RESUMEN
It is well established that only a fraction of Abeta peptides in the brain of Alzheimer's disease (AD) patients start with N-terminal aspartate (Abeta(1D)) which is generated by proteolytic processing of amyloid precursor protein (APP) by BACE. N-terminally truncated and pyroglutamate modified Abeta starting at position 3 and ending with amino acid 42 [Abeta(3(pE)-42)] have been previously shown to represent a major species in the brain of AD patients. When compared with Abeta(1-42), this peptide has stronger aggregation propensity and increased toxicity in vitro. Although it is unknown which peptidases remove the first two N-terminal amino acids, the cyclization of Abeta at N-terminal glutamate can be catalyzed in vitro. Here, we show that Abeta(3(pE)-42) induces neurodegeneration and concomitant neurological deficits in a novel mouse model (TBA2 transgenic mice). Although TBA2 transgenic mice exhibit a strong neuronal expression of Abeta(3-42) predominantly in hippocampus and cerebellum, few plaques were found in the cortex, cerebellum, brain stem and thalamus. The levels of converted Abeta(3(pE)-42) in TBA2 mice were comparable to the APP/PS1KI mouse model with robust neuron loss and associated behavioral deficits. Eight weeks after birth TBA2 mice developed massive neurological impairments together with abundant loss of Purkinje cells. Although the TBA2 model lacks important AD-typical neuropathological features like tangles and hippocampal degeneration, it clearly demonstrates that intraneuronal Abeta(3(pE)-42) is neurotoxic in vivo.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Encéfalo/patología , Neuronas/patología , Fragmentos de Péptidos/metabolismo , Péptidos beta-Amiloides/genética , Análisis de Varianza , Animales , Peso Corporal , Encéfalo/metabolismo , Encefalopatías/genética , Encefalopatías/metabolismo , Encefalopatías/patología , Muerte Celular/genética , Ensayo de Inmunoadsorción Enzimática , Inmunohistoquímica , Ratones , Ratones Transgénicos , Degeneración Nerviosa/genética , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Neuronas/metabolismo , Fragmentos de Péptidos/genética , Fenotipo , Células de Purkinje/metabolismo , Células de Purkinje/patologíaRESUMEN
Abeta accumulation has an important function in the etiology of Alzheimer's disease (AD) with its typical clinical symptoms, like memory impairment and changes in personality. However, the mode of this toxic activity is still a matter of scientific debate. We used the APP/PS1KI mouse model for AD, because it is the only model so far which develops 50% hippocampal CA1 neuron loss at the age of 1 year. Previously, we have shown that this model develops severe learning deficits occurring much earlier at the age of 6 months. This observation prompted us to study the anatomical and cellular basis at this time point in more detail. In the current report, we observed that at 6 months of age there is already a 33% CA1 neuron loss and an 18% atrophy of the hippocampus, together with a drastic reduction of long-term potentiation and disrupted paired pulse facilitation. Interestingly, at 4 months of age, there was no long-term potentiation deficit in CA1. This was accompanied by reduced levels of pre- and post-synaptic markers. We also observed that intraneuronal and total amount of different Abeta peptides including N-modified, fibrillar and oligomeric Abeta species increased and coincided well with CA1 neuron loss. Overall, these data provide the basis for the observed robust working memory deficits in this mouse model for AD at 6 months of age.
Asunto(s)
Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Precursor de Proteína beta-Amiloide/genética , Hipocampo/patología , Hipocampo/fisiopatología , Neuronas/fisiología , Receptores de Superficie Celular/genética , Sinapsis/fisiología , Péptidos beta-Amiloides/metabolismo , Animales , Atrofia , Muerte Celular , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores , Humanos , Técnicas In Vitro , Potenciación a Largo Plazo , Ratones , Ratones Transgénicos , Péptidos/metabolismo , Presenilina-1/genética , Nexinas de ProteasasRESUMEN
Accumulating evidence points to an important role of intraneuronal beta-amyloid (Abeta) in the development of Alzheimer's disease (AD), with its typical clinical symptoms like memory impairment and changes in personality. We have previously reported on the Abeta precursor protein and presenilin-1 knock-out (APP/PS1KI) mouse model with abundant intraneuronal Abeta(42) accumulation and a 50% loss of CA1 neurons at 10 months of age. In addition, we observed reduced short- and long-term synaptic plasticity, hippocampal neuron loss, and reduced performance in a working memory task. These observations support a pivotal role of intraneuronal Abeta accumulation as a principal pathological trigger in AD.
Asunto(s)
Péptidos beta-Amiloides/fisiología , Precursor de Proteína beta-Amiloide/fisiología , Modelos Animales de Enfermedad , Neuronas/metabolismo , Neuronas/patología , Fragmentos de Péptidos/fisiología , Presenilina-1/fisiología , Péptidos beta-Amiloides/biosíntesis , Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/biosíntesis , Precursor de Proteína beta-Amiloide/deficiencia , Precursor de Proteína beta-Amiloide/genética , Animales , Humanos , Ratones , Ratones Noqueados , Fragmentos de Péptidos/biosíntesis , Fragmentos de Péptidos/genética , Presenilina-1/biosíntesis , Presenilina-1/genética , Factores de RiesgoRESUMEN
A large number of studies deals with the association of cholesterol and Abeta levels, however, the results are so far controversial. Whereas some studies report on increased cholesterol levels, other authors refer to an association of decreased peripheral cholesterol and the incidence of Alzheimer's disease. It is also questionable whether plasma cholesterol levels could be used as a predictive biomarker for the incidence of Alzheimer's disease. In the present report, we studied the relationship between these two parameters during aging in different transgenic mouse models of Alzheimer's disease, expressing both mutant human amyloid precursor protein and mutant human presenilin-1. Measurements of plasma cholesterol levels revealed a significant reduction in aged APP/PS1 and APP/PS1ki mice, whereas plasma levels in young and aged control mice remained almost unchanged. Furthermore, statistical analysis revealed a significant negative correlation between plasma cholesterol and brain Abeta42 levels during aging in the mice expressing both APP and PS1.
