RESUMO
The nucleus accumbens (NAc) is central to motivation and action, exhibiting one of the highest densities of neuropeptide Y (NPY) in the brain. Within the NAc, NPY plays a role in reward and is involved in emotional behavior and in increasing alcohol and drug addiction and fat intake. Here, we examined NPY innervation and neurons of the NAc in humans and other anthropoid primates in order to determine whether there are differences among these various species that would correspond to behavioral or life history variables. We quantified NPY-immunoreactive axons and neurons in the NAc of 13 primate species, including humans, great apes, and monkeys. Our data show that the human brain is unique among primates in having denser NPY innervation within the NAc, as measured by axon length density to neuron density, even after accounting for brain size. Combined with our previous finding of increased dopaminergic innervation in the same region, our results suggest that the neurochemical profile of the human NAc appears to have rendered our species uniquely susceptible to neurophysiological conditions such as addiction. The increase in NPY specific to the NAc may represent an adaptation that favors fat intake and contributes to an increased vulnerability to eating disorders, obesity, as well as alcohol and drug dependence. Along with our findings for dopamine, these deeply rooted structural attributes of the human brain are likely to have emerged early in the human clade, laying the groundwork for later brain expansion and the development of cognitive and behavioral specializations.
Assuntos
Comportamento Aditivo , Núcleo Accumbens , Animais , Humanos , Neuropeptídeo Y , Encéfalo , Obesidade , Dopamina , EtanolRESUMO
Aging and neurodegenerative disorders, such as Alzheimer's disease (AD), trigger an immune response known as glial activation in the brain. Recent evidence indicates species differences in inflammatory responses to AD pathology, highlighting the need for additional comparative studies to further understand human-specific neuropathologies. In the present study, we report on the occurrence of astrogliosis, microglial activation, and their relationship with age and AD-like pathology in a cohort of male and female chimpanzees (Pan troglodytes). Chimpanzees with severe astrogliosis exhibited widespread upregulation of hypertrophic astrocytes immunoreactive for glial fibrillary acidic protein (GFAP) throughout all layers of the dorsolateral prefrontal cortex and a loss of the interlaminar palisade. In addition, extreme astrogliosis was associated with increased astrocyte density in the absence of significant microglial activation and AD lesions. A shift from decreased resting to increased phagocytotic microglia occurred with aging, although proliferation was absent and no changes in astrogliosis was observed. Vascular amyloid correlated with decreased astrocyte and microglia densities, while tau lesions were associated with morphological changes in microglia and greater total glia density and glia: neuron ratio. These results further our understanding of inflammatory processes within the chimpanzee brain and provide comparative data to improve our understanding of human aging and neuropathological processes.
Assuntos
Doença de Alzheimer , Animais , Masculino , Humanos , Feminino , Doença de Alzheimer/metabolismo , Pan troglodytes , Microglia/metabolismo , Gliose/patologia , Encéfalo/metabolismo , Astrócitos/metabolismoRESUMO
Several aspects of diabetes pathophysiology and complications result from hyperglycemia-induced alterations in the structure and function of plasma proteins. Furthermore, insulin has a significant influence on protein metabolism by affecting both the synthesis and degradation of proteins in various tissues. To understand the role of progressive hyperglycemia on plasma proteins, in this study, we measured the turnover rates of high-density lipoprotein (HDL)-associated proteins in control (chow diet), prediabetic [a high-fat diet (HFD) for 8 wk] or diabetic [HFD for 8 wk with low-dose streptozotocin (HFD + STZ) in weeks 5-8 of HFD] C57BL/6J mice using heavy water (2H2O)-based metabolic labeling approach. Compared with control mice, HFD and HFD + STZ mice showed elevations of fasting plasma glucose levels in the prediabetic and diabetic range, respectively. Furthermore, the HFD and HFD + STZ mice showed increased hepatic triglyceride (TG) levels, total plasma cholesterol, and plasma TGs. The kinetics of 40 proteins were quantified using the proteome dynamics method, which revealed an increase in the fractional synthesis rate (FSR) of HDL-associated proteins in the prediabetic mice compared with control mice, and a decrease in FSR in the diabetic mice. The pathway analysis revealed that proteins with altered turnover rates were involved in acute-phase response, lipid metabolism, and coagulation. In conclusion, prediabetes and diabetes have distinct effects on the turnover rates of HDL proteins. These findings suggest that an early dysregulation of the HDL proteome dynamics can provide mechanistic insights into the changes in protein levels in these conditions.NEW & NOTEWORTHY This study is the first to examine the role of gradual hyperglycemia during diabetes disease progression on HDL-associated protein dynamics in the prediabetes and diabetic mice. Our results show that the fractional synthesis rate of HDL-associated proteins increased in the prediabetic mice whereas it decreased in the diabetic mice compared with control mice. These kinetic changes can help to elucidate the mechanism of altered protein levels and HDL dysfunction during diabetes disease progression.
