aß from Alzheimer's disease (AD) brain. Remarkably, the inhibition of LTP induction caused by a single injection of sodium dodecyl sulfate-stable Aß dimer-containing AD brain extract persisted for at least a week. These findings highlight the need to increase our understanding of non-NMDAR mechanisms and of developing novel means of overcoming, rather than just preventing, the deleterious synaptic actions of Aß.


Assuntos
Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Fragmentos de Peptídeos/metabolismo , Sinapses/fisiologia , Acetilcolina/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/farmacologia , Análise de Variância , Animais , Química Encefálica , Potenciais Pós-Sinápticos Excitadores/fisiologia , Líquido Extracelular/metabolismo , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Nicotínicos/metabolismo , Sinapses/efeitos dos fármacos
12.
Mol Brain ; 6: 47, 2013 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-24284042

RESUMO

BACKGROUND: Exosomes, small extracellular vesicles of endosomal origin, have been suggested to be involved in both the metabolism and aggregation of Alzheimer's disease (AD)-associated amyloid ß-protein (Aß). Despite their ubiquitous presence and the inclusion of components which can potentially interact with Aß, the role of exosomes in regulating synaptic dysfunction induced by Aß has not been explored. RESULTS: We here provide in vivo evidence that exosomes derived from N2a cells or human cerebrospinal fluid can abrogate the synaptic-plasticity-disrupting activity of both synthetic and AD brain-derived Aß. Mechanistically, this effect involves sequestration of synaptotoxic Aß assemblies by exosomal surface proteins such as PrPC rather than Aß proteolysis. CONCLUSIONS: These data suggest that exosomes can counteract the inhibitory action of Aß, which contributes to perpetual capability for synaptic plasticity.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Exossomos/metabolismo , Plasticidade Neuronal , Sinapses/metabolismo , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Líquido Cefalorraquidiano/metabolismo , Difusão , Exossomos/efeitos dos fármacos , Feminino , Humanos , Ligantes , Potenciação de Longa Duração , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas PrPC/metabolismo , Ratos , Ratos Wistar , Sinapses/efeitos dos fármacos
13.
Mol Brain ; 5: 25, 2012 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-22805374

RESUMO

Alzheimer's disease (AD) is characterized by episodic memory impairment that often precedes clinical diagnosis by many years. Probing the mechanisms of such impairment may provide much needed means of diagnosis and therapeutic intervention at an early, pre-dementia, stage. Prior to the onset of significant neurodegeneration, the structural and functional integrity of synapses in mnemonic circuitry is severely compromised in the presence of amyloidosis. This review examines recent evidence evaluating the role of amyloid-ß protein (Aß) in causing rapid disruption of synaptic plasticity and memory impairment. We evaluate the relative importance of different sizes and conformations of Aß, including monomer, oligomer, protofibril and fibril. We pay particular attention to recent controversies over the relevance to the pathophysiology of AD of different water soluble Aß aggregates and the importance of cellular prion protein in mediating their effects. Current data are consistent with the view that both low-n oligomers and larger soluble assemblies present in AD brain, some of them via a direct interaction with cellular prion protein, cause synaptic memory failure. At the two extremes of aggregation, monomers and fibrils appear to act in vivo both as sources and sinks of certain metastable conformations of soluble aggregates that powerfully disrupt synaptic plasticity. The same principle appears to apply to other synaptotoxic amyloidogenic proteins including tau, α-synuclein and prion protein.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Plasticidade Neuronal , Sinapses/metabolismo , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Peptídeos beta-Amiloides/química , Animais , Humanos , Memória , Dados de Sequência Molecular , Príons/metabolismo
14.
J Neurochem ; 119(1): 189-201, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21781116

RESUMO

Diverse lines of evidence indicate that pre-fibrillar, diffusible assemblies of the amyloid ß-protein (Aß) play an important role in Alzheimer's disease pathogenesis. Although the precise molecular identity of these soluble toxins remains unsettled, recent experiments suggest that sodium dodecyl sulfate (SDS)-stable Aß dimers may be the basic building blocks of Alzheimer's disease-associated synaptotoxic assemblies and as such present an attractive target for therapeutic intervention. In the absence of sufficient amounts of highly pure cerebral Aß dimers, we have used synthetic disulfide cross-linked dimers (free of Aß monomer or fibrils) to generate conformation-specific monoclonal antibodies. These dimers aggregate to form kinetically trapped protofibrils, but do not readily form fibrils. We identified two antibodies, 3C6 and 4B5, which preferentially bind assemblies formed from covalent Aß dimers, but do not bind to Aß monomer, amyloid precursor protein, or aggregates formed by other amyloidogenic proteins. Monoclonal antibody 3C6, but not an IgM isotype-matched control antibody, ameliorated the plasticity-disrupting effects of Aß extracted from the aqueous phase of Alzheimer's disease brain, thus suggesting that 3C6 targets pathogenically relevant Aß assemblies. These data prove the usefulness of covalent dimers and their assemblies as immunogens and recommend further investigation of the therapeutic and diagnostic utility of monoclonal antibodies raised to such assemblies.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/imunologia , Anticorpos Monoclonais/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/farmacologia , Animais , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/isolamento & purificação , Western Blotting , Química Encefálica , Reagentes para Ligações Cruzadas , Eletroforese em Gel de Poliacrilamida , Fenômenos Eletrofisiológicos , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulina M/imunologia , Imunoprecipitação , Potenciação de Longa Duração/efeitos dos fármacos , Camundongos , Ligação Proteica , Extratos de Tecidos/química
15.
Nat Commun ; 2: 336, 2011 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-21654636

