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INTRODUCTION: Vervets are non-human primates that share high genetic homology with humans and develop amyloid beta (Aß) pathology with aging. We expand current knowledge by examining Aß pathology, aging, cognition, and biomarker proteomics. METHODS: Amyloid immunoreactivity in the frontal cortex and temporal cortex/hippocampal regions from archived vervet brain samples ranging from young adulthood to old age was quantified. We also obtained cognitive scores, plasma samples, and cerebrospinal fluid (CSF) samples in additional animals. Plasma and CSF proteins were quantified with platforms utilizing human antibodies. RESULTS: We found age-related increases in Aß deposition in both brain regions. Bioinformatic analyses assessed associations between biomarkers and age, sex, cognition, and CSF Aß levels, revealing changes in proteins related to immune-related inflammation, metabolism, and cellular processes. DISCUSSION: Vervets are an effective model of aging and early-stage Alzheimer's disease, and we provide translational biomarker data that both align with previous results in humans and provide a basis for future investigations. HIGHLIGHTS: We found changes in immune and metabolic plasma biomarkers associated with age and cognition. Cerebrospinal fluid (CSF) biomarkers revealed changes in cell signaling indicative of adaptative processes. TNFRSF19 (TROY) and Artemin co-localize with Alzheimer's disease pathology. Vervets are a relevant model for translational studies of early-stage Alzheimer's disease.
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Envejecimiento , Péptidos beta-Amiloides , Biomarcadores , Disfunción Cognitiva , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/sangre , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/sangre , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/sangre , Masculino , Femenino , Animales , Hipocampo , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/sangre , Modelos Animales de Enfermedad , Humanos , EncéfaloRESUMEN
As an essential component of our innate immune system, the complement system is responsible for our defense against pathogens. The complement cascade has complex roles in the central nervous system (CNS), most of what we know about it stems from its role in brain development. However, in recent years, numerous reports have implicated the classical complement cascade in both brain development and decline. More specifically, complement dysfunction has been implicated in neurodegenerative disorders, such as Alzheimer's disease (AD), which is the most common form of dementia. Synapse loss is one of the main pathological hallmarks of AD and correlates with memory impairment. Throughout the course of AD progression, synapses are tagged with complement proteins and are consequently removed by microglia that express complement receptors. Notably, astrocytes are also capable of secreting signals that induce the expression of complement proteins in the CNS. Both astrocytes and microglia are implicated in neuroinflammation, another hallmark of AD pathogenesis. In this review, we provide an overview of previously known and newly established roles for the complement cascade in the CNS and we explore how complement interactions with microglia, astrocytes, and other risk factors such as TREM2 and ApoE4 modulate the processes of neurodegeneration in both amyloid and tau models of AD.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/etiología , Proteínas del Sistema Complemento , Sistema Nervioso Central , Transducción de Señal , Activación de ComplementoRESUMEN
Alzheimer's disease (AD) is a devastating disorder with a global prevalence estimated at 55 million people. In clinical studies administering certain anti-beta-amyloid (Aß) antibodies, amyloid-related imaging abnormalities (ARIAs) have emerged as major adverse events. The frequency of these events is higher among apolipoprotein ε4 allele carriers (APOE4) compared to non-carriers. To reflect patients most at risk for vascular complications of anti-Aß immunotherapy, we selected an APPswe/PS1dE9 transgenic mouse model bearing the human APOE4 gene (APPPS1:E4) and compared it with the same APP/PS1 mouse model bearing the human APOE3 gene (APOE ε3 allele; APPPS1:E3). Using histological and biochemical analyses, we characterized mice at three ages: 8, 12, and 16 months. Female and male mice were assayed for general cerebral fibrillar and pyroglutamate (pGlu-3) Aß deposition, cerebral amyloid angiopathy (CAA), microhemorrhages, apoE and cholesterol composition, astrocytes, microglia, inflammation, lysosomal dysfunction, and neuritic dystrophy. Amyloidosis, lipid deposition, and astrogliosis increased with age in APPPS1:E4 mice, while inflammation did not reveal significant changes with age. In general, APOE4 carriers showed elevated Aß, apoE, reactive astrocytes, pro-inflammatory cytokines, microglial response, and neuritic dystrophy compared to APOE3 carriers at different ages. These results highlight the potential of the APPPS1:E4 mouse model as a valuable tool in investigating the vascular side effects associated with anti-amyloid immunotherapy.
