RESUMEN
AIMS: The deposition of amyloid-ß (Aß) peptides in the form of extracellular plaques in the brain represents one of the classical hallmarks of Alzheimer's disease (AD). In addition to 'full-length' Aß starting with aspartic acid (Asp-1), considerable amounts of various shorter, N-terminally truncated Aß peptides have been identified by mass spectrometry in autopsy samples from individuals with AD. METHODS: Selectivity of several antibodies detecting full-length, total or N-terminally truncated Aß species has been characterized with capillary isoelectric focusing assays using a set of synthetic Aß peptides comprising different N-termini. We further assessed the N-terminal heterogeneity of extracellular and vascular Aß peptide deposits in the human brain by performing immunohistochemical analyses using sporadic AD cases with antibodies targeting different N-terminal residues, including the biosimilar antibodies Bapineuzumab and Crenezumab. RESULTS: While antibodies selectively recognizing Aß1-x showed a much weaker staining of extracellular plaques and tended to accentuate cerebrovascular amyloid deposits, antibodies detecting Aß starting with phenylalanine at position 4 of the Aß sequence showed abundant amyloid plaque immunoreactivity in the brain parenchyma. The biosimilar antibody Bapineuzumab recognized Aß starting at Asp-1 and demonstrated abundant immunoreactivity in AD brains. DISCUSSION: In contrast to other studied Aß1-x -specific antibodies, Bapineuzumab displayed stronger immunoreactivity on fixed tissue samples than with sodium dodecyl sulfate-denatured samples on Western blots. This suggests conformational preferences of this antibody. The diverse composition of plaques and vascular deposits stresses the importance of understanding the roles of various Aß variants during disease development and progression in order to generate appropriate target-developed therapies.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Anticuerpos Monoclonales Humanizados/farmacología , Encéfalo/metabolismo , Placa Amiloide/metabolismo , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Fragmentos de Péptidos/metabolismoRESUMEN
The evidence for a protective role of physical activity on the risk and progression of Alzheimer's disease (AD) has been growing in the last years. Here we studied the influence of a prolonged physical and cognitive stimulation on neurodegeneration, with special emphasis on hippocampal neuron loss and associated behavioral impairment in the Tg4-42 mouse model of AD. Tg4-42 mice overexpress Aß4-42 without any mutations, and develop an age-dependent hippocampal neuron loss associated with a severe memory decline. We demonstrate that long-term voluntary exercise diminishes CA1 neuron loss and completely rescues spatial memory deficits in different experimental settings. This was accompanied by changes in the gene expression profile of Tg4-42 mice. Deep sequencing analysis revealed an upregulation of chaperones involved in endoplasmatic reticulum protein processing, which might be intimately linked to the beneficial effects seen upon long-term exercise. We believe that we provide evidence for the first time that enhanced physical activity counteracts neuron loss and behavioral deficits in a transgenic AD mouse model. The present findings underscore the relevance of increased physical activity as a potential strategy in the prevention of dementia.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Hipocampo/fisiopatología , Trastornos de la Memoria/complicaciones , Enfermedades Neurodegenerativas/complicaciones , Condicionamiento Físico Animal , Enfermedad de Alzheimer/fisiopatología , Animales , Modelos Animales de Enfermedad , Trastornos de la Memoria/fisiopatología , Ratones , Ratones Transgénicos , Enfermedades Neurodegenerativas/fisiopatología , Neuronas/fisiología , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
AIMS: Currently available animal models incompletely capture the complex pathophysiology of Alzheimer's disease (AD), typically involving ß-amyloidosis, neurofibrillary tangle formation and loss of basal forebrain cholinergic projection neurones (CPN). While age-dependent ß-amyloidosis and tau hyperphosphorylation are mimicked in triple-transgenic mice (3xTg), experimental induction of CPN loss in these mice is still lacking. Here, we introduce a more-complex animal model of AD by inducing cellular loss of CPN in an already existing transgenic background aiming to elucidate subsequent changes of hippocampal ß-amyloid (Aß) and tau pathology. METHODS: Twelve-month-old 3xTg mice intracerebroventricularly received the rabbit-anti-low affinity neurotrophin receptor p75-saporin, an immunotoxin specifically targeting forebrain CPN. After histochemical verification of immunolesion in immersion-fixed forebrains, markers of Aß and tau metabolism