RESUMO
The cellular, molecular, and metabolic mechanisms that underlie the development of mesial temporal lobe epilepsy are incompletely understood. Here we review the role of astrocytes in epilepsy development (a.k.a. epileptogenesis), particularly astrocyte pathologies related to: aquaporin 4, the inwardly rectifying potassium channel Kir4.1, monocarboxylate transporters MCT1 and MCT2, excitatory amino acid transporters EAAT1 and EAAT2, and glutamine synthetase. We propose that inhibition, dysfunction or loss of astrocytic glutamine synthetase is an important causative factor for some epilepsies, particularly mesial temporal lobe epilepsy and glioblastoma-associated epilepsy. We postulate that the regulatory mechanisms of glutamine synthetase as well as the downstream effects of glutamine synthetase dysfunction, represent attractive, new targets for antiepileptogenic interventions. Currently, no antiepileptogenic therapies are available for human use. The discovery of such interventions is important as it will fundamentally change the way we approach epilepsy by preventing the disease from ever becoming manifest after an epileptogenic insult to the brain.
Assuntos
Astrócitos/fisiologia , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Epilepsia do Lobo Temporal/enzimologia , Glutamato-Amônia Ligase/metabolismo , Animais , Astrócitos/enzimologia , Epilepsia do Lobo Temporal/fisiopatologia , Glutamato-Amônia Ligase/deficiência , HumanosRESUMO
Deposition of ß -amyloid (Aß) peptides, cleavage products of ß-amyloid precursor protein (APP) by ß-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer's disease (AD). γ-Secretase inhibition is a therapeutical anti-Aß approach, although changes in the enzyme's activity in AD brain are unclear. Cerebrospinal fluid (CSF) Aß peptides are thought to derive from brain parenchyma and thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aß efficacy. The present study compared active γ-secretase binding sites with Aß deposition in aged and AD human cerebrum, and explored the possibility of Aß production and secretion by the choroid plexus (CP). The specific binding density of [(3) H]-L-685,458, a radiolabeled high-affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with similar ages and post-mortem delays. The CP in post-mortem samples exhibited exceptionally high [(3) H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and ß-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins and released Aß40 and Aß42 into the medium. Overall, our results suggest that γ-secretase activity appears unaltered in the cerebrum in AD and is not correlated with regional amyloid plaque pathology. The CP appears to be a previously unrecognised non-neuronal contributor to CSF Aß, probably at reduced levels in AD.
Assuntos
Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Cérebro/metabolismo , Plexo Corióideo/metabolismo , Fragmentos de Peptídeos/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Ligação Proteica , Ensaio Radioligante , Ratos , Ratos Sprague-DawleyRESUMO
A considerable number of cells expressing typical immature neuronal markers including doublecortin (DCX+) are present around layer II in the cerebral cortex of young and adult guinea pigs and other larger mammals, and their origin and biological implication await further characterization. We show here in young adult guinea pigs that these DCX+ cells are accompanied by in situ cell division around the superficial cortical layers mostly in layer I, but they co-express proliferating cell nuclear antigen (PCNA) and an early neuronal fate determining factor, PAX6. A small number of these DCX+ cells also colocalize with BrdU following administration of this mitotic indicator. Cranial X-ray irradiation causes a decline of DCX+ cells around layer II, and novel environmental exploration induces c-Fos expression among these cells in several neocortical areas. Together, these data are compatible with a notion that DCX+ cortical neurons around layer II might derive from proliferable neuronal precursors around layer I in young adult guinea pig cerebrum, and that these cells might be modulated by experience under physiological conditions.
