RESUMEN
The authors describe in this paper a Moroccan family presenting Alzheimer's disease with early onset and rapid course (6 members, of whom 3 died at 34 and 40 years old in a severe picture of dementia). Among these 6 members, Mr M.K., 36 years old, was admitted in the University Psychiatric Department for 4 years of depressive syndrome, -memory impairment and cognitive deficit. In the literature, the cases of Alzheimer's disease begining before 60 years have been reported since 1991; the transmission of this syndrome is autosomal dominant. The genetic studies showed a multifactorial determinism. For the familial cases with early onset, the mutation occurs on the amyloïd precursor protein and on the presenilin 1 and 2. In this case, the result of the familial investigations was compatible with Alzheimer's disease, a dominant autosomic disorder, with early onset between 32 and 40 years old. The clinical course evoked a mutation of presenilin 1. The identification of such mutation in one of his sisters living in France confirmed the genetic transmission. Despite progress made in understanding the pathogenesis, the development of a curative treatment in Alzheimer's disease remains difficult. Selective inhibitors of cholinesterase can improve patients with mild to moderate Alzheimer's disease forms. In Morocco, only donepezil is available, but it is inaccessible for patients who need this treatment because of its high price. For Mr M.K., who still has a professional activity, symptomatic treatment, cognitive and psychological supports may allow him to maintain an adequate life for years. The family support is essential.
Asunto(s)
Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/análogos & derivados , Cromosomas Humanos Par 21/genética , Adulto , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/terapia , Precursor de Proteína beta-Amiloide/genética , Atrofia/patología , Corteza Cerebral/patología , Inhibidores de la Colinesterasa/uso terapéutico , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/terapia , Terapia Cognitivo-Conductual , Donepezilo , Femenino , Humanos , Indanos/uso terapéutico , Imagen por Resonancia Magnética , Masculino , Proteínas de la Membrana/genética , Pruebas Neuropsicológicas , Linaje , Piperidinas/uso terapéutico , Mutación Puntual/genética , Presenilina-1 , Presenilina-2 , Calidad de Vida , Índice de Severidad de la Enfermedad , Apoyo SocialRESUMEN
Regulated intramembrane proteolysis (RIP) of the amyloid precursor protein (APP) produces amyloid beta-protein (Abeta), the probable causative agent of Alzheimer's disease (AD), and is therefore an important target for therapeutic intervention. However, there is a burgeoning consensus that gamma-secretase, one of the proteases that generates Abeta, is also critical for the signal transduction of APP and a growing list of other receptors. APP is a member of a gene family that includes two amyloid precursor-like proteins, APLP1 and APLP2. Although APP and the APLPs undergo similar proteolytic processing, there is little information about the role of their gamma-secretase-generated intracellular domains (ICDs). Here, we show that APLP1 and 2 undergo presenilin-dependent RIP similar to APP, resulting in the release of a approximately 6 kDa ICD for each protein. Each of the ICDs are degraded by an insulin degrading enzyme-like activity, but they can be stabilized by members of the FE65 family and translocate to the nucleus. Given that modulation of APP processing is a therapeutic target and that the APLPs are processed in a manner similar to APP, any strategy aimed at altering APP proteolysis will have to take into account possible effects on signaling by APLP 1 and 2.
Asunto(s)
Precursor de Proteína beta-Amiloide/análogos & derivados , Precursor de Proteína beta-Amiloide/metabolismo , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Endopeptidasas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/metabolismo , Secuencia de Aminoácidos , Secretasas de la Proteína Precursora del Amiloide , Precursor de Proteína beta-Amiloide/química , Animales , Ácido Aspártico Endopeptidasas , Células CHO , Células COS , Clonación Molecular , Cricetinae , Endopeptidasas/química , Técnica del Anticuerpo Fluorescente Directa/métodos , Humanos , Datos de Secuencia Molecular , Unión Proteica , Procesamiento Proteico-Postraduccional , Estructura Terciaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transducción de SeñalAsunto(s)
Precursor de Proteína beta-Amiloide/análogos & derivados , Encéfalo/metabolismo , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/fisiopatología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/fisiopatología , Estructura Secundaria de Proteína/fisiología , Precursor de Proteína beta-Amiloide/metabolismo , Humanos , Componente Amiloide P Sérico/metabolismoRESUMEN
Extracting protein interaction relationships from textual repositories, such as MEDLINE, may prove useful in generating novel biological hypotheses. Using abstracts relevant to two known functionally related proteins, we modified an existing natural language processing tool to extract protein interaction terms. We were able to obtain functional information about two proteins, Amyloid Precursor Protein and Prion Protein, that have been implicated in the etiology of Alzheimer's Disease and Creutzfeldt-Jakob Disease, respectively.
