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1.
Neuroscience ; 324: 69-81, 2016 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-26964679

RESUMEN

Inter-alpha Inhibitor Proteins (IAIPs) are a family of related serine protease inhibitors. IAIPs are important components of the systemic innate immune system. We have identified endogenous IAIPs in the central nervous system (CNS) of sheep during development and shown that treatment with IAIPs reduces neuronal cell death and improves behavioral outcomes in neonatal rats after hypoxic-ischemic brain injury. The presence of IAIPs in CNS along with their exogenous neuroprotective properties suggests that endogenous IAIPs could be part of the innate immune system in CNS. The purpose of this study was to characterize expression and localization of IAIPs in CNS. We examined cellular expressions of IAIPs in vitro in cultured cortical mouse neurons, in cultured rat neurons, microglia, and astrocytes, and in vivo on brain sections by immunohistochemistry from embryonic (E) day 18 mice and postnatal (P) day 10 rats. Cultured cortical mouse neurons expressed the light chain gene Ambp and heavy chain genes Itih-1, 2, 3, 4, and 5 mRNA transcripts and IAIP proteins. IAIP proteins were detected by immunohistochemistry in cultured cells as well as brain sections from E18 mice and P10 rats. Immunoreactivity was found in neurons, microglia, astrocytes and oligodendroglia in multiple brain regions including cortex and hippocampus, as well as within both the ependyma and choroid plexus. Our findings suggest that IAIPs are endogenous proteins expressed in a wide variety of cell types and regions both in vitro and in vivo in rodent CNS. We speculate that endogenous IAIPs may represent endogenous neuroprotective immunomodulatory proteins within the CNS.


Asunto(s)
alfa-Globulinas/metabolismo , Encéfalo/citología , Encéfalo/metabolismo , Animales , Astrocitos/citología , Astrocitos/metabolismo , Encéfalo/crecimiento & desarrollo , Células Cultivadas , Inmunohistoquímica , Ratones Endogámicos C57BL , Microglía/citología , Microglía/metabolismo , Neuronas/citología , Neuronas/metabolismo , ARN Mensajero/metabolismo , Ratas Wistar
2.
J Nutr Health Aging ; 16(10): 888-90, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23208027

RESUMEN

Circadian rhythmicity was repeatedly determined in a patient with Alzheimer's disease by measuring his core temperature with a rectal thermistor and motor activity by an ambulatory activity monitor. The first recording, performed 9 years after he was diagnosed with Alzheimer's disease, showed well organized 24 hr circadian rhythm of core body temperature. The second recording, made four months later, showed very poor fit of core body temperature to 24 hour rhythm, but excellent fit with 36 hour rhythm. The third recording, made two months later, showed again good fit of core body temperature with 24 hour cycle. The last recording, which was performed 5 months later, showed almost complete disappearance of circadian rhythm of body temperature. These changes probably reflect gradual lengthening of the circadian cycle that at one point became extremely lengthened before returning to the 24 hr cycle.


Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Temperatura Corporal/fisiología , Ritmo Circadiano/fisiología , Actividad Motora/fisiología , Anciano , Humanos , Masculino , Monitoreo Fisiológico/métodos
3.
J Neuroendocrinol ; 24(6): 962-72, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22296042

RESUMEN

The inhibin/activin family of proteins is known to have a broad distribution of synthesis and expression in many species, as well as a variety of functions in reproductive and other physiological systems. Yet, our knowledge regarding the production and function of inhibin and activin in the central nervous system is relatively limited, especially in humans. The present study aimed to explore the distribution of inhibin/activin protein subunits and receptors in the adult human brain. The human hypothalamus and surrounding basal forebrain was examined using post-mortem tissues from 29 adults. Immunocytochemical studies were conducted with antibodies directed against the inhibin/activin α, ßA, and ßB subunits, betaglycan and the activin type IIA and IIB receptors. An immunoassay was also utilised to measure dimeric inhibin A and B levels in tissue homogenates of the infundibulum of the hypothalamus. Robust ßA subunit immunoreactivity was present in the paraventricular, supraoptic, lateral hypothalamic, infundibular, dorsomedial and suprachiasmatic nuclei of the hypothalamus, in the basal ganglia, and in the nucleus basalis of Meynert. A similar staining distribution was noted for the ßB subunit, betaglycan and the type II receptor antibodies, whereas α subunit staining was not detected in any of the major anatomical regions of the human brain. Inhibin B immunoreactivity was present in all tissues, whereas inhibin A levels were below detectable limits. These studies show for the first time that the inhibin/activin protein subunits and receptors can be co-localised in the human brain, implicating potential, diverse neural functions.