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Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Ratones Transgénicos , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Ratones , Humanos , Femenino , Masculino , Péptidos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Angiopatía Amiloide Cerebral/metabolismo , Angiopatía Amiloide Cerebral/patología , Angiopatía Amiloide Cerebral/genética , Encéfalo/metabolismo , Encéfalo/patologíaRESUMEN
Understanding the hazards of space radiation is imperative as astronauts begin voyaging on missions with increasing distances from Earth's protective shield. Previous studies investigating the acute or long-term effects of specific ions comprising space radiation have revealed threats to organs generally considered radioresistant, like the brain, and have shown males to be more vulnerable than their female counterparts. However, astronauts will be exposed to a combination of ions that may result in additive effects differing from those of any one particle species. To better understand this nuance, we irradiated 4-month-old male and female, wild-type and Alzheimer's-like mice with 0, 0.5, or 0.75 Gy galactic cosmic ray simulation (GCRsim) or 0, 0.75, or 2 Gy gamma radiation (wild-type only). At 11 months, mice underwent brain and heart MRIs or behavioral tests, after which they were euthanized to assess amyloid-beta pathology, heart and kidney gene expression and fibrosis, and plasma cytokines. Although there were no changes in amyloid-beta pathology, we observed many differences in brain MRIs and behavior, including opposite effects of GCRsim on motor coordination in male and female transgenic mice. Additionally, several genes demonstrated persistent changes in the heart and kidney. Overall, we found sex- and genotype-specific, long-term effects of GCRsim and gamma radiation on the brain, heart, and kidney.
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Enfermedad de Alzheimer , Encéfalo , Radiación Cósmica , Rayos gamma , Corazón , Riñón , Ratones Transgénicos , Animales , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/patología , Femenino , Masculino , Rayos gamma/efectos adversos , Encéfalo/efectos de la radiación , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Ratones , Riñón/efectos de la radiación , Riñón/metabolismo , Riñón/patología , Corazón/efectos de la radiación , Radiación Cósmica/efectos adversos , Mutación , Caracteres Sexuales , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/genética , Modelos Animales de Enfermedad , Factores SexualesRESUMEN
INTRODUCTION: At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias. METHODS: The meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry. RESULTS: During the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor α [TNFα]). DISCUSSION: This manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/patología , Microglía/patología , Inflamación , Apolipoproteínas E/genéticaRESUMEN
Whole-body exposure to high-energy particle radiation remains an unmitigated hazard to human health in space. Ongoing experiments at the NASA Space Radiation Laboratory and elsewhere repeatedly show persistent changes in brain function long after exposure to simulations of this unique radiation environment, although, as is also the case with proton radiotherapy sequelae, how this occurs and especially how it interacts with common comorbidities is not well-understood. Here, we report modest differential changes in behavior and brain pathology between male and female Alzheimer's-like and wildtype littermate mice 7-8 months after exposure to 0, 0.5, or 2 Gy of 1 GeV proton radiation. The mice were examined with a battery of behavior tests and assayed for amyloid beta pathology, synaptic markers, microbleeds, microglial reactivity, and plasma cytokines. In general, the Alzheimer's model mice were more prone than their wildtype littermates to radiation-induced behavior changes, and hippocampal staining for amyloid beta pathology and microglial activation in these mice revealed a dose-dependent reduction in males but not in females. In summary, radiation-induced, long-term changes in behavior and pathology, although modest, appear specific to both sex and the underlying disease state.
