RESUMEN
The amyloid-ß protein (Aß) protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). It is believed that Aß deposited in the brain originates from the brain tissue itself. However, Aß is generated in both brain and peripheral tissues. Whether circulating Aß contributes to brain AD-type pathologies remains largely unknown. In this study, using a model of parabiosis between APPswe/PS1dE9 transgenic AD mice and their wild-type littermates, we observed that the human Aß originated from transgenic AD model mice entered the circulation and accumulated in the brains of wild-type mice, and formed cerebral amyloid angiopathy and Aß plaques after a 12-month period of parabiosis. AD-type pathologies related to the Aß accumulation including tau hyperphosphorylation, neurodegeneration, neuroinflammation and microhemorrhage were found in the brains of the parabiotic wild-type mice. More importantly, hippocampal CA1 long-term potentiation was markedly impaired in parabiotic wild-type mice. To the best of our knowledge, our study is the first to reveal that blood-derived Aß can enter the brain, form the Aß-related pathologies and induce functional deficits of neurons. Our study provides novel insight into AD pathogenesis and provides evidence that supports the development of therapies for AD by targeting Aß metabolism in both the brain and the periphery.
Asunto(s)
Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/fisiología , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Angiopatía Amiloide Cerebral/metabolismo , Modelos Animales de Enfermedad , Femenino , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/metabolismo , Parabiosis/métodos , Placa Amiloide/etiología , Placa Amiloide/metabolismo , Presenilina-1/metabolismoRESUMEN
In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Aß) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aß and mediates Aß-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aß. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aß deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aß deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing ß-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aß toxicity and would be a novel therapeutic target and biomarker for AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Encéfalo/patología , Proteínas del Tejido Nervioso/química , Estructura Terciaria de Proteína/fisiología , Receptores de Factor de Crecimiento Nervioso/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Factores de Edad , Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/toxicidad , Precursor de Proteína beta-Amiloide/genética , Animales , Apoptosis/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Estudios de Casos y Controles , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/terapia , Modelos Animales de Enfermedad , Regulación hacia Abajo/genética , Humanos , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Transgénicos , Mutación/genética , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Presenilina-1/genética , Receptores de Factor de Crecimiento Nervioso/deficiencia , Receptores de Factor de Crecimiento Nervioso/genética , Proteínas Recombinantes/uso terapéutico , Transducción GenéticaRESUMEN
Alzheimer's disease (AD), a progressive neurodegenerative disorder that is the most common cause of dementia in the elderly, is characterized by the accumulation of amyloid-ß (Aß) plaques and neurofibrillary tangles, as well as a progressive loss of synapses and neurons in the brain. The major pertinacious component of amyloid plaques is Aß, a variably sized peptide derived from the integral membrane protein amyloid precursor protein (APP). The Aß region of APP locates partly within its ecto- and trans-membrane domains. APP is cleaved by three proteases, designated as α-, ß-, and γ-secretases. Processing by ß- and γ-secretase cleaves the N- and C-terminal ends of the Aß region, respectively, releasing Aß, whereas α-secretase cleaves within the Aß sequence, releasing soluble APPα (sAPPα). The γ-secretase cleaves at several adjacent sites to yield Aß species containing 39-43 amino acid residues. Both α- and ß-cleavage sites of human wild-type APP are located in APP672-699 region (ectodomain of ß-C-terminal fragment, ED-ß-CTF or ED-C99). Therefore, the amino acid residues within or near this region are definitely pivotal for human wild-type APP function and processing. Here, we report that one ED-C99-specific monoclonal antibody (mAbED-C99) blocks human wild-type APP endocytosis and shifts its processing from α- to ß-cleavage, as evidenced by elevated accumulation of cell surface full-length APP and ß-CTF together with reduced sAPPα and α-CTF levels. Moreover, mAbED-C99 enhances the interactions of APP with cholesterol. Consistently, intracerebroventricular injection of mAbED-C99 to human wild-type APP transgenic mice markedly increases membrane-associated ß-CTF. All these findings suggest that APP672-699 region is critical for human wild-type APP processing and may provide new clues for the pathogenesis of sporadic AD.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Anticuerpos Monoclonales/inmunología , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/inmunología , Animales , Sitios de Unión de Anticuerpos , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Endocitosis , Femenino , Humanos , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Ratones , Ratones Transgénicos , Neuronas/citología , Neuronas/metabolismo , Estructura Terciaria de ProteínaRESUMEN
Some 15-20% of the population over the age of 65 years suffer from dementia, currently one of the leading causes of death behind cardiovascular diseases, cancer and cerebrovascular diseases. The major forms of dementia share in common overactivation of the CD40-CD40-L complex, leading to high levels of proinflammatory cytokine production by immune cells of the central nervous system (CNS), including microglia and astrocytes. Consequently, both neuronal survival and signaling are negatively affected, leading to the characteristic progressive loss of higher cortical functions. We have reviewed the literature concerning the involvement of this complex in the pathology of three major forms of dementia: Alzheimer's-type, HIV-associated and vascular dementia. This is followed by a discussion of current preclinical and clinical therapies that may influence this interaction, and thus point the way toward a future neuroimmunological approach to inhibiting the effects of CD40-CD40-L in neuropsychiatric disease.
RESUMEN
Amyloid-beta (Abeta) immunization efficiently reduces amyloid plaque load and memory impairment in transgenic mouse models of Alzheimer's disease (AD). Active Abeta immunization has also yielded favorable results in a subset of AD patients. However, a small percentage of patients developed severe aseptic meningoencephalitis associated with brain inflammation and infiltration of T-cells. We have shown that blocking the CD40-CD40 ligand (L) interaction mitigates Abeta-induced inflammatory responses and enhances Abeta clearance. Here, we utilized genetic and pharmacologic approaches to test whether CD40-CD40L blockade could enhance the efficacy of Abeta(1-42) immunization, while limiting potentially damaging inflammatory responses. We show that genetic or pharmacologic interruption of the CD40-CD40L interaction enhanced Abeta(1-42) immunization efficacy to reduce cerebral amyloidosis in the PSAPP and Tg2576 mouse models of AD. Potentially deleterious pro-inflammatory immune responses, cerebral amyloid angiopathy (CAA) and cerebral microhemorrhage were reduced or absent in these combined approaches. Pharmacologic blockade of CD40L decreased T-cell neurotoxicity to Abeta-producing neurons. Further reduction of cerebral amyloidosis in Abeta-immunized PSAPP mice completely deficient for CD40 occurred in the absence of Abeta immunoglobulin G (IgG) antibodies or efflux of Abeta from brain to blood, but was rather correlated with anti-inflammatory cytokine profiles and reduced plasma soluble CD40L. These results suggest CD40-CD40L blockade promotes anti-inflammatory cellular immune responses, likely resulting in promotion of microglial phagocytic activity and Abeta clearance without generation of neurotoxic Abeta-reactive T-cells. Thus, combined approaches of Abeta immunotherapy and CD40-CD40L blockade may provide for a safer and more effective Abeta vaccine.
Asunto(s)
Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides/inmunología , Ligando de CD40/metabolismo , Angiopatía Amiloide Cerebral/terapia , Inmunoterapia Activa/métodos , Inflamación/terapia , Fragmentos de Péptidos/inmunología , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/sangre , Precursor de Proteína beta-Amiloide/genética , Análisis de Varianza , Animales , Anticuerpos/sangre , Antígenos CD40/deficiencia , Citocinas/metabolismo , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fragmentos de Péptidos/sangre , Presenilina-1/genética , Factores de TiempoRESUMEN
Chronic brain inflammation is the common final pathway in the majority of neurodegenerative diseases and central to this phenomenon is the immunological activation of brain mononuclear phagocyte cells, called microglia. This inflammatory mechanism is a central component of HIV-associated dementia (HAD). In the healthy state, there are endogenous signals from neurons and astrocytes, which limit excessive central nervous system (CNS) inflammation. However, the signals controlling this process have not been fully elucidated. Studies on the peripheral nervous system suggest that a cholinergic anti-inflammatory pathway regulates systemic inflammatory response by way of acetylcholine acting at the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) found on blood-borne macrophages. Recent data from our laboratory indicates that cultured microglial cells also express this same receptor and that microglial anti-inflammatory properties are mediated through it and the p44/42 mitogen-activated protein kinase (MAPK) system. Here we report for the first time the creation of an in vitro model of HAD composed of cultured microglial cells synergistically activated by the addition of IFN-gamma and the HIV-1 coat glycoprotein, gp120. Furthermore, this activation, as measured by TNF-alpha and nitric oxide (NO) release, is synergistically attenuated through the alpha7 nAChR and p44/42 MAPK system by pretreatment with nicotine, and the cholinesterase inhibitor, galantamine. Our findings suggest a novel therapeutic combination to treat or prevent the onset of HAD through this modulation of the microglia inflammatory mechanism.
Asunto(s)
Galantamina/farmacología , Proteína gp120 de Envoltorio del VIH/farmacología , Microglía/efectos de los fármacos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Análisis de Varianza , Animales , Animales Recién Nacidos , Western Blotting/métodos , Células Cultivadas , Corteza Cerebral/citología , Inhibidores de la Colinesterasa/farmacología , Sinergismo Farmacológico , Ensayo de Inmunoadsorción Enzimática/métodos , Interferón gamma/metabolismo , Ratones , Microglía/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Óxido Nítrico/metabolismo , Factores de Tiempo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The authors describe a case of choroideremia. Discussion is upon clinical and evolutive data, others diagnosis, pigmentary retinopathy or rubeolic retinopathy at the beginning of the disease, diffuse chorio capillary atrophy, gyrate atrophy of the choroid and retina. Biomicroscopic finding of heterozygous females (the mother and his sister) are described. Genetic council is those of recessive X linked hereditary with the possibility of prenatal diagnosis using genic marker.