Asunto(s)
Receptores de Activinas Tipo II/biosíntesis , Receptores de Activinas/biosíntesis , Activinas/biosíntesis , Hipotálamo/metabolismo , Subunidades beta de Inhibinas/biosíntesis , Inhibinas/biosíntesis , Prosencéfalo/metabolismo , Receptores de Péptidos/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
4.
Neurology ; 75(14): 1285-91, 2010 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-20921514

RESUMEN

OBJECTIVE: Neurotrophins promote neurogenesis and help regulate synaptic reorganization. Their dysregulation has been implicated in a number of neurologic and psychiatric disorders. Previous studies have shown decreased levels of brain-derived neurotrophic factor (BDNF) in the serum of patients with psychiatric disorders such as major depressive disorder (MDD) and conversion disorder (CD). In human patients with temporal lobe epilepsy, there is an increase in both BDNF mRNA and protein levels in surgically resected hippocampi compared to controls. One study of children with epilepsy has found normal to increased serum BDNF levels compared to controls. Plasma [corrected] BDNF levels have not been investigated in adult patients with epileptic seizures (ES). We hypothesized that BDNF would differentiate between ES and psychogenic nonepileptic seizures (PNES). METHODS: We assessed plasma [corrected] BDNF immunoreactivity in 15 patients with ES, 12 patients with PNES, and 17 healthy volunteers. Plasma [corrected] BDNF levels were measured using an enzyme-linked immunoassay. RESULTS: Healthy controls showed higher BDNF levels (4,289 ± 1,810 pg/mL) compared to patients with PNES (1,033 ± 435 pg/mL) (p < 0.001). However, unexpectedly, healthy controls also showed higher levels of BDNF compared to patients with ES without comorbid MDD (977 ± 565 pg/mL) (p < 0.001). CONCLUSIONS: Unlike children, adults with epilepsy appear to have decreased levels of plasma [corrected] BDNF. Reduced plasma [corrected] BDNF levels can be used to differentiate adult patients with ES or PNES from healthy controls. Further human studies are needed to better understand the pathophysiology explaining the decreased plasma [corrected] BDNF levels found in epilepsy and in PNES.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/sangre , Epilepsia/sangre , Trastornos Psicofisiológicos/sangre , Convulsiones/sangre , Convulsiones/psicología , Adulto , Anciano , Análisis de Varianza , Factor Neurotrófico Derivado del Encéfalo/genética , Electroencefalografía/métodos , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Psicofisiológicos/complicaciones , Convulsiones/complicaciones , Adulto Joven
5.
Neurobiol Aging ; 28(7): 977-86, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16782234

RESUMEN

Thinning and discontinuities within the vascular basement membrane (VBM) are associated with leakage of the plasma protein prothrombin across the blood-brain barrier (BBB) in Alzheimer's disease (AD). Prothrombin immunohistochemistry and ELISA assays were performed on prefrontal cortex. In severe AD, prothrombin was localized within the wall and neuropil surrounding microvessels. Factor VIII staining in severe AD patients indicated that prothrombin leakage was associated with shrinkage of endothelial cells. ELISA revealed elevated prothrombin levels in prefrontal cortex AD cases that increased with the Braak stage (Control=1.39, I-II=1.76, III-IV=2.28, and V-VI=3.11 ng prothrombin/mg total protein). Comparing these four groups, there was a significant difference between control and Braak V-VI (p=0.0095) and also between Braak stages I-II and V-VI (p=0.0048). There was no significant difference in mean prothrombin levels when cases with versus without cerebral amyloid angiopathy (CAA) were compared (p-value=0.3627). When comparing AD patients by APOE genotype (ApoE3,3=2.00, ApoE3,4=2.49, and ApoE4,4=2.96 ng prothrombin/mg total protein) an analysis of variance indicated a difference between genotypes at the 10% significance level (p=0.0705). Tukey's test indicated a difference between the 3,3 and 4,4 groups (p=0.0607). These studies provide evidence that in advanced AD (Braak stage V-VI), plasma proteins like prothrombin can be found within the microvessel wall and surrounding neuropil, and that leakage of the blood-brain barrier may be more common in patients with at least one APOE4 allele.