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Enfermedad de Alzheimer , Masculino , Ratones , Femenino , Humanos , Animales , Enfermedad de Alzheimer/patología , Protones , Péptidos beta-Amiloides/metabolismo , Relación Dosis-Respuesta en la Radiación , Hipocampo/metabolismo , Mutación , Ratones TransgénicosRESUMEN
Compelling evidence suggests that pyroglutamate-modified Aß (pGlu3-Aß; AßN3pG) peptides play a pivotal role in the development and progression of Alzheimer's disease (AD). Approaches targeting pGlu3-Aß by glutaminyl cyclase (QC) inhibition (Varoglutamstat) or monoclonal antibodies (Donanemab) are currently in clinical development. Here, we aimed at an assessment of combination therapy of Varoglutamstat (PQ912) and a pGlu3-Aß-specific antibody (m6) in transgenic mice. Whereas the single treatments at subtherapeutic doses show moderate (16-41%) but statistically insignificant reduction of Aß42 and pGlu-Aß42 in mice brain, the combination of both treatments resulted in significant reductions of Aß by 45-65%. Evaluation of these data using the Bliss independence model revealed a combination index of ≈1, which is indicative for an additive effect of the compounds. The data are interpreted in terms of different pathways, in which the two drugs act. While PQ912 prevents the formation of pGlu3-Aß in different compartments, the antibody is able to clear existing pGlu3-Aß deposits. The results suggest that combination of the small molecule Varoglutamstat and a pE3Aß-directed monoclonal antibody may allow a reduction of the individual compound doses while maintaining the therapeutic effect.
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Enfermedad de Alzheimer , Aminoaciltransferasas/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Anticuerpos Monoclonales de Origen Murino/farmacología , Bencimidazoles/farmacología , Imidazolinas/farmacología , Fragmentos de Péptidos/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Animales , Humanos , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/genéticaRESUMEN
Space radiation presents a substantial threat to travel beyond Earth. Relatively low doses of high-energy particle radiation cause physiological and behavioral impairments in rodents and may pose risks to human spaceflight. There is evidence that 56Fe irradiation, a significant component of space radiation, may be more harmful to males than to females and worsen Alzheimer's disease pathology in genetically vulnerable models. Yet, research on the long-term, sex- and genotype-specific effects of 56Fe irradiation is lacking. Here, we irradiated 4-month-old male and female, wild-type and Alzheimer's-like APP/PS1 mice with 0, 0.10, or 0.50 Gy of 56Fe ions (1GeV/u). Mice underwent microPET scans before and 7.5 months after irradiation, a battery of behavioral tests at 11 months of age and were sacrificed for pathological and biochemical analyses at 12 months of age. 56Fe irradiation worsened amyloid-beta (Aß) pathology, gliosis, neuroinflammation and spatial memory, but improved motor coordination, in male transgenic mice and worsened fear memory in wild-type males. Although sham-irradiated female APP/PS1 mice had more cerebral Aß and gliosis than sham-irradiated male transgenics, female mice of both genotypes were relatively spared from radiation effects 8 months later. These results provide evidence for sex-specific, long-term CNS effects of space radiation.
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Enfermedad de Alzheimer , Conducta Animal/efectos de la radiación , Rayos gamma , Genotipo , Radioisótopos de Hierro , Presenilina-1 , Caracteres Sexuales , Memoria Espacial/efectos de la radiación , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Femenino , Masculino , Ratones , Ratones Transgénicos , Presenilina-1/genética , Presenilina-1/metabolismo , Factores de TiempoRESUMEN
From its inception in 1980, advancement of research was one of the primary missions of the Alzheimer's Association (also known as Alzheimer's Disease and Related Disorders Association) in addition to leading in family caregiver support, better care, public education, and awareness. Over the past 30 years, the Association has grown and expanded its engagement with the scientific community. In the past 10 years, its research budget has more than doubled, greatly increasing the number of research grants funded and the number of strategic projects supported. The leadership and members of the Medical and Scientific Advisory Council recognized that the growth of the Alzheimer's Association and the expanded mission of Medical & Scientific Relations Division necessitated a change in the mission and charge of the external scientific advisory function to the Association.
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Enfermedad de Alzheimer , Colaboración Intersectorial , Investigación , Sociedades , HumanosRESUMEN
Both aging and Alzheimer's disease (AD) are associated with widespread epigenetic changes, with most evidence suggesting global hypomethylation in AD. It is, however, unclear how these age-related epigenetic changes are linked to molecular aberrations as expressed in animal models of AD. Here, we investigated age-related changes of epigenetic markers of DNA methylation and hydroxymethylation in a range of animal models of AD, and their correlations with amyloid plaque load. Three transgenic mouse models, including the J20, APP/PS1dE9 and 3xTg-AD models, as well as Caribbean vervets (a non-transgenic non-human primate model of AD) were investigated. In the J20 mouse model, an age-related decrease in DNA methylation was found in the dentate gyrus (DG) and a decrease in the ratio between DNA methylation and hydroxymethylation was found in the DG and cornu ammonis (CA) 3. In the 3xTg-AD mice, an age-related increase in DNA methylation was found in the DG and CA1-2. No significant age-related alterations were found in the APP/PS1dE9 mice and non-human primate model. In the J20 model, hippocampal plaque load showed a significant negative correlation with DNA methylation in the DG, and with the ratio a negative correlation in the DG and CA3. For the APP/PS1dE9 model a negative correlation between the ratio and plaque load was observed in the CA3, as well as a negative correlation between DNA methyltransferase 3A (DNMT3A) levels and plaque load in the DG and CA3. Thus, only the J20 model showed an age-related reduction in global DNA methylation, while DNA hypermethylation was observed in the 3xTg-AD model. Given these differences between animal models, future studies are needed to further elucidate the contribution of different AD-related genetic variation to age-related epigenetic changes.