were analysed using quantitative Western blot analyses of hippocampi from these mice. In parallel, these markers and glial activation were investigated by multiple immunofluorescence labelling of perfusion-fixed hippocampi and confocal laser-scanning microscopy. RESULTS: Four months after immunolesion, the selective lesion of CPN was verified by disappearance of choline acetyltransferase and p75 immunolabelling. Biochemical analysis of hippocampi from immunolesioned mice revealed enhanced levels of Aß, amyloid precursor protein (APP) and its fragment C99. Furthermore, immunolesion-induced increase in levels of phospho-tau and tau with AD-like conformation were seen in 16-month-old mice. Immunofluorescence staining confirmed an age-dependent occurrence of hippocampal Aß-deposits and phospho-tau, and demonstrated drastic gliosis around Aß-plaques after immunolesion. CONCLUSION: Overall, this extended model promises further insights into the complexity of AD and contributes to novel treatment strategies also targeting the cholinergic system.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Amiloidosis , Neuronas Colinérgicas/patología , Hipocampo/metabolismo , Proteínas tau/metabolismo , Animales , Modelos Animales de Enfermedad , Gliosis , Hipocampo/patología , Inmunotoxinas/toxicidad , Ratones , Ratones Transgénicos , Fosforilación , Proteínas Inactivadoras de Ribosomas Tipo 1/toxicidad , SaporinasRESUMEN
The currently approved but only mildly efficient drugs against Alzheimer's disease treat merely the symptoms. Genetic, neuropathological, and biochemical data support the importance of the amyloid hypothesis of Alzheimer's disease, at the moment the most influential hypothesis. Many treatment strategies have been performed based on this hypothesis and were markedly successful in preclinical animal models. Unfortunately the treatment is still unsuccessful in humans. This could be due to the animal models showing marginal behavioural deficits but no Alzheimer-like nerve cell loss, although they all developed a more or less pronounced plaque load. Today we know however that Alzheimer plaques are not mainly responsible for the cell loss. Therefore novel animal models have been developed that show age-dependent axonal degeneration, massive neuronal loss, and robust behavioural deficits. Successful treatment of an animal model with such robust deficits would be very likely better suited to transferral into the clinic. The final validation or disproof of individual Alzheimer hypotheses and their resulting treatment strategies can however be obtained only after clinical proof.
Asunto(s)
Enfermedad de Alzheimer/patología , Modelos Animales de Enfermedad , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/terapia , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Apoptosis/genética , Encéfalo/patología , Análisis Mutacional de ADN , Humanos , Ratones , Ratones Transgénicos , Neuronas/patología , Nootrópicos/uso terapéutico , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Placa Amiloide/genética , Placa Amiloide/patología , Degeneración Retrógrada/genéticaRESUMEN
In this commentary, we accent the accumulating evidence for motor impairment as a common feature of early Alzheimer's disease (AD) pathology. In addition, we summarize the state of knowledge on this phenotype in experimental mouse models, expressing AD-associated genes like tau or amyloid precursor protein.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Modelos Animales de Enfermedad , Ratones , Trastornos del Movimiento/etiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Axones/patología , Humanos , Ratones Transgénicos , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
Accumulating evidence points to an important role of intraneuronal Abeta as a trigger of the pathological cascade of events leading to neurodegeneration and eventually to Alzheimer's disease (AD) with its typical clinical symptoms, like memory impairment and change in personality. As a new concept, intraneuronal accumulation of Abeta instead of extracellular Abeta deposition has been introduced to be the disease-triggering event in AD. The present review compiles current knowledge on the amyloid precursor protein (APP)/PS1KI mouse model with early and massive intraneuronal Abeta42 accumulation: (1) The APP/PS1KI mouse model exhibits early robust brain and spinal cord axonal degeneration and hippocampal CA1 neuron loss. (2) At the same time-point, a dramatic, age-dependent reduced ability to perform working memory and motor tasks is observed. (3) The APP/PS1KI mice are smaller and show development of a thoracolumbar kyphosis, together with an incremental loss of body weight. (4) Onset of the observed behavioral alterations correlates well with robust axonal degeneration in brain and spinal cord and with abundant hippocampal CA1 neuron loss.