Asunto(s)
Precursor de Proteína beta-Amiloide/análogos & derivados , Precursor de Proteína beta-Amiloide/fisiología , Procesamiento de Lenguaje Natural , Precursor de Proteína beta-Amiloide/química , Priones/química , Priones/fisiologíaRESUMEN
Antibodies to human amyloid precursor protein (APP(695)) and beta-amyloid peptide (A beta(1-42)) were used to determine timing of amyloidosis in the brain of kokanee salmon (Oncorhynchus nerka kennerlyi) in one of four reproductive stages: immature (IM), maturing (MA), sexually mature (SM), and spawning (SP), representing a range of aging from somatically mature but sexually immature to spawning and somatic senescence. In IM fish, immunoreactive (ir) intracellular APP occurred in 18 of 23 brain regions. During sexual maturation and aging, the number of neurons expressing APP increased in 11 of these APP-ir regions. A beta-ir was absent in IM fish, present in seven regions in MA fish, moderately abundant in 15 regions in SM fish, and was most abundant in all brain regions of SP fish exhibiting A beta-ir. Intracellular APP-ir was observed in brain regions involved in sensory integration, olfaction, vision, stress responses, reproduction, and coordination. Intra- and extracellular A beta(1-42) immunoreactivity (A beta-ir) was present in all APP-ir regions except the nucleus lateralis tuberis (hypothalamus) and Purkinje cells (cerebellum). APP-ir and A beta deposition increase during aging. APP-ir is present in IM fish; A beta-ir usually appears first in MA or SM fish and increases in SM fish as does APP-ir. Extracellular A beta deposition dramatically increases between SM and SP stages (1-2 weeks) in all fish, indicating an extremely rapid and synchronized process. Rapid senescence observed in pacific salmon could make them a useful model to investigate timing of amyloidosis and neurodegeneration during brain aging.
Asunto(s)
Envejecimiento/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/análogos & derivados , Precursor de Proteína beta-Amiloide/metabolismo , Neuronas/metabolismo , Fragmentos de Péptidos/metabolismo , Animales , Química Encefálica/fisiología , Femenino , Inmunohistoquímica , Masculino , SalmónRESUMEN
The familial Alzheimer's disease gene product beta-amyloid (Abeta) precursor protein (APP) is processed by the beta- and gamma-secretases to produce Abeta as well as AID (APP Intracellular Domain) which is derived from the extreme carboxyl terminus of APP. AID was originally shown to lower the cellular threshold to apoptosis and more recently has been shown to modulate gene expression such that it represses Notch-dependent gene expression while in combination with Fe65 it enhances gene activation. Here we report that the two other members of the APP family, beta-amyloid precursor-like protein-1 and -2 (APLP1 and APLP2), are also processed by the gamma-secretase in a Presenilin 1-dependent manner. Furthermore, the extreme carboxyl-terminal fragments produced by this processing (here termed APP-like Intracellular Domain or ALID1 and ALID2) are able to enhance Fe65-dependent gene activation, similar to what has been reported for AID. Considering that only APP and not the APLPs have been linked to familial Alzheimer's disease (AD), this data should help in understanding the physiologic roles of the APP family members and in differentiating these functions from the pathologic role of APP in Alzheimer's disease.