Assuntos
Diabetes Mellitus Experimental , Hiperglicemia , Estado Pré-Diabético , Camundongos , Animais , Estado Pré-Diabético/complicações , Lipoproteínas HDL , Diabetes Mellitus Experimental/induzido quimicamente , Glicemia/metabolismo , Proteoma , Camundongos Endogâmicos C57BL , Estreptozocina , Dieta Hiperlipídica , Hiperglicemia/metabolismo , Progressão da DoençaRESUMO
Inherited autosomal recessive mutations of the manganese (Mn) transporter gene SLC39A14 in humans, results in elevated blood and brain Mn concentrations and childhood-onset dystonia-parkinsonism. The pathophysiology of this disease is unknown, but the nigrostriatal dopaminergic system of the basal ganglia has been implicated. Here, we describe pathophysiological studies in Slc39a14-knockout (KO) mice as a preclinical model of dystonia-parkinsonism in SLC39A14 mutation carriers. Blood and brain metal concentrations in Slc39a14-KO mice exhibited a pattern similar to the human disease with highly elevated Mn concentrations. We observed an early-onset backward-walking behavior at postnatal day (PN) 21 which was also noted in PN60 Slc39a14-KO mice as well as dystonia-like movements. Locomotor activity and motor coordination were also impaired in Slc39a14-KO relative to wildtype (WT) mice. From a neurochemical perspective, striatal dopamine (DA) and metabolite concentrations and their ratio in Slc39a14-KO mice did not differ from WT. Striatal tyrosine hydroxylase (TH) immunohistochemistry did not change in Slc39a14-KO mice relative to WT. Unbiased stereological cell quantification of TH-positive and Nissl-stained estimated neuron number, neuron density, and soma volume in the substantia nigra pars compacta (SNc) was the same in Slc39a14-KO mice as in WT. However, we measured a marked inhibition (85-90%) of potassium-stimulated DA release in the striatum of Slc39a14-KO mice relative to WT. Our findings indicate that the dystonia-parkinsonism observed in this genetic animal model of the human disease is associated with a dysfunctional but structurally intact nigrostriatal dopaminergic system. The presynaptic deficit in DA release is unlikely to explain the totality of the behavioral phenotype and points to the involvement of other neuronal systems and brain regions in the pathophysiology of the disease.
Assuntos
Comportamento Animal , Proteínas de Transporte de Cátions/genética , Distonia/induzido quimicamente , Intoxicação por Manganês/metabolismo , Intoxicação por Manganês/psicologia , Doença de Parkinson Secundária/induzido quimicamente , Animais , Encéfalo/metabolismo , Dopamina/metabolismo , Distonia/genética , Feminino , Masculino , Intoxicação por Manganês/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Neostriado/metabolismo , Doença de Parkinson Secundária/genética , Desempenho Psicomotor , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
While humans exhibit a significant degree of neuropathological changes associated with deficits in cognitive and memory functions during aging, non-human primates (NHP) present with more variable expressions of pathological alterations among individuals and species. As such, NHP with long life expectancy in captivity offer an opportunity to study brain senescence in the absence of the typical cellular pathology caused by age-related neurodegenerative illnesses commonly seen in humans. Age-related changes at neuronal population, single cell, and synaptic levels have been well documented in macaques and marmosets, while age-related and Alzheimer's disease-like neuropathology has been characterized in additional species including lemurs as well as great apes. We present a comparative overview of existing neuropathologic observations across the primate order, including classic age-related changes such as cell loss, amyloid deposition, amyloid angiopathy, and tau accumulation. We also review existing cellular and ultrastructural data on neuronal changes, such as dendritic attrition and spine alterations, synaptic loss and pathology, and axonal and myelin pathology, and discuss their repercussions on cellular and systems function and cognition.