Assuntos
Cérebro/fisiologia , Neocórtex/fisiologia , Neurogênese , Animais , Divisão Celular , Cérebro/citologia , Cérebro/efeitos da radiação , Proteínas do Domínio Duplacortina , Proteínas do Olho/análise , Cobaias , Proteínas de Homeodomínio/análise , Proteínas Associadas aos Microtúbulos/metabolismo , Neocórtex/citologia , Neocórtex/efeitos da radiação , Proteínas do Tecido Nervoso/análise , Neuropeptídeos/metabolismo , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/análise , Antígeno Nuclear de Célula em Proliferação/análise , Proteínas Proto-Oncogênicas c-fos/análise , Proteínas Repressoras/análiseRESUMO
An age-related decrease in hippocampal metabolism correlates with cognitive decline. Hippocampus-dependent learning and memory requires glutamatergic neurotransmission supported by glutamate-glutamine (GLU-GLN) cycling between neurons and astrocytes. We examined whether GLU-GLN cycling in hippocampal subregions (dentate gyrus and CA1) in Fischer 344 rats was altered with age and cognitive status. Hippocampal slices from young adult, aged cognitively-unimpaired (AU) and aged cognitively-impaired (AI) rats were incubated in artificial cerebrospinal fluid (aCSF) containing 1-13C-glucose to assess neural metabolism. Incorporation of 13C-glucose into glutamate and glutamine, measured by mass spectroscopy/liquid chromatography tandem mass spectroscopy, did not significantly differ between groups. However, when 13C-acetate, a preferential astrocytic metabolite, was used, a significant increase in 13C-labeled glutamate was observed in slices from AU rats. Taken together, the data suggest that resting state neural metabolism and GLU-GLN cycling may be preserved during aging when sufficient extracellular glucose is available, but that enhanced astroglial metabolism can occur under resting state conditions. This may be an aging-related compensatory change to maintain hippocampus-dependent cognitive function.
Assuntos
Envelhecimento/metabolismo , Envelhecimento/psicologia , Astrócitos/metabolismo , Glucose/metabolismo , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Memória , Aprendizagem Espacial , Animais , Cognição , Masculino , Neurônios/metabolismo , Ratos Endogâmicos F344RESUMO
Alzheimer's disease (AD) is the most common dementia-causing disorder in the elderly; it may be related to multiple risk factors, and is characterized pathologically by cerebral hypometabolism, paravascular ß-amyloid peptide (Aß) plaques, neuritic dystrophy, and intra-neuronal aggregation of phosphorylated tau. To explore potential pathogenic links among some of these lesions, we examined ß-secretase-1 (BACE1) alterations relative to Aß deposition, neuritic pathology and vascular organization in aged monkey and AD human cerebral cortex. Western blot analyses detected increased levels of BACE1 protein and ß-site-cleavage amyloid precursor protein C-terminal fragments in plaque-bearing human and monkey cortex relative to controls. In immunohistochemistry, locally elevated BACE1 immunoreactivity (IR) occurred in AD but not in control human cortex, with a trend for increased overall density among cases with greater plaque pathology. In double-labeling preparations, BACE1 IR colocalized with immunolabeling for Aß but not for phosphorylated tau. In perfusion-fixed monkey cortex, locally increased BACE1 IR co-existed with intra-axonal and extracellular Aß IR among virtually all neuritic plaques, ranging from primitive to typical cored forms. This BACE1 labeling localized to swollen/sprouting axon terminals that might co-express one or another neuronal phenotype markers (GABAergic, glutamatergic, cholinergic, or catecholaminergic). Importantly, these BACE1-labeled dystrophic axons resided near to or in direct contact with blood vessels. These findings suggest that plaque formation in AD or normal aged primates relates to a multisystem axonal pathogenesis that occurs in partnership with a potential vascular or metabolic deficit. The data provide a mechanistic explanation for why senile plaques are present preferentially near the cerebral vasculature.
Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Vasos Sanguíneos/patologia , Córtex Cerebral/enzimologia , Córtex Cerebral/patologia , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/ultraestrutura , Complexo IV da Cadeia de Transporte de Elétrons , Feminino , Regulação da Expressão Gênica/fisiologia , Humanos , Macaca mulatta , Masculino , Peso Molecular , NADPH Desidrogenase , Proteínas do Tecido Nervoso/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Placa Amiloide/ultraestrutura , Mudanças Depois da Morte , Terminações Pré-Sinápticas/metabolismo , Terminações Pré-Sinápticas/patologia , Coloração pela Prata/métodos , Estatísticas não Paramétricas , Proteínas tau/metabolismoRESUMO
Cerebral hypometabolism and amyloid accumulation are principal neuropathological manifestations of Alzheimer's disease (AD). Whether and how brain/neuronal activity might modulate certain pathological processes of AD are interesting topics of recent clinical and basic research in the field, and may be of potential medical relevance in regard to both the disease etiology and intervention. Using the Tg2576 transgenic mouse model of AD, this study characterized a promotive effect of neuronal hypoactivity associated with functional deprivation on amyloid plaque pathogenesis in the olfactory pathway. Unilateral naris-occlusion caused beta-secretase-1 (BACE1) elevation in neuronal terminals in the deprived relative to the non-deprived bulb and piriform cortex in young adult mice. In parallel with the overall age-related plaque development in the forebrain, locally increased BACE1 immunoreactivity co-occurred with amyloid deposition first in the piriform cortex then within the bulb, more prominent on the deprived relative to the non-deprived side. Biochemical analyses confirmed elevated BACE1 protein levels, enzymatic activity and products in the deprived relative to non-deprived bulbs. Plaque-associated BACE1 immunoreactivity in the bulb and piriform cortex was localized preferentially to swollen/sprouting glutamatergic axonal terminals, with Abeta immunoreactivity occurring inside as well as around these terminals. Together, these findings suggest that functional deprivation or neuronal hypoactivity facilitates amyloid plaque formation in the forebrain in a transgenic model of AD, which operates synergistically with age effect. The data also implicate an intrinsic association of amyloid accumulation and plaque formation with progressive axonal pathology.
Assuntos
Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Bulbo Olfatório/metabolismo , Condutos Olfatórios/metabolismo , Placa Amiloide/metabolismo , Fatores Etários , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , NADPH Desidrogenase/metabolismo , Neurônios/metabolismo , Nariz/patologia , Bulbo Olfatório/patologia , Condutos Olfatórios/patologia , Terminações Pré-Sinápticas/metabolismo , Regulação para CimaRESUMO
The presence of neuritic plaques is a pathological hallmark of Alzheimer's disease (AD). However, the origin of extracellular beta-amyloid peptide (Abeta) deposits and the process of plaque development remain poorly understood. The present study attempted to explore plaque pathogenesis by localizing beta-secretase-1 (BACE1) elevation relative to Abeta accumulation and synaptic/neuritic alterations in the forebrain, using transgenic mice harboring familial AD (FAD) mutations (5XFAD and 2XFAD) as models. In animals with fully developed plaque pathology, locally elevated BACE1 immunoreactivity (IR) coexisted with compact-like Abeta deposition, with BACE1 IR occurring selectively in dystrophic axons of various neuronal phenotypes or origins (GABAergic, glutamatergic, cholinergic or catecholaminergic). Prior to plaque onset, localized BACE1/Abeta IR occurred at swollen presynaptic terminals and fine axonal processes. These BACE1/Abeta-containing axonal elements appeared to undergo a continuing process of sprouting/swelling and dystrophy, during which extracellular Abeta IR emerged and accumulated in surrounding extracellular space. These data suggest that BACE1 elevation and associated Abeta overproduction inside the sprouting/dystrophic axonal terminals coincide with the onset and accumulation of extracellular amyloid deposition during the development of neuritic plaques in transgenic models of AD. Our findings appear to be in harmony with an early hypothesis that axonal pathogenesis plays a key or leading role in plaque formation.