Asunto(s)
Precursor de Proteína beta-Amiloide/análogos & derivados , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Endopeptidasas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Enfermedad de Alzheimer/metabolismo , Secuencias de Aminoácidos , Secretasas de la Proteína Precursora del Amiloide , Animales , Ácido Aspártico Endopeptidasas , Western Blotting , Encéfalo/metabolismo , Diferenciación Celular , Línea Celular , Núcleo Celular/metabolismo , Células Cultivadas , Citoplasma/metabolismo , Glutatión Transferasa/metabolismo , Humanos , Inmunohistoquímica , Luciferasas/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Microscopía Fluorescente , Mutación Puntual , Pruebas de Precipitina , Unión Proteica , Estructura Terciaria de Proteína , Receptores Notch , Transcripción Genética , Activación Transcripcional , Tirosina/metabolismoRESUMEN
The synapse loss and neuronal cell death characteristic of Alzheimer's disease (AD) are believed to result in large part from the neurotoxic effects of beta-amyloid peptide (Abeta), a 40-42 amino acid peptide(s) derived proteolytically from beta-amyloid precursor protein (APP). However, APP is also cleaved intracellularly to generate a second cytotoxic peptide, C31, and this cleavage event occurs in vivo as well as in vitro and preferentially in the brains of AD patients (Lu et al. 2000). Here we show that APPC31 is toxic to neurons in primary culture, and that like APP, the APP family members APLP1 and possibly APLP2 are cleaved by caspases at their C-termini. The carboxy-terminal peptide derived from caspase cleavage of APLP1 shows a degree of neurotoxicity comparable to APPC31. Our results suggest that even though APLP1 and APLP2 cannot generate Abeta, they may potentially contribute to the pathology of AD by generating peptide fragments whose toxicity is comparable to that of APPC31.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/análogos & derivados , Precursor de Proteína beta-Amiloide/metabolismo , Caspasas/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Epítopos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Inmunohistoquímica , Riñón/citología , Riñón/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuroglía/citología , Neuroglía/efectos de los fármacos , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fragmentos de Péptidos/biosíntesis , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/toxicidad , Ratas , TransfecciónRESUMEN
The gonadal estrogen estradiol-17beta (E(2)) is important for developing and regulating hypothalamic function and many aspects of reproduction in vertebrates. Pollutants such as octylphenol (OP) that mimic the actions of estrogens are therefore candidate endocrine-disrupting chemicals. We used a differential display strategy (RNA-arbitrarily primed polymerase chain reaction) to isolate partial cDNA sequences of neurotransmitter, developmental, and disease-related genes that may be regulated by OP or E(2) in the snapping turtle Chelydra serpentina serpentina hypothalamus. Hatchling and year-old male snapping turtles were exposed to a 10 ng/mL nominal concentration of waterborne OP or E(2) for 17 days. One transcript [421 base pairs (bp)] regulated by OP and E(2) was 93% identical to human APLP-2. APLP-2 and the amyloid precursor protein (APP) regulate neuronal differentiation and are also implicated in the genesis of Alzheimer disease in humans. Northern blot analysis determined that the turtle hypothalamus contains a single APLP-2 transcript of 3.75 kb in length. Exposure to OP upregulated hypothalamic APLP-2 mRNA levels 2-fold (p < 0.05) in month-old and yearling turtles. E(2) did not affect APLP-2 mRNA levels in hatchlings but stimulated a 2-fold increase (p < 0.05) in APLP-2 mRNA levels in yearling males. The protein beta-amyloid, a selectively processed peptide derived from APP, is also involved in neuronal differentiation, and accumulation of this neurotoxic peptide causes neuronal degeneration in the brains of patients with Alzheimer disease. Therefore, we also sought to determine the effects of estrogens on the expression of beta-amyloid. Using homology cloning based on known sequences, we isolated a cDNA fragment (474 bp) from turtle brain with 88% identity to human APP. Northern blot analysis determined that a single 3.5-kb transcript was expressed in the turtle hypothalamus. Waterborne OP also increased the expression of hypothalamic APP after 35 days of exposure. Our results indicate that low levels of OP are bioactive and can alter the expression of APLP-2 and APP. Because members of the APP gene family are involved in neuronal development, we hypothesize that OP exposure may disrupt hypothalamic development in young turtles.