Assuntos
Envelhecimento , Encéfalo/patologia , Primatas , Doença de Alzheimer , Animais , Angiopatia Amiloide CerebralRESUMO
It has always been difficult to account for the evolution of certain human characters such as language, empathy, and altruism via individual reproductive success. However, the striatum, a subcortical region originally thought to be exclusively motor, is now known to contribute to social behaviors and "personality styles" that may link such complexities with natural selection. We here report that the human striatum exhibits a unique neurochemical profile that differs dramatically from those of other primates. The human signature of elevated striatal dopamine, serotonin, and neuropeptide Y, coupled with lowered acetylcholine, systematically favors externally driven behavior and greatly amplifies sensitivity to social cues that promote social conformity, empathy, and altruism. We propose that selection induced an initial form of this profile in early hominids, which increased their affiliative behavior, and that this shift either preceded or accompanied the adoption of bipedality and elimination of the sectorial canine. We further hypothesize that these changes were critical for increased individual fitness and promoted the adoption of social monogamy, which progressively increased cooperation as well as a dependence on tradition-based cultural transmission. These eventually facilitated the acquisition of language by elevating the reproductive advantage afforded those most sensitive to social cues.
Assuntos
Evolução Biológica , Corpo Estriado/fisiologia , Neuroquímica , Seleção Genética , Comportamento Social , Altruísmo , Animais , Cães , Humanos , Personalidade , Primatas , Conformidade SocialRESUMO
Inflammation arising from central and/or peripheral sources contributes to the pathogenesis of multiple neurodegenerative diseases including Parkinson's disease (PD). Emerging data suggest that differential activation of glia could lead to the pathogenesis and progression of PD. Here, we sought to determine the relationship between lipopolysaccharide (LPS) treatment, loss of dopaminergic neurons and differential activation of glia. Using a model of repeated injections with LPS (1mg/kg, i.p. for 4days), we found that LPS induced a 34% loss of dopamine neurons in the substantia nigra 19days after initiation of treatment, but no further cell loss was observed at 36days. LPS induced a strong pro-inflammatory response with increased mRNA expression of pro-inflammatory markers, including tumor necrosis factor-α (4.8-fold), inducible nitric oxide synthase (2.0-fold), interleukin-1 beta (8.9-fold), interleukin-6 (10.7-fold), and robust glial activation were observed at 1day after final dose of LPS. These pro-inflammatory genes were then reduced at 19days after treatment, when there was a rise in the anti-inflammatory genes Ym1 (1.8-fold) and arginase-1 (2.6-fold). Additionally, 36days after the last LPS injection there was a significant increase in interleukin-10 (2.1-fold) expression. The qPCR data results were supported by protein data, including cytokine measurements, western blotting, and immunofluorescence in brain microglia. Taken together, these data demonstrate that progressive neurodegeneration in the substantia nigra following LPS is likely arrested by microglia shifting to an anti-inflammatory phenotype. Thus, strategies to promote resolution of neuroinflammation may be a promising avenue to slow the progressive loss of dopamine neurons in PD.
Assuntos
Neurônios Dopaminérgicos/imunologia , Lipopolissacarídeos/toxicidade , Microglia/imunologia , Degeneração Neural/imunologia , Animais , Astrócitos/imunologia , Astrócitos/patologia , Morte Celular/fisiologia , Corpo Estriado/imunologia , Corpo Estriado/patologia , Citocinas/metabolismo , Progressão da Doença , Neurônios Dopaminérgicos/patologia , Inflamação/patologia , Inflamação/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/patologia , Degeneração Neural/patologia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia , Neuroimunomodulação/fisiologia , RNA Mensageiro/metabolismo , Distribuição Aleatória , Fatores de TempoRESUMO
Humans and chimpanzees are genetically similar and share a number of life history, behavioral, cognitive and neuroanatomical similarities. Notwithstanding, our understanding of age-related changes in cognitive and motor functions in chimpanzees remains largely unstudied despite recent evident demonstrating that chimpanzees exhibit many of the same neuropathological features of Alzheimer's disease observed in human postmortem brains. Here, we examined age-related differences in cognition and cortical thickness measured from magnetic resonance images in a sample of 215 chimpanzees ranging in age between 9 and 54 years. We found that chimpanzees showed global and region-specific thinning of cortex with increasing age. Further, within the elderly cohort, chimpanzees that performed better than average had thicker cortex in frontal, temporal and parietal regions compared to chimpanzees that performed worse than average. Independent of age, we also found sex differences in cortical thickness in 4 brain regions. Males had higher adjusted cortical thickness scores for the caudal anterior cingulate, rostral anterior cingulate, and medial orbital frontal while females had higher values for the inferior parietal cortex. We found no evidence that increasing age nor sex was associated with asymmetries in cortical thickness. Moreover, age-related differences in cognitive function were only weakly associated with asymmetries in cortical thickness. In summary, as has been reported in humans and other primates, elderly chimpanzees show thinner cortex and variation in cortical thickness is associated with general cognitive functions.