Asunto(s)
Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/patología , Barrera Hematoencefálica/fisiopatología , Trastornos Cerebrovasculares/etiología , Trastornos Cerebrovasculares/patología , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Análisis de Varianza , Apolipoproteínas E/genética , Membrana Basal/metabolismo , Membrana Basal/patología , Corteza Cerebral/metabolismo , Trastornos Cerebrovasculares/metabolismo , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática/métodos , Factor VIII/metabolismo , Femenino , Humanos , Inmunohistoquímica/métodos , Masculino , Persona de Mediana Edad , Músculo Liso/metabolismo , Cambios Post Mortem , Protrombina/metabolismo
6.
Acta Neurochir Suppl ; 96: 451-6, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16671503

RESUMEN

Evidence continues to build for the role of atrial natriuretic peptide (ANP) in reducing cerebrospinal fluid (CSF) formation rate, and thus, intracranial pressure. ANP binds to choroid plexus (CP) epithelial cells. This generates cGMP, which leads to altered ion transport and the slowing of CSF production. Binding sites for ANP in CP are plentiful and demonstrate plasticity in fluid imbalance disorders; however, specific ANP receptors in epithelial cells need confirmation. Using antibodies directed against NPR-A and NPR-B, we now demonstrate immunostaining not only in the choroidal epithelium (including cytoplasm), but also in the ependyma and some endothelial cells of cerebral microvessels in adult rats (Sprague-Dawley). The choroidal and ependymal cells stained almost universally, thus substantiating the initial autoradiographic binding studies with 125I-ANP. Because ANP titers in human CSF have previously been shown to increase proportionally to increments in ICP, we propose a compensatory ANP modulation of CP function to down-regulate ICP in hydrocephalus. Further evidence for this notion comes from the current finding of increased frequency of "dark" epithelial cells in CP of hydrocephalic (HTx) rats, which fits our earlier observation that the "dark" choroidal cells, associated with states of reduced CSF formation, are increased by elevated ANP in CSF. Altogether, ANP neuroendocrine-like regulation at CSF transport interfaces and blood-brain barrier impacts brain fluid homeostasis.


Asunto(s)
Factor Natriurético Atrial/metabolismo , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Plexo Coroideo/metabolismo , Presión Intracraneal/fisiología , Animales , Ratas , Ratas Sprague-Dawley , Distribución Tisular
9.
J Alzheimers Dis ; 4(2): 97-103, 2002 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-12214133

RESUMEN

Thyrotropin-releasing hormone (TRH) is best known for its hypothalamic neuroendocrine role in regulating thyroid function. In extra-hypothalamic regions in vitro, we have shown TRH to have a protective effect against synaptic loss and neuronal apoptosis. A role for TRH in Alzheimer's disease (AD) has not been established previously. In this study, we examined the content of the TRH peptide in the hippocampus of elderly controls (n=5) and AD patients (n=7) by radioimmunoassay (RIA). The TRH concentration was decreased in the AD hippocampus compared to normal elderly controls (p < 0.01). In a separate series of experiments utilizing primary cell cultures made from rat hippocampus, TRH peptide concentration was depleted by the addition of TRH antiserum. TRH withdrawal was found to enhance the activity of glycogen synthetase kinase-3 (GSK-3beta), a critical enzyme necessary for the phosphorylation of tau, as well as the phosphorylation of the tau protein itself. This TRH depletion induced upregulation in phosphorylation that was observed to initiate axonal retraction in cultured neurons. These data suggest that TRH within the hippocampus can regulate the activity of various proteins by phosphorylation/dephosphorylation that may be involved in the pathogenesis of AD.


Asunto(s)
Enfermedad de Alzheimer/patología , Hipocampo/patología , Hormona Liberadora de Tirotropina/metabolismo , Animales , Axones/patología , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Células Cultivadas , Glucógeno Sintasa Quinasa 3 , Humanos , Microscopía Electrónica de Rastreo , Neuronas/patología , Fosforilación , Radioinmunoensayo , Ratas , Hormona Liberadora de Tirotropina/fisiología , Regulación hacia Arriba/fisiología
10.
J Endocrinol ; 173(3): 437-48, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12065233

