RESUMO
Degeneration of basal forebrain cholinergic neurons (BFCNs) contributes to cognitive dysfunction in Alzheimer's disease (AD) and Down's syndrome (DS). We used Ts65Dn and Ts1Cje mouse models of DS to show that the increased dose of the amyloid precursor protein gene, App, acts to markedly decrease NGF retrograde transport and cause degeneration of BFCNs. NGF transport was also decreased in mice expressing wild-type human APP or a familial AD-linked mutant APP; while significant, the decreases were less marked and there was no evident degeneration of BFCNs. Because of evidence suggesting that the NGF transport defect was intra-axonal, we explored within cholinergic axons the status of early endosomes (EEs). NGF-containing EEs were enlarged in Ts65Dn mice and their App content was increased. Our study thus provides evidence for a pathogenic mechanism for DS in which increased expression of App, in the context of trisomy, causes abnormal transport of NGF and cholinergic neurodegeneration.
Assuntos
Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/metabolismo , Fibras Colinérgicas/patologia , Síndrome de Down/fisiopatologia , Degeneração Neural/metabolismo , Fator de Crescimento Neural/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/biossíntese , Precursor de Proteína beta-Amiloide/genética , Animais , Transporte Axonal/genética , Núcleo Basal de Meynert/metabolismo , Núcleo Basal de Meynert/patologia , Núcleo Basal de Meynert/fisiopatologia , Fibras Colinérgicas/metabolismo , Modelos Animais de Doenças , Síndrome de Down/genética , Síndrome de Down/metabolismo , Endossomos/genética , Endossomos/metabolismo , Endossomos/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Degeneração Neural/genética , Degeneração Neural/fisiopatologia , Fator de Crescimento Neural/genética , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Transporte Proteico/genética , Regulação para Cima/genéticaRESUMO
Down syndrome is characterized by a host of behavioral abnormalities including sleep disturbances. Sleep and EEG was studied at the age of 3 months in two mouse models of the condition, Ts65Dn and Ts1Cje, carrying one extra copy of partially overlapping segments of the mmu chromosome 16 (equivalent to the human chromosome 21). We found that the Ts65Dn mice showed increased waking amounts at the expense of non-REM sleep, increased theta power during sleep and a delayed sleep rebound after sleep deprivation. In contrast, Ts1Cje had limited sleep and EEG abnormalities, showing only a delayed sleep rebound after sleep deprivation and no difference in theta power. We previously found that mice over-expressing the human APPwt transgene, a gene triplicated in Ts65Dn but not Ts1Cje, also show increased wake and theta power during sleep. These results demonstrate abnormalities in sleep and EEG in Ts65Dn mice and underscore a possible correlation between App overexpression and hippocampal theta oscillations.
Assuntos
Modelos Animais de Doenças , Síndrome de Down/genética , Síndrome de Down/fisiopatologia , Eletroencefalografia , Sono/fisiologia , Análise de Variância , Animais , Eletromiografia , Análise de Fourier , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Deleção de Sequência , Sono/genética , Privação do Sono/fisiopatologia , TrissomiaRESUMO
Down syndrome (DS) is a neurological disorder causing impaired learning and memory. Partial trisomy 16 mice (Ts65Dn) are a genetic model for DS. Previously, we demonstrated widespread alterations of pre- and postsynaptic elements and physiological abnormalities in Ts65Dn mice. The average diameter of presynaptic boutons and spines in the neocortex and hippocampus was enlarged. Failed induction of long-term potentiation (LTP) due to excessive inhibition was observed. In this paper we investigate the morphological substrate for excessive inhibition in Ts65Dn. We used electron microscopy (EM) to characterize synapses, confocal microscopy to analyze colocalization of the general marker for synaptic vesicle protein with specific protein markers for inhibitory and excitatory synapses, and densitometry to characterize the distribution of the receptor and several proteins essential for synaptic clustering of neurotransmitter receptors. EM analysis of synapses in the Ts65Dn vs. 2N showed that synaptic opposition lengths were significantly greater for symmetric synapses (approximately 18%), but not for asymmetric ones. Overall, a significant increase in colocalization coefficients of glutamic acid decarboxylase (GAD)65/p38 immunoreactivity (IR) (approximately 27%) and vesicular GABA transporter (VGAT)/p38 IR (approximately 41%) was found, but not in vesicular glutamate transporter 1 (VGLUT1)/p38 IR. A significant overall decrease of IR in the hippocampus of Ts65Dn mice compared with 2N mice for glutamate receptor 2 (GluR2; approximately 13%) and anti-gamma-aminobutyric acid (GABA)(A) receptor beta2/3 subunit (approximately 20%) was also found. The study of proteins essential for synaptic clustering of receptors revealed a significant increase in puncta size for neuroligin 2 (approximately 13%) and GABA(A) receptor-associated protein (GABARAP; approximately 13%), but not for neuroligin 1 and gephyrin. The results demonstrate a significant alteration of inhibitory synapses in the fascia dentata of Ts65Dn mice.
Assuntos
Giro Denteado , Modelos Animais de Doenças , Síndrome de Down , Terminações Pré-Sinápticas/ultraestrutura , Sinapses/ultraestrutura , Animais , Biomarcadores/metabolismo , Proteínas de Transporte/metabolismo , Moléculas de Adesão Celular Neuronais , Espinhas Dendríticas/patologia , Espinhas Dendríticas/ultraestrutura , Giro Denteado/citologia , Giro Denteado/metabolismo , Síndrome de Down/metabolismo , Síndrome de Down/patologia , Feminino , Glutamato Descarboxilase/metabolismo , Humanos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Moléculas de Adesão de Célula Nervosa/metabolismo , Fragmentos de Peptídeos/metabolismo , Terminações Pré-Sinápticas/patologia , Receptores de GABA/metabolismo , Receptores de Glutamato/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Sinapses/patologia , Sinaptofisina/metabolismo , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismoRESUMO
We describe recent advances in the understanding of patterning in the vertebrate post-cranial mesoderm. Specifically, we discuss the integration of local information into global level information that results in the overall coordination along the anterioposterior axis. Experiments related to the integration of the axial and appendicular musculoskeletal systems are considered, and examples of genetic interactions between these systems are outlined. We emphasize the utility of the terms primaxial and abaxial as an aid to understanding development of the vertebrate musculoskeletal system, and hypothesize that the lateral somitic frontier is a catalyst for evolutionary change.