Assuntos
Doença de Alzheimer , Pan troglodytes , Animais , Humanos , Masculino , Feminino , Idoso , Lobo Parietal , Cognição , Encéfalo , Doença de Alzheimer/patologia , Imageamento por Ressonância Magnética/métodos , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologiaRESUMO
Over the last decade, several clinical reports have outlined cases of early-onset manganese (Mn)-induced dystonia-parkinsonism, resulting from loss of function mutations of the Mn transporter gene SLC39A14. Previously, we have performed characterization of the behavioral, neurochemical, and neuropathological changes in 60-day old (PN60) Slc39a14-knockout (KO) murine model of the human disease. Here, we extend our studies to aging Slc39a14-KO mice to assess the progression of the disease. Our results indicate that 365-day old (PN365) Slc39a14-KO mice present with markedly elevated blood and brain Mn levels, similar to those found in the PN60 mice and representative of the human cases of the disease. Furthermore, aging Slc39a14-KO mice consistently manifest a hypoactive and dystonic behavioral deficits, similar to the PN60 animals, suggesting that the behavioral changes are established early in life without further age-associated deterioration. Neurochemical, neuropathological, and functional assessment of the dopaminergic system of the basal ganglia revealed absence of neurodegenerative changes of dopamine (DA) neurons in the substantia nigra pars compacta (SNc), with no changes in DA or metabolite concentrations in the striatum of Slc39a14-KO mice relative to wildtype (WT). Similar to the PN60 animals, aging Slc39a14-KO mice expressed a marked inhibition of potassium-stimulated DA release in the striatum. Together our findings indicate that the pathophysiological changes observed in the basal ganglia of aging Slc39a14-KO animals are similar to those at PN60 and aging does not have a significant effect on these parameters.
Assuntos
Proteínas de Transporte de Cátions , Distonia , Transtornos Parkinsonianos , Animais , Camundongos , Humanos , Manganês/metabolismo , Camundongos Knockout , Distonia/induzido quimicamente , Distonia/genética , Distonia/metabolismo , Proteínas de Transporte de Cátions/genética , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Envelhecimento , Substância NegraRESUMO
Astrocytes are the main homeostatic cell of the brain involved in many processes related to cognition, immune response, and energy expenditure. It has been suggested that the distribution of astrocytes is associated with brain size, and that they are specialized in humans. To evaluate these, we quantified astrocyte density, soma volume, and total glia density in layer I and white matter in Brodmann's area 9 of humans, chimpanzees, baboons, and macaques. We found that layer I astrocyte density, soma volume, and ratio of astrocytes to total glia cells were highest in humans and increased with brain size. Overall glia density in layer I and white matter were relatively invariant across brain sizes, potentially due to their important metabolic functions on a per volume basis. We also quantified two transporters involved in metabolism through the astrocyte-neuron lactate shuttle, excitatory amino acid transporter 2 (EAAT2) and glucose transporter 1 (GLUT1). We expected these transporters would be increased in human brains due to their high rate of metabolic consumption and associated gene activity. While humans have higher EAAT2 cell density, GLUT1 vessel volume, and GLUT1 area fraction compared to baboons and chimpanzees, they did not differ from macaques. Therefore, EAAT2 and GLUT1 are not related to increased energetic demands of the human brain. Taken together, these data provide evidence that astrocytes play a unique role in both brain expansion and evolution among primates, with an emphasis on layer I astrocytes having a potentially significant role in human-specific metabolic processing and cognition.