RESUMEN

SALL1 was originally identified on the basis of its DNA sequence homology to the region-specific homeotic gene Sal, in Drosophila melanogaster, which acts as a downstream target of hedgehog/tumor growth factor-beta-like decapentaplegic signals. The SALL1 gene has been associated with the Townes-Brocks Syndrome (TBS), a disorder characterized by multiorgan dysgenesis including renal and genital malformations. In this study, SALL1 message production was evaluated in association with the tissue localization of the protein product of SALL1, p140. SALL1 protein expression was observed in various adult and fetal tissues which elaborate reproductive endocrine hormones. The p140 was localized in specific microanatomic sites of the pituitary, adrenal cortex and the placenta. In the human pituitary, SALL1 protein expression was limited to the adenohypophysis, where it colocalized to those cells producing GH and the gonadotropins, LH and FSH. SALL1 expression was also found in most of the fetal and adult adrenal cortex in addition to the trophoblastic cells of the placenta. This pattern of expression complements prior studies demonstrating p140 in testicular fetal Leydig cells, adult Leydig and Sertoli cells, and granulosa cells of the ovary. The SALL1 protein was also shown here to be highly expressed in trophoblast tumors, which overproduce sex hormones. The expression patterns of SALL1 at multiple levels of the reproductive endocrine axis and the phenotypic effects associated with TBS suggest that SALL1 may have an important role in the interaction of the pituitary-adrenal/gonadal axis during reproduction.


Asunto(s)
Glándulas Suprarrenales/química , Adenohipófisis/química , Factores de Transcripción/análisis , Glándulas Suprarrenales/embriología , Hormona Adrenocorticotrópica/análisis , Femenino , Expresión Génica , Gonadotropinas Hipofisarias/análisis , Células de la Granulosa/química , Hormona del Crecimiento/análisis , Humanos , Inmunohistoquímica/métodos , Células Intersticiales del Testículo/química , Masculino , Adenohipófisis/embriología , Embarazo , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células de Sertoli/química , Testículo/embriología , Factores de Transcripción/genética , Neoplasias Trofoblásticas/química , Trofoblastos/química , Neoplasias Uterinas/química
12.
Neurosci Lett ; 315(1-2): 21-4, 2001 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-11711205

RESUMEN

The syndrome of frontotemporal dementia represents a diverse group of diseases presenting with behavioral and cognitive disturbances. The expression of the microtubule-associated protein tau was studied in postmortem samples of frontal cortex of 19 cases (12 Pick's disease A, B, C; 4 dementia lacking distinct histology; 3 motor neuron disease type) by Western blotting with a phosphorylation-independent anti-tau antibody. The presence of tau protein was detected in all cases evaluated, including the 11 brains classified as frontotemporal lobe degeneration (diagnostic categories Pick's disease B, C and dementia lacking distinct histology). These findings indicate that the recently reported decreased expression of tau protein in frontotemporal lobe degeneration represents pathogenic mechanism of neurodegeneration detectable only in a special subset of these disorders.


Asunto(s)
Demencia/metabolismo , Lóbulo Frontal/patología , Lóbulo Temporal/patología , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Western Blotting , Demencia/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Enfermedad de Pick/metabolismo , Enfermedad de Pick/patología
13.
Arch Gen Psychiatry ; 58(4): 353-60, 2001 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11296096

RESUMEN

BACKGROUND: Caregiver exhaustion is a frequent consequence of sleep disturbance and rest-activity rhythm disruption that occurs in dementia. This exhaustion is the causal factor most frequently cited by caregivers in making the decision to institutionalize patients with dementia. Recent studies have implicated dysfunction of the circadian pacemaker in the etiology of these disturbances in dementia. METHODS: We studied the activity and core-body temperature rhythms in a cohort of 38 male patients with a clinical diagnosis of probable Alzheimer disease (AD) approximately 2 years before death. These patients were later given a confirmed diagnosis of AD (n = 23), frontotemporal degeneration (FTD) (n = 9), or diffuse Lewy body disease (DLB) with mixed AD or FTD pathologies (n = 6) after autopsy and neuropathological examination. Physiological rhythms of patients with AD and FTD were then compared with a group of normal, elderly men (n = 8) from the community. RESULTS: Alzheimer patients showed increased nocturnal activity and a significant phase-delay in their rhythms of core-body temperature and activity compared with patients with FTD and controls. The activity rhythm of FTD patients was highly fragmented and phase-advanced in comparison with controls and apparently uncoupled from the rhythm of core-body temperature. CONCLUSIONS: Patients with AD and patients with FTD show different disturbances in their rhythms of activity and temperature compared with each other and with normal elderly patients.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Temperatura Corporal/fisiología , Ritmo Circadiano/fisiología , Demencia/diagnóstico , Actividad Motora/fisiología , Factores de Edad , Anciano , Enfermedad de Alzheimer/patología , Encéfalo/patología , Estudios de Cohortes , Demencia/patología , Humanos , Masculino , Factores Sexuales , Sueño/fisiología , Núcleo Supraquiasmático/fisiología , Vigilia/fisiología
14.
Exp Neurol ; 167(1): 40-7, 2001 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-11161591