Asunto(s)
Péptidos beta-Amiloides/biosíntesis , Precursor de Proteína beta-Amiloide/análogos & derivados , Precursor de Proteína beta-Amiloide/biosíntesis , Estradiol/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas del Tejido Nervioso/biosíntesis , Fenoles/farmacología , Tortugas/fisiología , Enfermedad de Alzheimer/fisiopatología , Animales , Diferenciación Celular , ADN Complementario/análisis , Estrógenos no Esteroides/efectos adversos , Estrógenos no Esteroides/farmacología , Hipotálamo/fisiología , Masculino , Fenoles/efectos adversos , Reacción en Cadena de la Polimerasa , ARN Mensajero/análisisRESUMEN
Even though the exact cause of Alzheimer's disease is not known, it is clear that genetic factors play a major role. Screening of familial cases has so far linked four genes to Alzheimer's disease: amyloid precursor protein, presenilin 1, presenilin 2 and apolipoprotein E. Mutations in the amyloid precursor protein, presenilin 1 and presenilin 2 genes cause the enhanced production of b amyloid that is found in neuritic plaques. While apolipoprotein E allele e4 does not cause enhanced production of amyloid, it does enhance its deposition. The genes identified so far are linked to only about 10% of total Alzheimer's disease cases, and there are a number of familial cases that are not linked to any of the four genes. This suggests that important genetic factors have yet to be identified. The key events in Alzheimer's disease are cytoskeletal changes and the formation of paired helical filaments, and these are common to the two hallmarks of Alzheimer's disease: neuritic plaques and neurofibrillary tangles. So far there is no explanation as to how the identified genes cause these events. Here we speculate that paired helical filaments can form as a result of overexpression of the DSCR1 (Adap78) gene. b Amyloids and/or other stress factors can induce DSCR1 (Adap78) and cause decreased activity of calcineurin. Chronic downregulation of calcineurin can lead to gradual accumulation of hyperphosphorylated tau, the formation of paired helical filaments and Alzheimer's disease-like cytoskeletal changes.
Asunto(s)
Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/análogos & derivados , Precursor de Proteína beta-Amiloide/genética , Apolipoproteínas E/genética , Proteínas de la Membrana/genética , Enfermedad de Alzheimer/patología , Humanos , Presenilina-1 , Presenilina-2RESUMEN
To examine the in vivo function of presenilin-1 (PS1), we selectively deleted the PS1 gene in excitatory neurons of the adult mouse forebrain. These conditional knockout mice were viable and grew normally, but they exhibited a pronounced deficiency in enrichment-induced neurogenesis in the dentate gyrus. This reduction in neurogenesis did not result in appreciable learning deficits, indicating that addition of new neurons is not required for memory formation. However, our postlearning enrichment experiments lead us to postulate that adult dentate neurogenesis may play a role in the periodic clearance of outdated hippocampal memory traces after cortical memory consolidation, thereby ensuring that the hippocampus is continuously available to process new memories. A chronic, abnormal clearance process in the hippocampus may conceivably lead to memory disorders in the mammalian brain.
Asunto(s)
Precursor de Proteína beta-Amiloide/análogos & derivados , Hipocampo/crecimiento & desarrollo , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Memoria/fisiología , Prosencéfalo/crecimiento & desarrollo , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Química Encefálica/genética , Electrofisiología , Hipocampo/patología , Trastornos de la Memoria/genética , Trastornos de la Memoria/patología , Trastornos de la Memoria/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Noqueados , Ratones Transgénicos , Neuronas/patología , Presenilina-1 , Prosencéfalo/patología , ARN Mensajero/genética , ARN Mensajero/metabolismoAsunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/fisiopatología , Precursor de Proteína beta-Amiloide/análogos & derivados , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Inhibidores de la Colinesterasa/farmacología , Tacrina/farmacología , Anciano , Precursor de Proteína beta-Amiloide/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The workshop on Multiple Sclerosis and Chemokines: Prospects for Therapeutic and Prophylactic Intervention was held in Chevy Chase, MD, USA, from 9-10 July 2001.
Asunto(s)
Precursor de Proteína beta-Amiloide/análogos & derivados , Quimiocinas/metabolismo , Quimiotaxis de Leucocito , Esclerosis Múltiple/patología , Esclerosis Múltiple/terapia , Receptores de Quimiocina/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Humanos , Inflamación/metabolismo , Inflamación/patología , Leucocitos/inmunología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
We tested the hypothesis that amyloid precursor protein (APP) and its relatives function as vesicular receptor proteins for kinesin-I. Deletion of the Drosophila APP-like gene (Appl) or overexpression of human APP695 or APPL constructs caused axonal transport phenotypes similar to kinesin and dynein mutants. Genetic reduction of kinesin-I expression enhanced while genetic reduction of dynein expression suppressed these phenotypes. Deletion of the C terminus of APP695 or APPL, including the kinesin binding region, disrupted axonal transport of APP695 and APPL and abolished the organelle accumulation phenotype. Neuronal apoptosis was induced only by overexpression of constructs containing both the C-terminal and Abeta regions of APP695. We discuss the possibility that axonal transport disruption may play a role in the neurodegenerative pathology of Alzheimer's disease.