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Envejecimiento/patología , Enfermedad de Alzheimer/patología , Modelos Animales de Enfermedad , Epigénesis Genética/fisiología , Hipocampo/patología , Envejecimiento/genética , Envejecimiento/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Chlorocebus aethiops , Metilación de ADN/fisiología , ADN Metiltransferasa 3A , Hipocampo/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Especificidad de la EspecieRESUMEN
Passive immunotherapy has emerged as a very promising approach for the treatment of Alzheimer's disease and other neurodegenerative disorders, which are characterized by the misfolding and deposition of amyloid peptides. On the basis of the amyloid hypothesis, the majority of antibodies in clinical development are directed against amyloid ß (Aß), the primary amyloid component in extracellular plaques. This review focuses on the current status of Aß antibodies in clinical development, including their characteristics and challenges that came up in clinical trials with these new biological entities (NBEs). Emphasis is placed on the current view of common side effects observed with passive immunotherapy, so-called amyloid-related imaging abnormalities (ARIAs), and potential ways to overcome this issue. Among these new ideas, a special focus is placed on molecules that are directed against post-translationally modified variants of the Aß peptide, an emerging approach for development of new antibody molecules.
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Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/antagonistas & inhibidores , Anticuerpos Monoclonales/uso terapéutico , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/inmunología , Péptidos beta-Amiloides/metabolismo , Animales , Anticuerpos Monoclonales/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Ensayos Clínicos como Asunto , Citotoxicidad Inmunológica , Diagnóstico por Imagen , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Humanos , Inmunoterapia , Placa Amiloide/tratamiento farmacológico , Placa Amiloide/inmunología , Placa Amiloide/metabolismo , Procesamiento Proteico-PostraduccionalRESUMEN
The complement system is part of the innate immune response responsible for removing pathogens and cellular debris, in addition to helping to refine CNS neuronal connections via microglia-mediated pruning of inappropriate synapses during brain development. However, less is known about the role of complement during normal aging. Here, we studied the role of the central complement component, C3, in synaptic health and aging. We examined behavior as well as electrophysiological, synaptic, and neuronal changes in the brains of C3-deficient male mice (C3 KO) compared with age-, strain-, and gender-matched C57BL/6J (wild-type, WT) control mice at postnatal day 30, 4 months, and 16 months of age. We found the following: (1) region-specific and age-dependent synapse loss in aged WT mice that was not observed in C3 KO mice; (2) age-dependent neuron loss in hippocampal CA3 (but not in CA1) that followed synapse loss in aged WT mice, neither of which were observed in aged C3 KO mice; and (3) significantly enhanced LTP and cognition and less anxiety in aged C3 KO mice compared with aged WT mice. Importantly, CA3 synaptic puncta were similar between WT and C3 KO mice at P30. Together, our results suggest a novel and prominent role for complement protein C3 in mediating aged-related and region-specific changes in synaptic function and plasticity in the aging brain. Significance statement: The complement cascade, part of the innate immune response to remove pathogens, also plays a role in synaptic refinement during brain development by the removal of weak synapses. We investigated whether complement C3, a central component, affects synapse loss during aging. Wild-type (WT) and C3 knock-out (C3 KO) mice were examined at different ages. The mice were similar at 1 month of age. However, with aging, WT mice lost synapses in specific brain regions, especially in hippocampus, an area important for memory, whereas C3 KO mice were protected. Aged C3 KO mice also performed better on learning and memory tests than aged WT mice. Our results suggest that complement C3, or its downstream signaling, is detrimental to synapses during aging.