RESUMO

A role for PrP in the toxic effect of oligomeric forms of Aß, implicated in Alzheimer's disease (AD), has been suggested but remains controversial. Here we show that PrP is required for the plasticity-impairing effects of ex vivo material from human AD brain and that standardized Aß-derived diffusible ligand (ADDL) preparations disrupt hippocampal synaptic plasticity in a PrP-dependent manner. We screened a panel of anti-PrP antibodies for their ability to disrupt the ADDL-PrP interaction. Antibodies directed to the principal PrP/Aß-binding site and to PrP helix-1, were able to block Aß binding to PrP suggesting that the toxic Aß species are of relatively high molecular mass and/or may bind multiple PrP molecules. Two representative and extensively characterized monoclonal antibodies directed to these regions, ICSM-35 and ICSM-18, were shown to block the Aß-mediated disruption of synaptic plasticity validating these antibodies as candidate therapeutics for AD either individually or in combination.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Modelos Moleculares , Plasticidade Neuronal/fisiologia , Príons/metabolismo , Sinapses/metabolismo , Sinapses/fisiologia , Doença de Alzheimer/imunologia , Animais , Anticorpos Monoclonais , Cromatografia em Gel , Cromatografia Líquida de Alta Pressão , Eletroforese em Gel de Poliacrilamida , Eletrofisiologia , Humanos , Ligantes , Potenciação de Longa Duração/fisiologia , Camundongos , Camundongos Knockout , Microscopia Eletrônica , Ultracentrifugação
16.
J Neurosci ; 31(20): 7259-63, 2011 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-21593310

RESUMO

Synthetic amyloid-ß protein (Aß) oligomers bind with high affinity to cellular prion protein (PrP(C)), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Aß in vitro is controversial. Here we report that intracerebroventricular injection of Aß-containing aqueous extracts of Alzheimer's disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampus in vivo. Moreover, the disruption of LTP was abrogated by immunodepletion of Aß. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Aß-binding site on PrP(C), prevented the inhibition of LTP by AD brain-derived Aß. In contrast, R1, a Fab directed to the C terminus of PrP(C), a region not implicated in binding of Aß, did not significantly affect the Aß-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Aß dimer and the role of PrP(C) in mediating synaptic plasticity disruption by soluble Aß.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/administração & dosagem , Hipocampo/patologia , Potenciação de Longa Duração/fisiologia , Inibição Neural/imunologia , Fragmentos de Peptídeos/administração & dosagem , Proteínas PrPC/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Animais , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Feminino , Hipocampo/metabolismo , Humanos , Injeções Intraventriculares , Masculino , Inibição Neural/fisiologia , Plasticidade Neuronal/fisiologia , Proteínas PrPC/imunologia , Ratos , Ratos Wistar
17.
Neurobiol Aging ; 32(4): 614-23, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19446369

RESUMO

Soluble amyloid-ß protein (Aß) may cause cognitive impairment in Alzheimer's disease in the absence of significant neurodegeneration. Here, the ability of the NMDA receptor (NMDAR) antagonist memantine to prevent synthetic Aß-mediated rapid functional deficits in learned behavior and synaptic plasticity was assessed in the rat. In vitro, pretreatment with a clinically relevant, NMDAR blocking concentration of memantine partially inhibited the induction of long-term potentiation (LTP) in the dentate gyrus and prevented further inhibition caused by exposure to Aß(1-42). Whereas systemic injection with memantine alone inhibited LTP in the CA1 area in vivo, a subthreshold dose partially abrogated the inhibition of LTP by intracerebroventricular soluble Aß(1-42). Similarly, systemic treatment with memantine alone impaired performance of an operant learning task and a subthreshold dose prevented the Aß(1-42)-mediated increase in perseveration errors. The acute protection afforded by memantine, albeit in a narrow dose range, against the rapid disruptive effects of soluble Aß(1-42) on synaptic plasticity and learned behavior strongly implicate NMDAR-dependent reversible dysfunction of synaptic mechanisms in Aß-mediated cognitive impairment.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Hipocampo/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Memantina/farmacologia , Fármacos Neuroprotetores/farmacologia , Sinapses/efeitos dos fármacos , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Eletrofisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Wistar
18.
J Biol Chem ; 285(2): 1066-74, 2010 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-19889627