Asunto(s)
Envejecimiento/fisiología , Enfermedad de Alzheimer/sangre , Colesterol/sangre , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/análisis , Precursor de Proteína beta-Amiloide/genética , Análisis de Varianza , Animales , Química Encefálica , Cromatografía de Gases , Ensayo de Inmunoadsorción Enzimática , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Ratones Transgénicos , Modelos Animales , Presenilina-1 , Estadísticas no ParamétricasRESUMEN
Inflammatory processes are considered to play an important role in the progression of neurodegenerative changes in Alzheimer's disease (AD). In the present study, we performed a systematic expression analysis of various inflammatory and oxidative stress markers in pre-symptomatic and diseased APP/PS1KI mice. This mouse model has been previously shown to harbor severe pathological alterations, including behavioral deficits, axonal degeneration and hippocampal neuron loss starting at the age of 6 months. While the expression levels of most markers remained unchanged in 2-month-old APP/PS1KI mice, at the age of 6 months different astro- and microglia markers including GFAP, Cathepsin D, members of the Toll-like receptor (Tlr) family, TGFbeta-1 and osteopontin were up-regulated. In addition, oxidative stress markers, including the metallothioneins, were also significantly elevated at that time point. As expected, both brain and spinal cord were affected, the latter showing early activation of GFAP-positive astrocytes and Iba1-positive microglia in white matter fiber tracts, which might contribute to the previously reported axonal defects in this mouse model. These data add further evidence to the assumption that inflammatory processes are tightly associated with axonal degeneration and neuron loss, as is evident in the APP/PS1KI mouse model.
Asunto(s)
Enfermedad de Alzheimer/patología , Encéfalo/patología , Inflamación/patología , Degeneración Nerviosa/patología , Médula Espinal/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Astrocitos/metabolismo , Astrocitos/patología , Western Blotting , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica , Inflamación/genética , Inflamación/metabolismo , Ratones , Ratones Transgénicos , Microglía/metabolismo , Degeneración Nerviosa/genética , Degeneración Nerviosa/metabolismo , Neuronas/metabolismo , Neuronas/patología , Presenilina-1/genética , Presenilina-1/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Médula Espinal/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
The APP/PS1ki mouse model for Alzheimer's disease (AD) exhibits robust brain and spinal cord axonal degeneration and hippocampal CA1 neuron loss starting at 6 months of age. It expresses human mutant APP751 with the Swedish and London mutations together with two FAD-linked knocked-in mutations (PS1 M233T and PS1 L235P) in the murine PS1 gene. The present report covers a phenotypical analysis of this model using either behavioral tests for working memory and motor performance, as well as an analysis of weight development and body shape. At the age of 6 months, a dramatic, age-dependent change in all of these properties and characteristics was observed, accompanied by a significantly reduced ability to perform working memory and motor tasks. The APP/PS1ki mice were smaller and showed development of a thoracolumbar kyphosis, together with an incremental loss of body weight. While 2-month-old APP/PS1ki mice were inconspicuous in all of these tasks and properties, there is a massive age-related impairment in all tested behavioral paradigms. We have previously reported robust axonal degeneration in brain and spinal cord, as well as abundant hippocampal CA1 neuron loss starting at 6 months of age in the APP/PS1ki mouse model, which coincides with the onset of motor and memory deficits described in the present report.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Precursor de Proteína beta-Amiloide/genética , Modelos Animales de Enfermedad , Trastornos de la Memoria/fisiopatología , Memoria , Desempeño Psicomotor , Enfermedad de Alzheimer/complicaciones , Animales , Femenino , Trastornos de la Memoria/complicaciones , Ratones , Ratones TransgénicosRESUMEN
Sortilin-related receptor with A-type repeats (SORLA) is a sorting receptor that impairs processing of amyloid precursor protein (APP) to soluble (s) APP and to the amyloid beta-peptide in cultured neurons and is poorly expressed in patients with Alzheimer disease (AD). Here, we evaluated the consequences of Sorla gene defects on brain anatomy and function using mouse models of receptor deficiency. In line with a protective role for SORLA in APP metabolism, lack of the receptor results in increased amyloidogenic processing of endogenous APP and in aggravated plaque deposition when introduced into PDAPP mice expressing mutant human APP. Surprisingly, increased levels of sAPP caused by receptor deficiency correlate with pro-found stimulation of neuronal ERK signaling and with enhanced neurogenesis, providing in vivo support for neurotrophic functions of sAPP. Our data document a role for SORLA not only in control of plaque burden but also in APP-dependent neuronal signaling and suggest a molecular explanation for increased neurogenesis observed in some AD patients.