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Envejecimiento/patología , Complemento C3/deficiencia , Hipocampo/patología , Adaptación Fisiológica/genética , Factores de Edad , Animales , Complemento C3/genética , Condicionamiento Psicológico/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Conducta Exploratoria/fisiología , Miedo , Hipocampo/metabolismo , Hipocampo/ultraestructura , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Plasticidad Neuronal/genética , Plasticidad Neuronal/fisiología , Fosfopiruvato Hidratasa/metabolismo , Sinapsis/patología , Sinapsis/ultraestructura , Sinapsinas/metabolismo , Sinaptofisina/metabolismo , Sinaptosomas/metabolismoRESUMEN
Alzheimer's disease (AD) is the most common cause of dementia. Neuroinflammation appears to play an important role in AD pathogenesis. Ligands of the 18 kDa translocator protein (TSPO), a marker for activated microglia, have been used as positron emission tomography (PET) tracers to reflect neuroinflammation in humans and mouse models. Here, we used the novel TSPO-targeted PET tracer (18)F-GE180 (flutriciclamide) to investigate differences in neuroinflammation between young and old WT and APP/PS1dE9 transgenic (Tg) mice. In vivo PET scans revealed an overt age-dependent elevation in whole-brain uptake of (18)F-GE180 in both WT and Tg mice, and a significant increase in whole-brain uptake of (18)F-GE180 (peak-uptake and retention) in old Tg mice compared with young Tg mice and all WT mice. Similarly, the (18)F-GE180 binding potential in hippocampus was highest to lowest in old Tg > old WT > young Tg > young WT mice using MRI coregistration. Ex vivo PET and autoradiography analysis further confirmed our in vivo PET results: enhanced uptake and specific binding (SUV75%) of (18)F-GE180 in hippocampus and cortex was highest in old Tg mice followed by old WT, young Tg, and finally young WT mice. (18)F-GE180 specificity was confirmed by an in vivo cold tracer competition study. We also examined (18)F-GE180 metabolites in 4-month-old WT mice and found that, although total radioactivity declined over 2 h, of the remaining radioactivity, â¼90% was due to parent (18)F-GE180. In conclusion, (18)F-GE180 PET scans may be useful for longitudinal monitoring of neuroinflammation during AD progression and treatment. SIGNIFICANCE STATEMENT: Microglial activation, a player in Alzheimer's disease (AD) pathogenesis, is thought to reflect neuroinflammation. Using in vivo microPET imaging with a novel TSPO radioligand, (18)F-GE180, we detected significantly enhanced neuroinflammation during normal aging in WT mice and in response to AD-associated pathology in APP/PS1dE9 Tg mice, an AD mouse model. Increased uptake and specific binding of (18)F-GE180 in whole brain and hippocampus were confirmed by ex vivo PET and autoradiography. The binding specificity and stability of (18)F-GE180 was further confirmed by a cold tracer competition study and a metabolite study, respectively. Therefore, (18)F-GE180 PET imaging may be useful for longitudinal monitoring of neuroinflammation during AD progression and treatment and may also be useful for other neurodegenerative diseases.
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Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Carbazoles/metabolismo , Radioisótopos de Flúor/metabolismo , Tomografía de Emisión de Positrones/métodos , Receptores de GABA/metabolismo , Envejecimiento/patología , Enfermedad de Alzheimer/diagnóstico por imagen , Animales , Progresión de la Enfermedad , Humanos , Inflamación/diagnóstico , Inflamación/diagnóstico por imagen , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Compelling genetic evidence links the amyloid precursor protein (APP) to Alzheimer's disease (AD). A leading hypothesis proposes that a small amphipathic fragment of APP, the amyloid ß-protein (Aß), self-associates to form soluble assemblies loosely referred to as "oligomers" and that these are primary mediators of synaptic dysfunction. As such, Aß, and specifically Aß oligomers, are targets for disease modifying therapies. Currently, the most advanced experimental treatment for AD relies on the use of anti-Aß antibodies. In this study, we tested the ability of the monomer-preferring antibody, m266 and a novel aggregate-preferring antibody, 1C22, to attenuate spatial reference memory impairments in J20 mice. Chronic treatment with m266 resulted in a ~70-fold increase in Aß detected in the bloodstream, and a ~50% increase in water-soluble brain Aß--and in both cases Aß was bound to m266. In contrast, 1C22 increased the levels of free Aß in the bloodstream, and bound to amyloid deposits in J20 brain. However, neither 1C22 nor m266 attenuated the cognitive deficits evident in 12month old J20 mice. Moreover, both antibodies failed to alter the levels of soluble Aß oligomers in J20 brain. These results suggest that Aß oligomers may mediate the behavioral deficits seen in J20 mice and highlight the need for the development of aggregate-preferring antibodies that can reach the brain in sufficient levels to neutralize bioactive Aß oligomers. Aside from the lack of positive effect of m266 and 1C22 on cognition, a substantial number of deaths occurred in m266- and 1C22-immunized J20 mice. These fatalities were specific to anti-Aß antibodies and to the J20 mouse line since treatment of wild type or PDAPP mice with these antibodies did not cause any deaths. These and other recent results indicate that J20 mice are particularly susceptible to targeting of the APP/Aß/tau axis. Notwithstanding the specificity of fatalities for J20 mice, it is worrying that the murine precursor (m266) of a lead experimental therapeutic, Solanezumab, did not engage with putatively pathogenic Aß oligomers.