RESUMO

We have previously shown that a subpopulation of naturally occurring human IgGs were cross-reactive against conformational epitopes on pathologic aggregates of Abeta, a peptide that forms amyloid fibrils in the brains of patients with Alzheimer disease, inhibited amyloid fibril growth, and dissociated amyloid in vivo. Here, we describe similar anti-amyloidogenic activity that is a general property of free human Ig gamma heavy chains. A gamma(1) heavy chain, F1, had nanomolar binding to an amyloid fibril-related conformational epitope on synthetic oligomers and fibrils as well as on amyloid-laden tissue sections. F1 did not bind to native Abeta monomers, further indicating the conformational nature of its binding site. The inherent anti-amyloidogenic activity of Ig gamma heavy chains was demonstrated by nanomolar amyloid fibril and oligomer binding by polyclonal and monoclonal human heavy chains that were isolated from inert or weakly reactive antibodies. Most importantly, the F1 heavy chain prevented in vitro fibril growth and reduced in vivo soluble Abeta oligomer-induced impairment of rodent hippocampal long term potentiation, a cellular mechanism of learning and memory. These findings demonstrate that free human Ig gamma heavy chains comprise a novel class of molecules for developing potential therapeutics for Alzheimer disease and other amyloid disorders. Moreover, establishing the molecular basis for heavy chain-amyloidogenic conformer interactions should advance understanding on the types of interactions that these pathologic assemblies have with biological molecules.


Assuntos
Peptídeos beta-Amiloides/química , Amiloide/química , Cadeias gama de Imunoglobulina/química , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Amiloide/genética , Amiloide/metabolismo , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Células Cultivadas , Feminino , Humanos , Cadeias gama de Imunoglobulina/genética , Cadeias gama de Imunoglobulina/metabolismo , Cadeias gama de Imunoglobulina/farmacologia , Camundongos
19.
Hippocampus ; 20(6): 758-67, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19623539

RESUMO

The persistent cognitive disruptive effects of stress have been strongly implicated in the pathophysiology of depression and post-traumatic stress disorder. Here we examined factors influencing the time course of recovery from the inhibitory effect of acute inescapable stressors on the ability to induce long-term potentiation (LTP) in the dorsal hippocampus in vivo. We tested different forms of LTP, different stressors and different inbred strains of rats. Acute elevated platform stress completely, but transiently (<3 h), inhibited induction of both NMDA receptor-dependent LTP induced by a standard high frequency (200 Hz) conditioning stimulus and an additional LTP that required voltage-dependent Ca(2+) channel activation triggered by strong (400 Hz) conditioning stimulation. In contrast, acute inescapable footshock stress, used to study learned helplessness, inhibited LTP for at least 4 weeks. Contrary to expectations, there was no clear relationship between the ability of the footshock to trigger helpless behavior, a model of stress-induced depression, and the magnitude of LTP inhibition. Moreover, LTP did not appear to be affected by genetic susceptibility to learned helplessness, a model of genetic vulnerability to depression. This long-lasting synaptic plasticity disruption may underlie persistent impairment of hippocampus-dependent cognition by excessive acute inescapable stress.


Assuntos
Desamparo Aprendido , Hipocampo/fisiopatologia , Potenciação de Longa Duração/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Eletrofisiologia , Potenciais Pós-Sinápticos Excitadores , Masculino , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo
20.
Neuromolecular Med ; 12(1): 13-26, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19757208

RESUMO

Alzheimer's disease (AD) is characterized neuropathologically by the deposition of different forms of amyloid beta-protein (A beta) including variable amounts of soluble species that correlate with severity of dementia. The extent of synaptic loss in the brain provides the best morphological correlate of cognitive impairment in clinical AD. Animal research on the pathophysiology of AD has therefore focussed on how soluble A beta disrupts synaptic mechanisms in vulnerable brain regions such as the hippocampus. Synaptic plasticity in the form of persistent activity-dependent increases or decreases in synaptic strength provide a neurophysiological substrate for hippocampal-dependent learning and memory. Acute treatment with human-derived or chemically prepared soluble A beta that contains certain oligomeric assemblies, potently and selectively disrupts synaptic plasticity causing inhibition of long-term potentiation (LTP) and enhancement of long-term depression (LTD) of glutamatergic transmission. Over time these and related actions of A beta have been implicated in reducing synaptic integrity. This review addresses the involvement of neurotransmitter intercellular signaling in mediating or modulating the synaptic plasticity disrupting actions of soluble A beta, with particular emphasis on the different roles of glutamatergic and cholinergic mechanisms. There is growing evidence to support the view that NMDA and possibly nicotinic receptors are critically involved in mediating the disruptive effect of A beta and that targeting muscarinic receptors can indirectly modulate A beta's actions. Such studies should help inform ongoing and future clinical trials of drugs acting through the glutamatergic and cholinergic systems.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Sinapses/metabolismo , Transmissão Sináptica/fisiologia , Acetilcolina/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Animais , Ácido Glutâmico/metabolismo , Humanos , Potenciação de Longa Duração/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Receptores Colinérgicos/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA