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/metabolismo

RESUMEN

In the field of Alzheimer's disease, there is an urgent need for novel analytical tools to identify disease-specific biomarkers and to evaluate therapeutics. Preclinical trials commonly employ amyloid beta (Aß) peptide signatures as a read-out. In this paper, we report a simplified and detailed protocol for robust immunoprecipitation of Aß in brain tissue prior to mass spectrometric detection exemplified by a study using transgenic mice. The established method employed murine monoclonal and rabbit polyclonal antibodies and was capable of yielding well-reproducible peaks of high intensity with low background signal intensities corresponding to various Aß forms.

RESUMEN

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/genética

RESUMEN

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/metabolismo

RESUMEN

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/genética

RESUMEN

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/fisiología

RESUMEN

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-1

RESUMEN

Increasing evidence links Alzheimer's disease (AD) with misbalanced Cu homeostasis. Recently, we have shown that dietary Cu supplementation in a transgenic mouse model for AD increases bioavailable brain Cu levels, restores Cu, Zn-super oxide-1 activity, prevents premature death, and lowers A beta levels. In the present report we investigated AD patients with normal levels of A beta 42, Tau and Phospho-Tau in the cerebrospinal fluid (CSF) in comparison with AD patients exhibiting aberrant levels in these CSF biomarkers. The influence of these cerebrospinal fluid (CSF) diagnostic markers with primary dependent variables blood Cu, Zn and ceruloplasmin (CB) and secondary with CSF profiles of Cu, Zn and neurotransmitters was determined. Multivariate tests revealed a significant effect of factor diagnostic group (no AD diagnosis in CSF or AD diagnosis in CSF) for variables plasma Cu and CB (F=4.80; df=2, 23; p=0.018). Subsequent univariate tests revealed significantly reduced plasma Cu (-12.7%; F=7.05; df=1, 25; p=0.014) and CB (-14.1%; F=9.44; df=1, 24; p=0.005) levels in patients with aberrant CSF biomarker concentrations. Although only AD patients were included, the reduced plasma Cu and CB levels in patients with a CSF diagnosis of advanced AD supports previous observations that a mild Cu deficiency might contribute to AD progression.

Asunto(s)

Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Ceruloplasmina/líquido cefalorraquídeo , Cobre/sangre , Proteínas tau/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/sangre , Biomarcadores/líquido cefalorraquídeo , Cromatografía Líquida de Alta Presión , Cobre/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Neurotransmisores/líquido cefalorraquídeo , Espectrofotometría Atómica , Zinc/sangre

RESUMEN

During the last three to four decades, interest in the interaction of circulating and brain cholesterol has increased. As the CNS matures and cholesterol pools in the brain become constant, the rate of de novo synthesis of cholesterol in the brain is expected to decline. We measured cholesterol, its precursors and its brain specific metabolite 24S-hydroxycholesterol in hippocampus from 7 female and 13 male corpses by highly sensitive and specific gas chromatography-mass spectrometry. Two age groups (young, n=10; elderly, n=10) were formed with a cut-off at the median age of 38 years. The amount of cholesterol was comparable in young and elderly subjects. The concentrations of the cholesterol precursors lanosterol and lathosterol were significantly higher in young (P=0.036 and 0.005, respectively) than in elderly subjects. In accordance, there was a significantly negative correlation between age and lathosterol concentrations (r=-0.505; P=0.023). Absolute levels of 24S-hydroxycholesterol in the brain were slightly, but not significantly, lower in the hippocampal specimens from the elderly subjects. We conclude that during aging, cholesterol synthesis is decreased in the hippocampus, while absolute cholesterol content remains at a stable level.

Asunto(s)

Envejecimiento/metabolismo , Colesterol/biosíntesis , Hipocampo/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

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/patología

RESUMEN

Alzheimer's dementia (AD) is a chronically progressive neurodegenerative disease. The key protein in the pathophysiology of AD is the amyloid precursor protein (APP) which releases the amyloid-beta peptide (Abeta) by proteolytic cleavage. APP is probably involved in the homeostasis of cellular copper (Cu) metabolism, because significantly changed Cu levels in the brain were found in AD patients as well as in mouse models. In vivo studies with transgenic mice showed that oral Cu supplements can restore lowered Cu levels in the brain to normal, can reduce Abeta production, and can reduce mortality of the animals. Currently, the influence of oral Cu supplementation (in addition to an established acetylcholinesterase inhibitor) on the progression of the disease is being studied in a prospective, double-blind, randomized and placebo-controlled longitudinal clinical trial in patients with mild AD.

Asunto(s)

Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Cobre/metabolismo , Animales , Biomarcadores/metabolismo , Ensayos Clínicos como Asunto , Humanos , Distribución Tisular

RESUMEN

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 Endopeptidasas

RESUMEN

We reported previously that the carbohydrate domain of the amyloid precursor protein is involved in amyloid precursor protein (APP)-APP interactions. Functional in vitro studies suggested that this interaction occurs through the collagen binding site of APP. The physiological significance remained unknown, because it is not understood whether and how APP dimerization occurs in vivo. Here we report that cellular APP exists as homodimers matching best with a two-site model. Consistent with our published crystallographic data, we show that a deletion of the entire sequence after the kunitz protease inhibitor domain did not abolish APP homodimerization, suggesting that two domains are critically involved but that neither is essential for homodimerization. Finally, we generated stabilized dimers by expressing mutant APP with a single cysteine in the ectodomain juxtamembrane region. Mutation of Lys(624) to cysteine produced approximately 6-8-fold more A beta than cells expressing normal APP. Our results suggest that amyloid A beta production can in principle be positively regulated by dimerization in vivo. We suggest that dimerization could be a physiologically important mechanism for regulating the proposed signal activity of APP.

Asunto(s)

Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/química , Animales , Sitios de Unión , Western Blotting , Células COS , Membrana Celular/metabolismo , Cromatografía en Gel , Colágeno/metabolismo , Reactivos de Enlaces Cruzados/farmacología , Cisteína/química , Dimerización , Disulfuros , Humanos , Immunoblotting , Lisina/química , Mutagénesis Sitio-Dirigida , Mutación , Unión Proteica , Estructura Terciaria de Proteína , Proteínas Recombinantes/metabolismo , Transducción de Señal , Transfección , Células Tumorales Cultivadas

RESUMEN

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-1

RESUMEN

Primitive neuroectodermal tumors (PNETs) such as human medulloblastomas are genetically heterogeneous and therefore poorly understood. In a rat model the SV40 large T antigen was used to induce neoplasms with characteristic features of PNETs. Tumor development requires a latency period of 8-11 months implicating secondary genetic alterations. To identify such secondary alterations we performed comparative analyses of two phenotypically identical PNET-derived cell lines. Indeed, these cell lines displayed distinct high-level amplification sites. Using a combination of subtractive cDNA analysis and radiation hybrid mapping we have now identified genes in the amplicon regions of the two cell lines. Interestingly, one of these genes encodes the rat homolog of a cytosolic branched chain aminotransferase (BCAT(C)) previously shown to be amplified in a mouse teratocarcinoma cell line. We propose that this simple cloning strategy may serve as a powerful tool for the isolation of genes implicated in known chromosomal aberrations in primary tumors and tumor cell lines.

Asunto(s)

Antígenos Transformadores de Poliomavirus/genética , Neoplasias Encefálicas/genética , Amplificación de Genes , Tumores Neuroectodérmicos Primitivos/genética , Secuencia de Aminoácidos , Animales , Neoplasias Encefálicas/inmunología , Mapeo Cromosómico , Clonación Molecular , ADN Complementario/genética , Ratones , Datos de Secuencia Molecular , Tumores Neuroectodérmicos Primitivos/inmunología , Hibridación de Ácido Nucleico , Ratas , Homología de Secuencia de Aminoácido , Transaminasas/genética , Células Tumorales Cultivadas

RESUMEN

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 Sináptica

RESUMEN

The involvement of immunological and immunopathological mechanisms in the etiopathogenesis of schizophrenia has been a matter of research, with recently increasing effort. This article reviews the findings focusing on postmortem neuropathology, the blood-brain barrier, antibodies, acute phase proteins, immunocompetent cells, and activation markers of immunocompetent cells. Evidence for the two primarily postulated hypotheses (the infectious hypothesis and the autoimmune hypothesis) is critically discussed. On the basis of the findings, perspectives for future research are outlined aiming at a precise and consequent strategy to elucidate a potential involvement of immune mechanisms in the etiopathogenesis of schizophrenia.

Asunto(s)

Sistema Inmunológico/patología , Esquizofrenia/inmunología , Esquizofrenia/patología , Humanos , Neuroinmunomodulación

RESUMEN

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.

Asunto(s)

Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/fisiología , Cuerpos de Lewy/patología , Proteínas del Tejido Nervioso/metabolismo , Neuritas/ultraestructura , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Cuerpos de Lewy/metabolismo , Masculino , Persona de Mediana Edad , Neuritas/fisiología , Sinucleínas , alfa-Sinucleína

RESUMEN

1. Recent studies have provided support for the notion that the high affinity neurotrophin receptor tyrosine receptor kinase B (trk B) may be involved in the treatment of depression. 2. Using a quantitative RT-PCR approach trk B mRNA levels were determined in brain material from cerebellum, temporal cortex, and frontal cortex of control specimen and patients with major depressive disorder, schizophrenia and bipolar disorder (15 subjects each). 3. Interestingly, elevated trk B mRNA levels were found in cerebellum (3.6-fold) in patients with major depressive disorder, reaching statistical significance (p=0.03). 4. The major depressive disorder-on drugs group differed from controls (p=0.006) in the cerebellum. 5. Since only patients with major depressive disorder received antidepressants, elevated trk B mRNA levels are possibly related to drug treatment.

Asunto(s)

Antidepresivos/farmacología , Trastorno Depresivo/tratamiento farmacológico , Proteínas Tirosina Quinasas Receptoras/biosíntesis , Lóbulo Temporal/química , Adulto , Autopsia , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/fisiopatología , Cerebelo/química , Trastorno Depresivo/fisiopatología , Femenino , Lóbulo Frontal/química , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/fisiopatología

RESUMEN

Neuropathological and neuroimaging studies suggest neuronal dysfunction in schizophrenia. N-acetyl aspartate (NAA) is a useful marker of neuronal dysfunction that can be measured with magnetic resonance spectroscopy (MRS). In the present study NAA, choline (Cho), phospho-creatine ((P)Cr), inositol containing compounds and glutamine/glutamate (Glx) were assessed in the left frontal lobe and basal ganglia of subjects with familial schizophrenia, family members with mixed psychiatric diagnoses, unaffected family members, and community controls. Concentrations of metabolites were analyzed and expressed as ratios. NAA/Cho, NAA/(P)Cr and Glx containing compounds showed a negative correlation with age in the frontal lobe. After covarying for age, subjects with schizophrenia had a significant reduction in the left frontal lobe NAA/Cho ratio compared with unaffected family members (P=0.018) as well as with community non-familial (P=0.037) controls. These MRS observations support the hypothesis of a disease-related neuronal deficit in the frontal lobe of schizophrenic patients, and relatively normal basal ganglia.

Asunto(s)

Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Colina/metabolismo , Lóbulo Frontal/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , Adulto , Ganglios Basales/metabolismo , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Protones