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Péptidos beta-Amiloides/inmunología , Anticuerpos/administración & dosificación , Encéfalo/metabolismo , Inmunización Pasiva , Trastornos de la Memoria/inmunología , Trastornos de la Memoria/terapia , Nootrópicos/administración & dosificación , Péptidos beta-Amiloides/sangre , Animales , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunohistoquímica , Infusiones Parenterales , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Transgénicos , Memoria Espacial/efectos de los fármacos , Memoria Espacial/fisiologíaRESUMEN
Alzheimer's disease (AD) is a multifactorial and fatal neurodegenerative disorder for which the mechanisms leading to profound neuronal loss are incompletely recognized. MicroRNAs (miRNAs) are recently discovered small regulatory RNA molecules that repress gene expression and are increasingly acknowledged as prime regulators involved in human brain pathologies. Here we identified two homologous miRNAs, miR-132 and miR-212, downregulated in temporal cortical areas and CA1 hippocampal neurons of human AD brains. Sequence-specific inhibition of miR-132 and miR-212 induces apoptosis in cultured primary neurons, whereas their overexpression is neuroprotective against oxidative stress. Using primary neurons and PC12 cells, we demonstrate that miR-132/212 controls cell survival by direct regulation of PTEN, FOXO3a and P300, which are all key elements of AKT signaling pathway. Silencing of these three target genes by RNAi abrogates apoptosis caused by the miR-132/212 inhibition. We further demonstrate that mRNA and protein levels of PTEN, FOXO3a, P300 and most of the direct pro-apoptotic transcriptional targets of FOXO3a are significantly elevated in human AD brains. These results indicate that the miR-132/miR-212/PTEN/FOXO3a signaling pathway contributes to AD neurodegeneration.
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Enfermedad de Alzheimer/genética , Apoptosis/genética , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica , MicroARNs/genética , Neuronas/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Apoptosis/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Regulación hacia Abajo , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/metabolismo , Humanos , Peróxido de Hidrógeno/farmacología , Ratones , MicroARNs/metabolismo , Modelos Biológicos , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Interferencia de ARN , Ratas , Transducción de Señal , Factores de Transcripción p300-CBP/metabolismoRESUMEN
Active amyloid-ß (Aß) immunotherapy is under investigation to prevent or treat early Alzheimer's disease (AD). In 2002, a Phase II clinical trial (AN1792) was halted due to meningoencephalitis in â¼6% of the AD patients, possibly caused by a T-cell-mediated immunological response. Thus, generating a vaccine that safely generates high anti-Aß antibody levels in the elderly is required. In this study, MER5101, a novel conjugate of Aß1-15 peptide (a B-cell epitope fragment) conjugated to an immunogenic carrier protein, diphtheria toxoid (DT), and formulated in a nanoparticular emulsion-based adjuvant, was administered to 10-month-old APPswe/PS1ΔE9 transgenic (Tg) and wild-type (Wt) mice. High anti-Aß antibody levels were observed in both vaccinated APPswe/PS1ΔE9 Tg and Wt mice. Antibody isotypes were mainly IgG1 and IgG2b, suggesting a Th2-biased response. Restimulation of splenocytes with the Aß1-15:DT conjugate resulted in a strong proliferative response, whereas proliferation was absent after restimulation with Aß1-15 or Aß1-40/42 peptides, indicating a cellular immune response against DT while avoiding an Aß-specific T-cell response. Moreover, significant reductions in cerebral Aß plaque burden, accompanied by attenuated microglial activation and increased synaptic density, were observed in MER5101-vaccinated APPswe/PS1ΔE9 Tg mice compared with Tg adjuvant controls. Last, MER5101-immunized APPswe/PS1ΔE9 Tg mice showed improvement of cognitive deficits in both contextual fear conditioning and the Morris water maze. Our novel, highly immunogenic Aß conjugate vaccine, MER5101, shows promise for improving Aß vaccine safety and efficacy and therefore, may be useful for preventing and/or treating early AD.
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Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/inmunología , Trastornos del Conocimiento/patología , Trastornos del Conocimiento/terapia , Toxoide Diftérico/inmunología , Inmunización/métodos , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animales , Formación de Anticuerpos/inmunología , Células CHO/química , Proliferación Celular/efectos de los fármacos , Corteza Cerebral/inmunología , Corteza Cerebral/metabolismo , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/inmunología , Condicionamiento Clásico/fisiología , Cricetinae , Medios de Cultivo Condicionados/farmacología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta Inmunológica , Ensayo de Inmunoadsorción Enzimática , Mapeo Epitopo , Miedo , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/inmunología , Gliosis/terapia , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoprecipitación , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Transgénicos , Mutación/genética , Fragmentos de Péptidos/inmunología , Presenilina-1/genética , Bazo/citología , Estadísticas no Paramétricas , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , TransfecciónRESUMEN
Complement receptor 1 (CR1) is an Alzheimer's disease (AD) susceptibility locus that also influences AD-related traits such as episodic memory decline and neuritic amyloid plaque deposition. We implemented a functional fine-mapping approach, leveraging intermediate phenotypes to identify functional variant(s) within the CR1 locus. Using 1709 subjects (697 deceased) from the Religious Orders Study and the Rush Memory and Aging Project, we tested 41 single-nucleotide polymorphisms (SNPs) within the linkage disequilibrium block containing the published CR1 AD SNP (rs6656401) for associations with episodic memory decline, and then examined the functional consequences of the top result. We report that a coding variant in the LHR-D (long homologous repeat D) region of the CR1 gene, rs4844609 (Ser1610Thr, minor allele frequency = 0.02), is associated with episodic memory decline and accounts for the known effect of the index SNP rs6656401 (D' = 1, r(2)= 0.084) on this trait. Further, we demonstrate that the coding variant's effect is largely dependent on an interaction with APOE-ε4 and mediated by an increased burden of AD-related neuropathology. Finally, in our data, this coding variant is also associated with AD susceptibility (joint odds ratio = 1.4). Taken together, our analyses identify a CR1 coding variant that influences episodic memory decline; it is a variant known to alter the conformation of CR1 and points to LHR-D as the functional domain within the CR1 protein that mediates the effect on memory decline. We thus implicate C1q and MBL, which bind to LHR-D, as likely targets of the variant's effect and suggest that CR1 may be an important intermediate in the clearance of Aß42 particles by C1q.
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Apolipoproteína E4/metabolismo , Trastornos del Conocimiento/genética , Receptores de Complemento/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Apolipoproteína E4/genética , Trastornos del Conocimiento/metabolismo , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Genotipo , Haplotipos , Humanos , Memoria Episódica , Persona de Mediana Edad , Oportunidad Relativa , Fenotipo , Placa Amiloide/metabolismo , Polimorfismo de Nucleótido Simple , Receptores de Complemento/metabolismoRESUMEN
Amyloid-ß (Aß) peptides, starting with pyroglutamate at the third residue (pyroGlu-3 Aß), are a major species deposited in the brain of Alzheimer disease (AD) patients. Recent studies suggest that this isoform shows higher toxicity and amyloidogenecity when compared to full-length Aß peptides. Here, we report the first comprehensive and comparative IHC evaluation of pyroGlu-3 Aß deposition in humans and animal models. PyroGlu-3 Aß immunoreactivity (IR) is abundant in plaques and cerebral amyloid angiopathy of AD and Down syndrome patients, colocalizing with general Aß IR. PyroGlu-3 Aß is further present in two nontransgenic mammalian models of cerebral amyloidosis, Caribbean vervets, and beagle canines. In addition, pyroGlu-3 Aß deposition was analyzed in 12 different AD-like transgenic mouse models. In contrast to humans, all transgenic models showed general Aß deposition preceding pyroGlu-3 Aß deposition. The findings varied greatly among the mouse models concerning age of onset and cortical brain region. In summary, pyroGlu-3 Aß is a major species of ß-amyloid deposited early in diffuse and focal plaques and cerebral amyloid angiopathy in humans and nonhuman primates, whereas it is deposited later in a subset of focal and vascular amyloid in AD-like transgenic mouse models. Given the proposed decisive role of pyroGlu-3 Aß peptides for the development of human AD pathology, this study provides insights into the usage of animal models in AD studies.