Assuntos
Doença de Alzheimer/fisiopatologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Axônios/fisiologia , Placa Amiloide/fisiologia , Prosencéfalo/fisiopatologia , Sinapses/fisiologia , Envelhecimento , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Ácido Aspártico Endopeptidases/genética , Axônios/patologia , Espaço Extracelular/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mutação , Neurônios/patologia , Neurônios/fisiologia , Placa Amiloide/patologia , Presenilina-1/genética , Terminações Pré-Sinápticas/patologia , Terminações Pré-Sinápticas/fisiologia , Prosencéfalo/patologia , Nexinas de Proteases , Receptores de Superfície Celular/genética , Sinapses/patologiaRESUMO
Several studies have demonstrated that mouse models of Alzheimer's disease (AD) can exhibit impaired peripheral glucose tolerance. Further, in the APP/PS1 mouse model, this is observed prior to the appearance of AD-related neuropathology (e.g., amyloid-ß plaques; Aß) or cognitive impairment. In the current study, we examined whether impaired glucose tolerance also preceded AD-like changes in the triple transgenic model of AD (3xTg-AD). Glucose tolerance testing (GTT), insulin ELISAs, and insulin tolerance testing (ITT) were performed at ages prior to (1-3 months and 6-8 months old) and post-pathology (16-18 months old). Additionally, we examined for altered insulin signaling in the hippocampus. Western blots were used to evaluate the two-primary insulin signaling pathways: PI3K/AKT and MAPK/ERK. Since the PI3K/AKT pathway affects several downstream targets associated with metabolism (e.g., GSK3, glucose transporters), western blots were used to examine possible alterations in the expression, translocation, or activation of these targets. We found that 3xTg-AD mice display impaired glucose tolerance as early as 1 month of age, concomitant with a decrease in plasma insulin levels well prior to the detection of plaques (â¼14 months old), aggregates of hyperphosphorylated tau (â¼18 months old), and cognitive decline (≥18 months old). These alterations in peripheral metabolism were seen at all time points examined. In comparison, PI3K/AKT, but not MAPK/ERK, signaling was altered in the hippocampus only in 18-20-month-old 3xTg-AD mice, a time point at which there was a reduction in GLUT3 translocation to the plasma membrane. Taken together, our results provide further evidence that disruptions in energy metabolism may represent a foundational step in the development of AD.
Assuntos
Doença de Alzheimer/metabolismo , Intolerância à Glucose/metabolismo , Transportador de Glucose Tipo 3/metabolismo , Hipocampo/metabolismo , Insulina/sangue , Proteínas Proto-Oncogênicas c-akt/metabolismo , Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Progressão da Doença , Intolerância à Glucose/patologia , Intolerância à Glucose/psicologia , Transportador de Glucose Tipo 4/metabolismo , Hipocampo/patologia , Humanos , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pâncreas/metabolismo , Pâncreas/patologia , Fosforilação , Plasma/metabolismoRESUMO
Epidemiological data have shown that metabolic disease can increase the propensity for developing cognitive decline and dementia, particularly Alzheimer's disease (AD). While this interaction is not completely understood, clinical studies suggest that both hyper- and hypoinsulinemia are associated with an increased risk for developing AD. Indeed, insulin signaling is altered in post-mortem brain tissue from AD patients and treatments known to enhance insulin signaling can improve cognitive function. Further, clinical evidence has shown that AD patients and mouse models of AD often display alterations in peripheral metabolism. Since insulin is primarily derived from the periphery, it is likely that changes in peripheral insulin levels lead to alterations in central nervous system (CNS) insulin signaling and could contribute to cognitive decline and pathogenesis. Developing a better understanding of the relationship between alterations in peripheral metabolism and cognitive function might provide a foundation for the development of better treatment options for patients with AD. In this article we will begin to piece together the present data defining this relationship by briefly discussing insulin signaling in the periphery and CNS, its role in cognitive function, insulin's relationship to AD, peripheral metabolic alterations in mouse models of AD and how information from these models helps understand the mechanisms through which these changes potentially lead to impairments in insulin signaling in the CNS, and potential ways to target insulin signaling that could improve cognitive function in AD. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'
Assuntos
Doença de Alzheimer/metabolismo , Receptor de Insulina/metabolismo , Animais , Humanos , Insulina/metabolismoRESUMO