Asunto(s)
Precursor de Proteína beta-Amiloide/metabolismo , Axones , Enfermedades del Sistema Nervioso Central/etiología , Modelos Animales de Enfermedad , Trastornos de la Memoria/etiología , Ratones , Neuronas/metabolismo , Presenilina-1/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Ratones Transgénicos , Presenilina-1/genéticaRESUMEN
Epidemiological studies have reported a higher prevalence and incidence of Alzheimer's disease (AD) in women. The biochemical basis for this gender-disparate susceptibility is unknown. A gender effect on AD-typical plaque pathology has been shown in APP transgenic mouse models of AD. Female mice elicit higher plaque load than male mice. In an effort to analyze gender-dependent APP processing during postnatal development, we examined APP transgenic mice at time points prior to plaque deposition. At 14 weeks of age there was a significant elevation of C99 and Abeta in female mice compared to males. Furthermore we observed a slight decrease of BACE-activity in male mice as well as higher cerebral manganese levels in females. Although the decline in estrogen levels due to menopause in female patients is still discussed to be a risk factor for AD our results implicates that additional factors like modified BACE-activity or metal levels may contribute to the higher prevalence and incidence of AD in females.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Caracteres Sexuales , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Estrógenos/metabolismo , Femenino , Masculino , Manganeso/metabolismo , Ratones , Ratones Transgénicos , Placa Amiloide/genética , Placa Amiloide/metabolismo , Regulación hacia Arriba/fisiologíaRESUMEN
Recent evidence indicates that both intraneuronal Abeta and Cu are involved in the pathological processes in Alzheimer's disease (AD). This perspective shows a possible interrelation of these factors. AbetaPP, the precursor of Abeta which represents the main constituent of amyloid plaques, is involved in Cu homeostasis in mammals. In vitro observations and in vivo data obtained from AbetaPP mouse models provide strong evidence that AbetaPP and the resulting Abeta overproduction facilitate intracellular Cu to leave the cell. An increased Cu efflux seems to lead to Cu deficiency and, subsequently, reduced SOD-1 activity. The Cu-dependent SOD-1 activity is the main enzyme involved in detoxifying free radicals. Several reports have shown that oxidative stress is an invariable age-dependent feature in the brain of AD patients. Increased oxidative stress leads to an increase in intraneuronal Abeta accumulation, which has been shown to be the main trigger for neuronal loss in transgenic mouse models. Thus, we conclude that bioavailability of Cu is a crucial point for the pathogenesis of AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Cobre/metabolismo , Estrés Oxidativo/fisiología , Enfermedades por Prión/metabolismo , Animales , Cobre/deficiencia , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , Neuronas/metabolismo , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1RESUMEN
Traumatic Brain Injury is the leading cause of death and disability among young individuals in our society. Moreover, according to some epidemiological studies, head trauma is one of the most potent environmental risk factors for subsequent development of Alzheimer's disease. Interestingly, pathological features that are present also in Alzheimer's disease (in particular deposition of beta-amyloid protein) were observed in traumatised brains already a few hours after the initial insult. The primary objective of this review is to present methodology and results of numerous recent human and animal studies dealing with this issue. Special emphasis was placed on head trauma experiments in transgenic mouse models of Alzheimer's disease. We further evaluate the connection between traumatic brain insults and subsequent development of dementia and try to differentiate between primary and secondary pathological mechanisms.