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Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Ácido Pirrolidona Carboxílico/metabolismo , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide , Animales , Encéfalo/patología , Angiopatía Amiloide Cerebral/metabolismo , Chlorocebus aethiops , Modelos Animales de Enfermedad , Perros , Síndrome de Down/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Placa Amiloide/metabolismoRESUMEN
Complement components and their receptors are found within and around amyloid ß (Aß) cerebral plaques in Alzheimer's disease (AD). Microglia defend against pathogens through phagocytosis via complement component C3 and/or engagement of C3 cleavage product iC3b with complement receptor type 3 (CR3, Mac-1). Here, we provide direct evidence that C3 and Mac-1 mediate, in part, phagocytosis and clearance of fibrillar amyloid-ß (fAß) by murine microglia in vitro and in vivo. Microglia took up not only synthetic fAß(42) but also amyloid cores from patients with AD, transporting them to lysosomes in vitro. Fibrillar Aß(42) uptake was significantly attenuated by the deficiency or knockdown of C3 or Mac-1 and scavenger receptor class A ligands. In addition, C3 or Mac-1 knockdown combined with a scavenger receptor ligand, fucoidan, further attenuated fibrillar Aß(42) uptake by N9 microglia. Fluorescent fibrillar Aß(42) microinjected cortically was significantly higher in C3 and Mac-1 knockout mice compared with wild-type mice 5 days after surgery, indicating reduced clearance in vivo. Together, these results demonstrate that C3 and Mac-1 are involved in phagocytosis and clearance of fAß by microglia, providing support for a potential beneficial role for microglia and the complement system in AD pathogenesis. © 2012 Wiley Periodicals, Inc.
Asunto(s)
Amiloide/metabolismo , Encéfalo/citología , Complemento C3c/metabolismo , Antígeno de Macrófago-1/metabolismo , Microglía/fisiología , Fagocitosis/fisiología , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/farmacología , Análisis de Varianza , Animales , Encéfalo/efectos de los fármacos , Línea Celular Transformada , Complemento C3c/deficiencia , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Ligandos , Proteínas de Membrana de los Lisosomas/metabolismo , Lisosomas/metabolismo , Antígeno de Macrófago-1/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/efectos de los fármacos , Microinyecciones , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/farmacología , Fagocitosis/efectos de los fármacos , Fagocitosis/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptores Depuradores de Clase A/metabolismo , Factores de Tiempo , Transfección/métodosRESUMEN
One of the most clinically advanced forms of experimental disease-modifying treatment for Alzheimer disease is immunization against the amyloid beta protein (Abeta), but how this may prevent cognitive impairment is unclear. We hypothesized that antibodies to Abeta could exert a beneficial action by directly neutralizing potentially synaptotoxic soluble Abeta species in the brain. Intracerebroventricular injection of naturally secreted human Abeta inhibited long-term potentiation (LTP), a correlate of learning and memory, in rat hippocampus in vivo but a monoclonal antibody to Abeta completely prevented the inhibition of LTP when injected after Abeta. Size fractionation showed that Abeta oligomers, not monomers or fibrils, were responsible for inhibiting LTP, and an Abeta antibody again prevented such inhibition. Active immunization against Abeta was partially effective, and the effects correlated positively with levels of antibodies to Abeta oligomers. The ability of exogenous and endogenous antibodies to rapidly neutralize soluble Abeta oligomers that disrupt synaptic plasticity in vivo suggests that treatment with such antibodies might show reversible cognitive deficits in early Alzheimer disease.