Assuntos
Astrócitos , Transportador 2 de Aminoácido Excitatório , Animais , Humanos , Astrócitos/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Transportador de Glucose Tipo 1 , Pan troglodytes , Encéfalo/metabolismo , Córtex Pré-Frontal/metabolismo , Macaca/metabolismo , Papio , Lactatos/metabolismoRESUMO
Background: Dehydroepiandrosterone-sulfate is the most abundant circulating androgen in humans and other catarrhines. It is involved in several biological functions, such as testosterone production, glucocorticoid antagonist actions, neurogenesis and neuroplasticty. Although the role of dehydroepiandrosterone-sulfate (DHEAS) in cognition remains elusive, the DHEAS/cortisol ratio has been positively associated with a slower cognitive age-decline and improved mood in humans. Whether this relationship is found in nonhuman primates remains unknown. Methods: We measured DHEAS and cortisol levels in serum of 107 adult chimpanzees to investigate the relationship between DHEAS levels and age. A subset of 21 chimpanzees was used to test the potential associations between DHEAS, cortisol, and DHEAS/cortisol ratio in cognitive function, taking into account age, sex, and their interactions. We tested for cognitive function using the primate cognitive test battery (PCTB) and principal component analyses to categorize cognition into three components: spatial relationship tasks, tool use and social communication tasks, and auditory-visual sensory perception tasks. Results: DHEAS levels, but not the DHEAS/cortisol ratio, declined with age in chimpanzees. Our analyses for spatial relationships tasks revealed a significant, positive correlation with the DHEAS/cortisol ratio. Tool use and social communication had a negative relationship with age. Our data show that the DHEAS/cortisol ratio, but not DHEAS individually, is a promising predictor of spatial cognition in chimpanzees.
Assuntos
Hidrocortisona , Pan troglodytes , Adulto , Animais , Humanos , Sulfato de Desidroepiandrosterona , Esteroides , Cognição , SulfatosRESUMO
BACKGROUND: The interaction of aging-related, genetic, and environmental factors is thought to contribute to the etiology of late-onset, sporadic Alzheimer's disease (AD). We previously reported that serum levels of p,p'-dichlorodiphenyldichloroethylene (DDE), a long-lasting metabolite of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT), were significantly elevated in patients with AD and associated with the risk of AD diagnosis. However, the mechanism by which DDT may contribute to AD pathogenesis is unknown. OBJECTIVES: This study sought to assess effects of DDT exposure on the amyloid pathway in multiple in vitro and in vivo models. METHODS: Cultured cells (SH-SY5Y and primary neurons), transgenic flies overexpressing amyloid beta (Aß), and C57BL/6J and 3xTG-AD mice were treated with DDT to assess impacts on the amyloid pathway. Real time quantitative polymerase chain reaction, multiplex assay, western immunoblotting and immunohistochemical methods were used to assess the effects of DDT on amyloid precursor protein (APP) and other contributors to amyloid processing and deposition. RESULTS: Exposure to DDT revealed significantly higher APP mRNA and protein levels in immortalized and primary neurons, as well as in wild-type and AD-models. This was accompanied by higher levels of secreted Aß in SH-SY5Y cells, an effect abolished by the sodium channel antagonist tetrodotoxin. Transgenic flies and 3xTG-AD mice had more Aß pathology following DDT exposure. Furthermore, loss of the synaptic markers synaptophysin and PSD95 were observed in the cortex of the brains of 3xTG-AD mice. DISCUSSION: Sporadic Alzheimer's disease risk involves contributions from genetic and environmental factors. Here, we used multiple model systems, including primary neurons, transgenic flies, and mice to demonstrate the effects of DDT on APP and its pathological product Aß. These data, combined with our previous epidemiological findings, provide a mechanistic framework by which DDT exposure may contribute to increased risk of AD by impacting the amyloid pathway. https://doi.org/10.1289/EHP10576.