Asunto(s)
Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/metabolismo , Lesiones Encefálicas/complicaciones , Encéfalo/metabolismo , Predisposición Genética a la Enfermedad/genética , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/inmunología , Animales , Encéfalo/patología , Encéfalo/fisiopatología , Lesiones Encefálicas/fisiopatología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Ratones , Ratones Transgénicos , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologíaRESUMEN
There is circumstantial evidence that the reelin signaling pathway may contribute to neurodegeneration in the adult brain and could be linked to Alzheimer's disease (AD). In the present immunohistochemical report we studied the reelin expression profile in double-transgenic mice that express both human mutant beta-amyloid precursor protein (APP) and human mutant presenilin-1. We were able to demonstrate that reelin immunostaining was found together with human APP in the neuritic component of many AD-typical plaques in both hippocampus and neocortex. This observation gives the first evidence for the association of reelin with amyloid deposits.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Moléculas de Adhesión Celular Neuronal/metabolismo , Corteza Cerebral/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Hipocampo/metabolismo , Proteínas de la Membrana/metabolismo , Placa Amiloide/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Animales , Moléculas de Adhesión Celular Neuronal/genética , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Proteínas de la Matriz Extracelular/genética , Femenino , Hipocampo/patología , Hipocampo/fisiopatología , Inmunohistoquímica , Interneuronas/metabolismo , Interneuronas/patología , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteínas del Tejido Nervioso , Placa Amiloide/genética , Placa Amiloide/patología , Presenilina-1 , Células Piramidales/metabolismo , Células Piramidales/patología , Proteína Reelina , Serina EndopeptidasasRESUMEN
beta-Amyloid peptides are key molecules that are involved in the pathology of Alzheimer's disease (AD). The source and place of the neurotoxic action of Abeta, however, is still a matter of controversial debates. In the present report, we studied the neuropathological events in a transgenic mouse model expressing human mutant beta-amyloid precursor protein and human mutant presenilin-1 in neurons. Western blot and immunohistochemical analysis revealed that intracellular Abeta staining preceded plaque deposition, which started in the hippocampal formation. At later stages, many neuritic Abeta positive plaques were found in all cortical, hippocampal and many other brain areas. Interestingly, intraneuronal Abeta staining was no longer detected in the brain of aged double-transgenic mice, which correlates with the typical neuropathology in the brain of chronic AD patients.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Proteínas de la Membrana/metabolismo , Neuronas/metabolismo , Placa Amiloide/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Animales , Encéfalo/patología , Encéfalo/fisiopatología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Gliosis/genética , Gliosis/patología , Gliosis/fisiopatología , Hipocampo/metabolismo , Hipocampo/patología , Hipocampo/fisiopatología , Humanos , Inmunohistoquímica , Proteínas de la Membrana/genética , Ratones , Ratones Transgénicos/genética , Ratones Transgénicos/metabolismo , Mutación/genética , Neuronas/patología , Placa Amiloide/genética , Placa Amiloide/patología , Presenilina-1RESUMEN
During the last years it has become evident that the beta-amyloid (Abeta) component of senile plaques may be the key molecule in the pathology of Alzheimer's disease (AD). The source and place of the neurotoxic action of Abeta, however, is still a matter of controversy. The precursor of the beta-amyloid peptide is the predominantly neuronal beta-amyloid precursor protein. We, and others, hypothesize that intraneuronal misregulation of APP leads to an accumulation of Abeta peptides in intracellular compartments. This accumulation impairs APP trafficking, which starts a cascade of pathological changes and causes the pyramidal neurons to degenerate. Enhanced Abeta secretion as a function of stressed neurons and remnants of degenerated neurons provide seeds for extracellular Abeta aggregates, which induce secondary degenerative events involving neighboring cells such as neurons, astroglia and macrophages/microglia. Beta-amyloid precursor protein has a pivotal role in Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/fisiología , Animales , Transporte Axonal , Cobre , Humanos , Plasticidad Neuronal , Transmisión SinápticaRESUMEN
The contribution of alpha-synuclein accumulation in Alzheimer's disease (AD) plaques is currently a matter of scientific debate. In the present study antisera against the N- and C-terminus, the full-length protein and the central so-called non-amyloid component (NAC) domain of the alpha-synuclein protein were used to address this question in brains of cases with typical AD and of cases with the Lewy body (LB) variant of AD. In typical AD cases, none of the antisera revealed evidence for co-accumulation of alpha-synuclein with extracellular A beta peptides in plaques or in dystrophic neurites decorating the plaque core. Interestingly, cases with mixed pathology of the LB variant of AD revealed accumulation of alpha-synuclein in LBs and in dystrophic neurites of A beta plaques.