BACKGROUND: Alzheimer's disease (AD) is a devastating neurodegenerative disorder bearing multiple pathological hallmarks suggestive of complex cellular/molecular interplay during pathogenesis. Transgenic mice and nonhuman primates are used as disease models for mechanistic and translational research into AD; the extent to which these animal models recapitulate AD-type neuropathology is an issue of importance. Putative C-terminal fragments from sortilin, a member of the vacuolar protein sorting 10 protein (Vps10p) family, have recently been shown to deposit in the neuritic ß-amyloid (Aß) plaques in the human brain. METHODS: We set out to explore if extracellular sortilin neuropathology exists in AD-related transgenic mice and nonhuman primates. Brains from different transgenic strains and ages developed overt cerebral Aß deposition, including the ß-amyloid precursor protein and presenilin 1 double-transgenic (APP/PS1) mice at ~ 14 months of age, the five familial Alzheimer's disease mutations transgenic (5×FAD) mice at ~ 8 months, the triple-transgenic Alzheimer's disease (3×Tg-AD) mice at ~ 22 months, and aged monkeys (Macaca mulatta and Macaca fascicularis) were examined. Brain samples from young transgenic mice, middle-aged/aged monkeys, and AD humans were used as negative and positive pathological controls. RESULTS: The C-terminal sortilin antibody, which labeled senile plaques in the AD human cerebral sections, did not display extracellular immunolabeling in the transgenic mouse or aged monkey brain sections with Aß deposition. In Western blot analysis, sortilin fragments ~ 15 kDa were not detectable in transgenic mouse cortical lysates, but they occurred in control AD lysates. CONCLUSIONS: In reference to their human brain counterparts, neuritic plaques seen in transgenic AD model mouse brains represent an incomplete form of this AD pathological hallmark. The species difference in neuritic plaque constituents also indicates more complex secondary proteopathies in the human brain relative to rodents and nonhuman primates during aging and in AD.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Líquido Extracelular/metabolismo , Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Ácido Aspártico Endopeptidases/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/fisiologia , Humanos , Macaca mulatta , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Presenilina-1/genética , Proteínas tau/metabolismoRESUMO
The availability of human hippocampi obtained through surgery (usually for treatment of temporal lobe epilepsy) has allowed us to investigate the properties of the human dentate in a way that cannot be done with other brain regions. The dentate has been the primary focus of these studies because of its relative preservation in all patient specimens. Moreover, there is extensive synaptic reorganization of numerous neurotransmitter systems in this the fascia dentate (dentate gyrus and the hilus) in humans with specific forms of TLE. These changes are not evident in tissue from patients with seizure that begin outside the hippocampus, and, as a result, this tissue provides an invaluable resource for comparisons. Physiological data using both slices and acutely dissociated cells demonstrate that the granule cells have membrane properties similar to those of rodents although there are specific changes that appear to be associated with seizures. Similarly, in the non-sclerotic hippocampi, the synaptic properties are similar to those reported in rodents. There are also a number of parallels between the findings in humans and in status animal models of temporal lobe epilepsy. This review will cover analyses of membrane properties as well as of glutamatergic, GABAergic, and neuromodulatory systems. Thus, while there are a number of issues that invariably arise with studies of pathological human tissue, this tissue is ideally suited to verify and refine animal models of temporal lobe epilepsy. In addition, one can argue that human tissue provides the only resource to evaluate the ways that granule cells recorded from laboratory animals approximate human granule cell physiology.
Assuntos
Giro Denteado/citologia , Neurônios/fisiologia , Humanos , Canais Iônicos/fisiologia , Potenciais da Membrana/fisiologia , Sinapses/fisiologiaRESUMO
The central nervous system (CNS) undergoes a variety of anatomic, physiologic, and behavioral changes during aging. One region that has received a great deal of attention is the hippocampal formation due to the increased incidence of impaired spatial learning and memory with age. The hippocampal formation is also highly susceptible to Alzheimer's disease, ischemia/hypoxia, and seizure generation, the three most common aging-related neurological disorders. While data reveal that the dentate gyrus plays a key role in hippocampal function and dysfunction, the majority of electrophysiological studies that have examined the effects of age on the hippocampal formation have focused on CA3 and CA1. We perceive this to be an oversight and consequently will highlight data in this review which demonstrate an age-related disruption in dentate circuitry and function, and propose that these changes contribute to the decline in hippocampal-dependent behavior seen with "normal" aging.
Assuntos
Envelhecimento/fisiologia , Giro Denteado/anatomia & histologia , Giro Denteado/fisiologia , Rede Nervosa/fisiologia , Animais , Humanos , Aprendizagem/fisiologia , Rede Nervosa/citologiaRESUMO
Cognitive function declines with age and appears to correlate with decreased cerebral metabolic rate (CMR). Caloric restriction, an antiaging manipulation that extends life-span and can preserve cognitive function, is associated with decreased glucose uptake, decreased lactate levels, and increased ketone body (KB) levels in the brain. Since the majority of brain nutrients come from the periphery, this study examined whether the capacity to regulate peripheral glucose levels and KB production differs in animals with successful cognitive aging (growth hormone receptor knockouts, GHRKOs) versus unsuccessful cognitive aging (the 3xTg-AD mouse model of Alzheimer's disease). Animals were fasted for 5 hours with their plasma glucose and KB levels subsequently measured. Intriguingly, in GHRKO mice, compared to those in controls, fasting plasma glucose levels were significantly decreased while their KB levels were significantly increased. Conversely, 3xTg-AD mice, compared to controls, exhibited significantly elevated plasma glucose levels and significantly reduced plasma KB levels. Taken together, these results suggest that the capacity to provide the brain with KBs versus glucose throughout an animal's life could somehow help preserve cognitive function with age, potentially through minimizing overall brain exposure to reactive oxygen species and advanced glycation end products and improving mitochondrial function.
RESUMO
Alzheimer's disease (AD) is the primary cause of dementia in the elderly. The cause of the disease is still unknown, but amyloid plaques and neurofibrillary tangles in the brain are thought to play a role. However, transgenic mouse models expressing these neuropathological features do not show severe or consistent cognitive impairments. There is accumulating evidence that diabetes increases the risk for developing AD. We tested the hypothesis that experimentally induced diabetes would exacerbate cognitive symptoms in a mouse model of AD. Diabetes was induced in 12-month old 3xTg mice using streptozotocin (STZ; 90mg/kg, i.p., on two successive days). Hyperglycemia was verified by sampling blood glucose levels. Three months after injection (at 15 months of age), the mice were behaviorally tested in the Morris water maze and contextual fear conditioning. Subsequently, the hippocampal region was examined using immunohistochemistry (6E10 antibody for amyloid) and immunoblotting (AT8 antibody for phosphorylated tau). No differences were found in learning or memory between the vehicle-treated control and STZ-treated groups. A significant increase in the number of amyloid-positive plaques was observed in the subiculum of STZ-treated mice; very few plaques were seen in other hippocampal regions in either group. No differences in AT8 load were observed. These results reinforce that amyloid plaques, per se, are not sufficient to cause memory impairments. Further, while diabetes can enhance this aspect of brain pathology, the combination of disrupted glucose metabolism and the transgenes is still not sufficient to cause the severe cognitive impairments associated with clinical AD.
Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/psicologia , Aprendizagem , Memória , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Western Blotting , Encéfalo/metabolismo , Diabetes Mellitus Experimental/metabolismo , Imuno-Histoquímica , Aprendizagem/fisiologia , Masculino , Memória/fisiologia , Camundongos Transgênicos , Testes Neuropsicológicos , Proteínas tau/metabolismoRESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by beta-amyloid (Aß) deposition, neurofibrillary tangles and cognitive decline. Clinical data suggests that both type 1 and type 2 diabetes are risk factors for AD-related dementia and several clinical studies have demonstrated that AD patients show alterations in peripheral glucose regulation characterized by insulin resistance (hyperinsulinemia) or hypoinsulinemia. Whether animal models of AD exhibit a pre-diabetic phenotype without additional dietary or experimental manipulation is unclear however, with contradictory data available. Further, most studies have not examined the time course of potential pre-diabetic changes relative to AD pathogenesis and cognitive decline. Thus, in this study we tested the hypothesis that a pre-diabetic phenotype (peripheral metabolic dysregulation) exists in the APP/PS1 transgenic model of AD under normal conditions and precedes AD-related pathology. Specifically, we examined glucose tolerance in male APP/PS1 mice on a C57BL/6J congenic background at 2, 4-6 and 8-9months of age by assessing fasting glucose levels, glucose tolerance, plasma insulin levels and insulin sensitivity as well as the development of pathological characteristics of AD and verified that our APP/PS1 mice develop cognitive impairment. Here we show that APP/PS1 mice, compared to wild-type controls, exhibit a significant impairment in glucose tolerance during an intraperitoneal glucose tolerance test (ipGTT) and a trend for increased fasting plasma insulin concentrations as early as 2months of age, while extracellular Aß1-42 deposition occurs later and cognitive decline exists at 8-9months of age. Moreover, APP/PS1 mice did not respond as well to exogenous insulin as the wild-type controls during an intraperitoneal insulin tolerance test (ipITT). Taken together, these data reveal that male APP/PS1 mice on a C57BL/6J congenic background exhibit a pre-diabetic phenotype prior to the development of AD-like pathology and that this metabolic deficit persists when they exhibit neuropathology and cognitive decline. This raises the question of whether altered glucose regulation and insulin production/secretion could contribute to AD pathogenesis.
Assuntos
Doença de Alzheimer/complicações , Disfunção Cognitiva/sangue , Hipocampo/patologia , Resistência à Insulina , Insulina/sangue , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Glicemia/análise , Modelos Animais de Doenças , Teste de Tolerância a Glucose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Placa Amiloide/patologia , Presenilina-1/genéticaRESUMO
The outcome of patients with traumatic brain injury (TBI) can be predicted by the extracellular potassium concentration and the change in energy homeostasis. In this study, the authors investigated the effects of high potassium concentrations on extracellular levels of glucose, pyruvate and lactate in the rat striatum. Applying artificial cerebrospinal fluid (ACSF) enriched with 120 mM potassium by reverse microdialysis leads to an increase in lactate and reduction in glucose and pyruvate. Consequently, the lactate to pyruvate ratio was also increased. These data are discussed in the context of recent studies on lactate/pyruvate conversion and the potential mechanisms whereby high potassium could affect this equilibrium. We conclude that ischemic-like events are unlikely to explain these K(+)-induced changes.
Assuntos
Glucose/metabolismo , Neostriado/metabolismo , Potássio/farmacologia , Animais , Ácido Láctico/metabolismo , Masculino , Microdiálise , Neostriado/efeitos dos fármacos , Ácido Pirúvico/metabolismo , Ratos , Ratos Endogâmicos F344RESUMO
Reeler mice are a model of cortical malformation with enhanced seizure susceptibility. Data suggest that the propensity to anesthesia-induced seizures may be enhanced in animal models with developmental anomalies. Consequently, reeler mice were monitored behaviorally before, during and after isoflurane anesthesia. During recovery, 12% of reeler homozygotes had class I/II seizures while the remaining 88% exhibited convulsive seizures entailing opisthotonus and forepaw drumming. Similar behavior was not observed in controls. These data reveal that reeler mice display isoflurane-induced seizures and provide support for the hypothesis that developmental anomalies may predispose the central nervous system to anesthesia-induced seizures.
Assuntos
Anestésicos Inalatórios/efeitos adversos , Córtex Cerebral/anormalidades , Isoflurano/efeitos adversos , Camundongos Mutantes Neurológicos , Convulsões/induzido quimicamente , Animais , Comportamento Animal , Modelos Animais de Doenças , Feminino , Genótipo , Masculino , Camundongos , Camundongos Mutantes Neurológicos/genética , Convulsões/genética , Especificidade da EspécieRESUMO
A PubMed search of the years 1965 to 2003 found only 30 articles that were directly related to modeling seizures or epilepsy in aged animals. This lack of research is disturbing but explainable because of the high cost of aged animals and their increasing infirmity. Many changes occur in the older brain: cell loss in the hippocampal formation, changes in long-term potentiation maintenance, alteration in kindling, increased susceptibility to status epilepticus, and neuronal damage from stroke. The effect of aging on voltage-gated sodium and calcium channels has not been studied sufficiently. With increasing numbers of elderly persons with epilepsy needing appropriate treatment, the need to better understand the basic mechanisms of epilepsy is crucial.
Assuntos
Envelhecimento/fisiologia , Anticonvulsivantes/farmacocinética , Epilepsia/fisiopatologia , Hipocampo/fisiopatologia , Convulsões/fisiopatologia , Idoso , Animais , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia/etiologia , Hipocampo/cirurgia , Humanos , Ratos , Acidente Vascular Cerebral/complicaçõesRESUMO
Human temporal lobe epilepsy (TLE) is associated with bioenergetic abnormalities including decreased phosphocreatine (PCr) normalized to ATP. The physiological consequences of these metabolic alterations have not been established. We hypothesized that impaired bioenergetics would correlate with alterations in physiological functions under conditions that strongly activate neural metabolism. We correlated several physiological variables obtained from epileptic human dentate granule cells studied in slices with hippocampal PCr/ATP measured using in vivo magnetic resonance spectroscopy. The physiological variables included: the ability to fire multiple action potentials in response to single stimuli, the inhibitory postsynaptic potential (IPSP) conductance and the responses to a 10 Hz, 10 s stimulus train. We noted a significant negative correlation between the ability to fire multiple spikes in response to single synaptic stimulation and PCr/ATP (P < 0.03) and a positive correlation between the IPSP conductance and PCr/ATP (P < 0.05). Finally, there was a strong correlation between PCr/ATP and the recovery of the membrane potential following a stimulus train (P < 0.01), with low PCr/ATP being associated with prolonged recovery times. These data suggest that the bioenergetic impairment seen in this tissue is associated with specific changes in excitatory and inhibitory neuronal responses to synchronized synaptic inputs.
Assuntos
Epilepsia do Lobo Temporal/fisiopatologia , Trifosfato de Adenosina/metabolismo , Adolescente , Adulto , Núcleos Cerebelares/fisiopatologia , Estimulação Elétrica , Metabolismo Energético , Epilepsia do Lobo Temporal/metabolismo , Potenciais Pós-Sinápticos Excitadores , Feminino , Humanos , Técnicas In Vitro , Espectroscopia de Ressonância Magnética/métodos , Masculino , Potenciais da Membrana , Pessoa de Meia-Idade , Fosfocreatina/metabolismoRESUMO
Neural stem/progenitor cells have been characterized at neurogenic sites in adult mammalian brain with various molecular markers. Here it has been demonstrated that Sp8, a transcription factor typically expressed among mature GABAergic interneurons, also labels putative neural precursors in adult guinea pig and human cerebrum. In guinea pigs, Sp8 immunoreactive (Sp8+) cells were localized largely in the superficial layers of the cortex including layer I, as well as the subventricular zone (SVZ) and subgranular zone (SGZ). Sp8+ cells at the SGZ showed little colocalization with mature and immature neuronal markers, but co-expressed neural stem cell markers including Sox2. Some layer I Sp8+ cells also co-expressed Sox2. The amount of Sp8+ cells in the dentate gyrus was maintained 2 weeks after X-ray irradiation, while that of doublecortin (DCX+) cells was greatly reduced. Mild ischemic insult caused a transient increase of Sp8+ cells in the SGZ and layer I, with the subgranular Sp8+ cells exhibited an increased colabeling for the mitotic marker Ki67 and pulse-chased bromodeoxyuridine (BrdU). Sp8+ cells in the dentate gyrus showed an age-related decline in guinea pigs, in parallel with the loss of DCX+ cells in the same region. In adult humans, Sp8+ cells exhibited comparable morphological features as seen in guinea pigs, with those at the SGZ and some in cortical layer I co-expressed Sox2. Together, these results suggested that Sp8 may label putative neural progenitors in guinea pig and human cerebrum, with the labeled cells in the SGZ appeared largely not mitotically active under normal conditions. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 939-955, 2016.