Assuntos
Doença de Alzheimer , Neuroblastoma , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , DDT/toxicidade , Diclorodifenil Dicloroetileno/toxicidade , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroblastoma/complicações , Neuroblastoma/patologiaRESUMO
Microglia are the primary immune cells of the central nervous system that help nourish and support neurons, clear debris, and respond to foreign stimuli. Greatly impacted by their environment, microglia go through rapid changes in cell shape, gene expression, and functional behavior during states of infection, trauma, and neurodegeneration. Aging also has a profound effect on microglia, leading to chronic inflammation and an increase in the brain's susceptibility to neurodegenerative processes that occur in Alzheimer's disease. Despite the scientific community's growing knowledge in the field of neuroinflammation, the overall success rate of drug treatment for age-related and neurodegenerative diseases remains incredibly low. Potential reasons for the lack of translation from animal models to the clinic include the use of a single species model, an assumption of similarity in humans, and ignoring contradictory data or information from other species. To aid in the selection of validated and predictive animal models and to bridge the translational gap, this review evaluates similarities and differences among species in microglial activation and density, morphology and phenotype, cytokine expression, phagocytosis, and production of oxidative species in aging and Alzheimer's disease.
Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Microglia/patologia , Animais , Evolução Molecular , HumanosRESUMO
Scavenger receptor CD36 contributes significantly to lipid homeostasis, inflammation, and amyloid deposition, while CD36 deficiency is associated with restored cerebrovascular function in an Alzheimer's disease (AD) mouse model. Yet the distribution of CD36 has not been examined in the brain. Here, we characterized CD36 gene and protein expression in the brains of young, middle aged, aged, and elderly male and female C57BL/6J mice. Age-related increases in CD36 mRNA expression were observed in the male hippocampus and female midbrain. Additionally, male mice had greater CD36 mRNA expression than females in the striatum, hippocampus, and midbrain. CD36 protein was primarily expressed intravascularly, and this expression differed by region, age, and sex in the mouse brain. Although male mice brains demonstrated an increase in CD36 protein with age in several cortices, basal ganglia, hippocampus, and midbrain, a decrease with age was observed in female mice in the same regions. These data suggest that distinctive age, region, and sex expression of CD36 in the brain may contribute to Aß deposition and neuroinflammation in AD.
Assuntos
Doença de Alzheimer/metabolismo , Antígenos CD36/metabolismo , Córtex Cerebral/metabolismo , Placa Amiloide/metabolismo , Caracteres Sexuais , Fatores Etários , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Antígenos CD36/genética , Córtex Cerebral/patologia , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Placa Amiloide/genética , Placa Amiloide/patologiaRESUMO
Williams syndrome (WS) is a rare neurodevelopmental disorder caused by the hemideletion of approximately 25-28 genes at 7q11.23. Its unusual social and cognitive phenotype is most strikingly characterized by the disinhibition of social behavior, in addition to reduced global IQ, with a relative sparing of language ability. Hypersociality and increased social approach behavior in WS may represent a unique inability to inhibit responses to specific social stimuli, which is likely associated with abnormalities of frontostriatal circuitry. The striatum is characterized by a diversity of interneuron subtypes, including inhibitory parvalbumin-positive interneurons (PV+) and excitatory cholinergic interneurons (Ch+). Animal model research has identified an important role for these specialized cells in regulating social approach behavior. Previous research in humans identified a depletion of interneuron subtypes associated with neuropsychiatric disorders. Here, we examined the density of PV+ and Ch+ interneurons in the striatum of 13 WS and neurotypical (NT) subjects. We found a significant reduction in the density of Ch+ interneurons in the medial caudate nucleus and nucleus accumbens, important regions receiving cortical afferents from the orbitofrontal and ventromedial prefrontal cortex, and circuitry involved in language and reward systems. No significant difference in the distribution of PV+ interneurons was found. The pattern of decreased Ch+ interneuron densities in WS differs from patterns of interneuron depletion found in other disorders.