Asunto(s)
Precursor de Proteína beta-Amiloide/análogos & derivados , Precursor de Proteína beta-Amiloide/genética , Transporte Axonal/genética , Drosophila/genética , Mutación , Neuronas/metabolismo , Precursor de Proteína beta-Amiloide/biosíntesis , Animales , Muerte Celular/genética , Supervivencia Celular/genética , Drosophila/metabolismo , Humanos , Cinesinas/biosíntesis , Cinesinas/genética , Mutación/genéticaAsunto(s)
Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide/análogos & derivados , Modelos Animales de Enfermedad , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animales , Apolipoproteínas E/genética , Proteína Ácida Fibrilar de la Glía/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas tau/genéticaRESUMEN
A subset of aged individuals with Down syndrome (DS) exhibits the clinical features of Alzheimer's disease (AD) but our ability to detect dementia in this population is hampered by developmental differences as well as the sensitivity of existing test tools. Despite the apparent clinical heterogeneity in aged individuals with DS, age-associated neuropathology is a consistent feature. This is due to the fact that trisomy 21 leads to a dose-dependent increase in the production of the amyloid precursor protein and subsequently the production of the amyloidogenic fragments leading to early and predominant senile plaque formation. A review of the existing literature indicates that oxidative damage and neuroinflammation may interact to accelerate the disease process particularly in individuals with DS over the age of 40 years. By combining clinical information with measures of brain-region specific neuropathology we can "work backwards" and identify the earliest and most sensitive clinical change that may signal the onset of AD. For the past 50 years, investigators in the fields of mental retardation, developmental disabilities, and aging have been interested in the curious link between AD and DS. The morphologic and biochemical origins of AD are seen in the early years of the lifespan for individuals with DS. Study of the process by which AD evolves in DS affords an opportunity to understand an important link between development and aging. This review will focus on advances in the molecular and clinical basis of this association.
Asunto(s)
Envejecimiento/fisiología , Enfermedad de Alzheimer/complicaciones , Precursor de Proteína beta-Amiloide/análogos & derivados , Trastornos del Conocimiento/complicaciones , Discapacidades del Desarrollo/complicaciones , Síndrome de Down/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Precursor de Proteína beta-Amiloide/metabolismo , Niño , Trastornos del Conocimiento/diagnóstico , Síndrome de Down/metabolismo , Síndrome de Down/fisiopatología , Lóbulo Frontal/metabolismo , Lóbulo Frontal/fisiopatología , Humanos , Persona de Mediana Edad , Pruebas NeuropsicológicasAsunto(s)
Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide/análogos & derivados , Investigación/tendencias , Anciano , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Humanos , Proteínas de la Membrana/genética , Presenilina-1RESUMEN
The amyloid precursor protein (APP) involved in Alzheimer's disease is a member of a larger gene family including amyloid precursor-like proteins APLP1 and APLP2. We generated and examined the phenotypes of mice lacking individual or all possible combinations of APP family members to assess potential functional redundancies within the gene family. Mice deficient for the nervous system-specific APLP1 protein showed a postnatal growth deficit as the only obvious abnormality. In contrast to this minor phenotype, APLP2(-/-)/APLP1(-/-) and APLP2(-/-)/APP(-/-) mice proved lethal early postnatally. Surprisingly, APLP1(-/-)/APP(-/-) mice were viable, apparently normal, and showed no compensatory upregulation of APLP2 expression. These data indicate redundancy between APLP2 and both other family members and corroborate a key physiological role for APLP2. This view gains further support by the observation that APLP1(-/-)/APP(-/-)/APLP2(+/-) mice display postnatal lethality. In addition, they provide genetic evidence for at least some distinct physiological roles of APP and APLP2 by demonstrating that combinations of single knock-outs with the APLP1 mutation resulted in double mutants of clearly different phenotypes, being either lethal, or viable. None of the lethal double mutants displayed, however, obvious histopathological abnormalities in the brain or any other organ examined. Moreover, cortical neurons from single or combined mutant mice showed unaltered survival rates under basal culture conditions and unaltered susceptibility to glutamate excitotoxicity in vitro.