Assuntos
Neurônios Colinérgicos/patologia , Corpo Estriado/patologia , Interneurônios/patologia , Síndrome de Williams/patologia , Adolescente , Adulto , Idoso , Colina O-Acetiltransferase/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Parvalbuminas/análise , Adulto JovemRESUMO
In the absence of disease, ageing in the human brain is accompanied by mild cognitive dysfunction, gradual volumetric atrophy, a lack of significant cell loss, moderate neuroinflammation, and an increase in the amyloid beta (Aß) and tau proteins. Conversely, pathologic age-related conditions, particularly Alzheimer's disease (AD), result in extensive neocortical and hippocampal atrophy, neuron death, substantial Aß plaque and tau-associated neurofibrillary tangle pathologies, glial activation and severe cognitive decline. Humans are considered uniquely susceptible to neurodegenerative disorders, although recent studies have revealed Aß and tau pathology in non-human primate brains. Here, we investigate the effect of age and AD-like pathology on cell density in a large sample of postmortem chimpanzee brains (n = 28, ages 12-62 years). Using a stereologic, unbiased design, we quantified neuron density, glia density and glia:neuron ratio in the dorsolateral prefrontal cortex, middle temporal gyrus, and CA1 and CA3 hippocampal subfields. Ageing was associated with decreased CA1 and CA3 neuron densities, while AD pathologies were not correlated with changes in neuron or glia densities. Differing from cerebral ageing and AD in humans, these data indicate that chimpanzees exhibit regional neuron loss with ageing but appear protected from the severe cell death found in AD. This article is part of the theme issue 'Evolution of the primate ageing process'.
Assuntos
Envelhecimento , Doença de Alzheimer/fisiopatologia , Contagem de Células , Hipocampo/fisiologia , Neurônios/fisiologia , Pan troglodytes/fisiologia , Córtex Pré-Frontal/fisiologia , Lobo Temporal/fisiologia , Doença de Alzheimer/patologia , Animais , Modelos Animais de Doenças , Feminino , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Masculino , Neuroglia , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Lobo Temporal/patologia , Lobo Temporal/fisiopatologiaRESUMO
Astrocytes are the main homeostatic cell of the central nervous system. In addition, astrocytes mediate an inflammatory response when reactive to injury or disease known as astrogliosis. Astrogliosis is marked by an increased expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Some degree of astrogliosis is associated with normal aging and degenerative conditions such as Alzheimer's disease (AD) and other dementing illnesses in humans. The recent observation of pathological markers of AD (amyloid plaques and neurofibrillary tangles) in aged chimpanzee brains provided an opportunity to examine the relationships among aging, AD-type pathology, and astrocyte activation in our closest living relatives. Stereologic methods were used to quantify GFAP-immunoreactive astrocyte density and soma volume in layers I, III, and V of the prefrontal and middle temporal cortex, as well as in hippocampal fields CA1 and CA3. We found that the patterns of astrocyte activation in the aged chimpanzee brain are distinct from humans. GFAP expression does not increase with age in chimpanzees, possibly indicative of lower oxidative stress loads. Similar to humans, chimpanzee layer I astrocytes in the prefrontal cortex are susceptible to AD-like changes. Both prefrontal cortex layer I and hippocampal astrocytes exhibit a high degree of astrogliosis that is positively correlated with accumulation of amyloid beta and tau proteins. However, unlike humans, chimpanzees do not display astrogliosis in other cortical layers. These results demonstrate a unique pattern of cortical aging in chimpanzees and suggest that inflammatory processes may differ between humans and chimpanzees in response to pathology.
Assuntos
Envelhecimento/patologia , Doença de Alzheimer/veterinária , Astrócitos/patologia , Encéfalo/patologia , Gliose/veterinária , Pan troglodytes/anatomia & histologia , Doenças dos Primatas/patologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/análise , Animais , Biomarcadores , Química Encefálica , Feminino , Proteína Glial Fibrilar Ácida/análise , Gliose/patologia , Masculino , Especificidade de Órgãos , Placa Amiloide/química , Placa Amiloide/patologia , Proteínas tau/análiseRESUMO
In Alzheimer's disease (AD), the brain's primary immune cells, microglia, become activated and are found in close apposition to amyloid beta (Aß) protein plaques and neurofibrillary tangles (NFT). The present study evaluated microglia density and morphology in a large group of aged chimpanzees (n = 20, ages 37-62 years) with varying degrees of AD-like pathology. Using immunohistochemical and stereological techniques, we quantified the density of activated microglia and morphological variants (ramified, intermediate, and amoeboid) in postmortem chimpanzee brain samples from prefrontal cortex, middle temporal gyrus, and hippocampus, areas that show a high degree of AD pathology in humans. Microglia measurements were compared to pathological markers of AD in these cases. Activated microglia were consistently present across brain areas. In the hippocampus, CA3 displayed a higher density than CA1. Aß42 plaque volume was positively correlated with higher microglial activation and with an intermediate morphology in the hippocampus. Aß42-positive vessel volume was associated with increased hippocampal microglial activation. Activated microglia density and morphology were not associated with age, sex, pretangle density, NFT density, or tau neuritic cluster density. Aged chimpanzees displayed comparable patterns of activated microglia phenotypes as well as an association of increased microglial activation and morphological changes with Aß deposition similar to AD patients. In contrast to human AD brains, activated microglia density was not significantly correlated with tau lesions. This evidence suggests that the chimpanzee brain may be relatively preserved during normal aging processes but not entirely protected from neurodegeneration as previously assumed.
Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Encéfalo/patologia , Microglia/patologia , Animais , Feminino , Masculino , Emaranhados Neurofibrilares/patologia , Pan troglodytes , Placa Amiloide/patologiaRESUMO
Parkinson's disease (PD) is the second most common age-related neurodegenerative disease. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a prototypical neurotoxicant used in mice to mimic primary features of PD pathology including striatal dopamine depletion and dopamine neuron loss in the substantia nigra pars compacta (SNc). In the literature, there are several experimental paradigms involving multiple doses of MPTP that are used to elicit dopamine neuron loss. However, a recent study reported that a single low dose caused significant loss of dopamine neurons. Here, we determined the effect of a single intraperitoneal injection of one of three doses of MPTP (0.1, 2 and 20mg/kg) on dopamine neurons, labeled by tyrosine hydroxylase (TH+), and total neuron number (Nissl+) in the SNc using unbiased stereological counting. Data reveal a significant loss of neurons in the SNc (TH+ and Nissl+) only in the group treated with 20mg/kg MPTP. Groups treated with lower dose of MPTP (0.1 and 2mg/kg) only showed significant loss of TH+ neurons rather than TH+ and Nissl+ neurons. Striatal dopamine levels were decreased in the groups treated with 2 and 20mg/kg MPTP and striatal terminal markers including, TH and the dopamine transporter (DAT), were only decreased in the groups treated with 20mg/kg MPTP. These data demonstrate that lower doses of MPTP likely result in loss of TH expression rather than actual dopamine neuron loss in the SN. This finding reinforces the need to measure both total neuron number along with TH+ cells in determining dopamine neuron loss.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/administração & dosagem , Corpo Estriado/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Substância Negra/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo , Animais , Catecolaminas/metabolismo , Contagem de Células , Corpo Estriado/metabolismo , Neurônios Dopaminérgicos/metabolismo , Intoxicação por MPTP , Masculino , Camundongos Endogâmicos C57BL , Substância Negra/metabolismoRESUMO
Cholinergic innervation of the basal ganglia is important in learning and memory. Striatal cholinergic neurons integrate cognitive and motivational states with behavior. Given these roles, it is not surprising that deficits in cortical cholinergic innervation have been correlated with loss of cognitive function in Alzheimer's disease and schizophrenia. Such evidence suggests the potential significance of subcortical cholinergic innervation in the evolution of the human brain. To compare humans with other closely related primates, the present study quantified axons and interneurons immunoreactive for choline acetyltransferase (ChAT) in regions of the executive and motor loops of the basal ganglia of humans, great apes, and monkeys. We also compared ChAT-immunoreactive (ir) interneuron morphological types among species within striatal regions. The results indicate that humans and great apes differ from monkeys in having a preponderance of multipolar ChAT-ir interneurons in the caudate nucleus and putamen, whereas monkeys have a more heterogeneous representation of multipolar, bipolar, and unipolar interneurons. Cholinergic innervation, as measured by axon and interneuron densities, did not differ across species in the medial caudate nucleus. Differences were detected in the dorsal caudate nucleus, putamen, and globus pallidus but the observed variation did not associate with the phylogenetic structure of the species in the sample. However, combining the present results with previously published data for dopamine revealed a unique pattern of innervation for humans, with higher amounts of dopamine compared with acetylcholine in the striatum. Taken together, these findings indicate a potential evolutionary shift in basal ganglia neurotransmission in humans that may favor increased synaptic plasticity. J. Comp. Neurol. 525:319-332, 2017. © 2016 Wiley Periodicals, Inc.