Asunto(s)
Precursor de Proteína beta-Amiloide/genética , Familia de Multigenes/genética , Proteínas del Tejido Nervioso/genética , Precursor de Proteína beta-Amiloide/análogos & derivados , Precursor de Proteína beta-Amiloide/deficiencia , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Northern Blotting , Western Blotting , Encéfalo/citología , Encéfalo/metabolismo , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Células Cultivadas , Cruzamientos Genéticos , Femenino , Genes Letales/genética , Prueba de Complementación Genética , Ácido Glutámico/metabolismo , Ácido Glutámico/farmacología , Heterocigoto , Homocigoto , Masculino , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/metabolismo , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fenotipo , ARN Mensajero/metabolismo , Sinapsis/ultraestructuraRESUMEN
Intensive investigation towards the understanding of the biology and physiological functions of the beta-amyloid precursor protein (APP) have been supported since it is known that a 39-43 amino acid fragment of APP, called the beta-amyloid protein (Abeta), accumulates in the brain parenchyma to form the typical lesions associated with Alzheimer's disease (AD). It emerges from extensive data that APP and its derivatives show a wide range of contrasting physiological properties and therefore might be involved in distinct physiological functions. Abeta has been shown to disrupt neuronal activity and to demonstrate neurotoxic properties in a wide range of experimental procedures. In contrast, both in vitro and in vivo studies suggest that APP and/or its secreted forms are important factors involved in the viability, growth and morphological and functional plasticity of nerve cells. Furthermore, several recent studies suggest that APP and its derivatives have an important role in learning and memory processes. Memory impairments can be induced in animals by intracerebral treatment with Abeta. Altered expression of the APP gene in aged animals or in genetically-modified animals also leads to memory deficits. By contrast, secreted forms of APP have recently been shown to facilitate learning and memory processes in mice. These interesting findings open novel perspectives to understand the involvement of APP in the development of cognitive deficits associated with AD. In this review, we summarize the current data concerning the biology and the behavioral effects of APP and its derivatives which may be relevant to the roles of these proteins in memory and in AD pathology.
Asunto(s)
Precursor de Proteína beta-Amiloide/análogos & derivados , Precursor de Proteína beta-Amiloide/fisiología , Aprendizaje/fisiología , Memoria/fisiología , Enfermedad de Alzheimer/psicología , Animales , Trastornos del Conocimiento/fisiopatología , HumanosRESUMEN
Amyloid precursor protein (APP) generates the beta-amyloid peptide, postulated to participate in the neurotoxicity of Alzheimer's disease. We report that APP and APLP bind to heme oxygenase (HO), an enzyme whose product, bilirubin, is antioxidant and neuroprotective. The binding of APP inhibits HO activity, and APP with mutations linked to the familial Alzheimer's disease (FAD) provides substantially greater inhibition of HO activity than wild-type APP. Cortical cultures from transgenic mice expressing Swedish mutant APP have greatly reduced bilirubin levels, establishing that mutant APP inhibits HO activity in vivo. Oxidative neurotoxicity is markedly greater in cerebral cortical cultures from APP Swedish mutant transgenic mice than wild-type cultures. These findings indicate that augmented neurotoxicity caused by APP-HO interactions may contribute to neuronal cell death in Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/enzimología , Precursor de Proteína beta-Amiloide/análogos & derivados , Precursor de Proteína beta-Amiloide/metabolismo , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Hemo Oxigenasa (Desciclizante)/metabolismo , Neuronas/enzimología , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/toxicidad , Animales , Bilirrubina/metabolismo , Unión Competitiva/genética , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/enzimología , Corteza Cerebral/patología , Relación Dosis-Respuesta a Droga , Hemo-Oxigenasa 1 , Hemina/toxicidad , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Proteínas de la Membrana , Ratones , Ratones Transgénicos , Mutación , Neuronas/efectos de los fármacos , Neuronas/patología , Estrés Oxidativo/genética , Estructura Terciaria de Proteína/genética , Transfección , Técnicas del Sistema de Dos HíbridosRESUMEN
In this study, we have investigated the effect of altered corticosteroid levels on the expression and processing of the amyloid beta precursor protein (A betaPP) and its amyloid precursor-like protein (APLP) homologue in rat brain. Four groups of animals were used in the study: sham operated, adrenalectomised, and adrenalectomised treated with either dexamethasone or aldosterone, with the A betaPP/APLP expression being determined by western blot analysis. While there were no changes in the levels of A betaPP/APLP following adrenalectomy, treatment with dexamethasone, but not aldosterone, resulted in a marked increase in protein expression levels with the level of increase varying between the brain regions examined. Corticosteroids had a more marked effect on the particulate rather than the soluble form of the protein, thus suggesting that elevated glucocorticoids may also be adversely influencing A betaPP/APLP processing.