RESUMEN

The choroid plexus plays a key role in supporting neuronal function by secreting cerebrospinal fluid (CSF) and may be involved in the regulation of various soluble factors. Because the choroid plexus is involved in growth factor secretion as well as CSF dynamics, it is important to understand how growth factors in CSF interact with the brain parenchyma as well as with cells in direct contact with the flowing CSF, i.e., choroid plexus and arachnoid villi. While the existence of growth factors in the choroid plexus has been documented in several animal models, the presence and distribution of growth factors in the human choroid plexus has not been extensively examined. This study describes the general distribution and possible functions of a number of key proteins in the human choroid plexus and arachnoid villi, including basic fibroblast growth factor, FGF receptor, and vascular endothelial growth factor. FGF and VEGF could both be readily demonstrated in choroid plexus epithelial cells. The presence of FGF and VEGF within the choroid plexus was also confirmed by ELISA analysis. Since Alzheimer's disease (AD) is known to be associated with a number of growth factor abnormalities, we examined the choroid plexus and arachnoid villi from AD patients. Immunohistochemical studies revealed the presence of FGF and VEGF within the AD choroid plexus and an increased density of FGFr in both the choroid plexus and the arachnoid villi of AD patients. No qualitative changes in the distribution of FGF and VEGF were observed in the AD choroid plexus. The appearance of FGFr in AD arachnoid was associated with robust amyloid and vimentin immunoreactivity. These findings confirm the presence of FGF and VEGF within the normal and AD choroid plexus and suggest that the alteration of growth factors and their receptors may contribute to the pathogenesis of the hydrocephalus ex vacuo that is characteristically seen in AD.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Líquido Cefalorraquídeo/metabolismo , Plexo Coroideo/metabolismo , Sustancias de Crecimiento/metabolismo , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Amiloide/metabolismo , Aracnoides/citología , Aracnoides/metabolismo , Plexo Coroideo/citología , Plexo Coroideo/patología , Factores de Crecimiento Endotelial/metabolismo , Ensayo de Inmunoadsorción Enzimática , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Humanos , Hidrocefalia/etiología , Hidrocefalia/metabolismo , Inmunohistoquímica , Linfocinas/metabolismo , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular , Vimentina/metabolismo
15.
Med Hypotheses ; 56(1): 124-7, 2001 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-11133269

RESUMEN

Alzheimer's disease (AD), as we think of it today, is the idiopathic progressive loss of cognitive function over a period of several years. The risk of late onset dementia increases significantly with each decade of life such that half of the population over the age of 80 is vulnerable to this disease (1). We know that proper functioning of the central nervous system is dependent on adequate blood flow to remove harmful metabolic products and supply nutrients such as glucose and oxygen to the brain. It has been suggested that cerebral hypoperfusion causes AD (2). Mean cerebral blood flow decreases with age and with sclerosis of cerebral blood vessels. Blood flow appears to increase in stimulated areas of the brain during different activities. However, there is a derangement of blood flow in disease states; this has been documented in the temporal lobes of AD patients, (3,4). English language journal articles located by a MEDLINE search (1960-1999) were reviewed with consideration to the hypothesis that Alzheimer's disease is an autoimmune disease initiated by low oxygen tension and microischemia. Inflammation is thought to be a known contributor to the pathology of AD (5,6). Recent reports support the concept of autoimmunity as a final common pathway of neuron death, particularly for cholinergic in Alzheimer's disease (6). A model of Alzheimer's disease is proposed and related research and treatment modalities are discussed.


Asunto(s)
Enfermedad de Alzheimer/inmunología , Isquemia/fisiopatología , Enfermedad de Alzheimer/fisiopatología , Autoinmunidad , Humanos
17.
J Neuroimmunol ; 111(1-2): 195-202, 2000 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-11063838

RESUMEN

Serologic studies of children with Tourette syndrome (TS) have detected anti-neuronal antibodies but their role in TS has not been explored. Stereotypies and episodic utterances, analogous to involuntary movements seen in TS, were induced in rats by intrastriatal microinfusion of TS sera or gamma immunoglobulins (IgG) under noninflammatory conditions, as found in TS. Immunohistochemical analysis confirmed the presence of IgG selectively bound to striatal neurons. These data support the hypothesis that binding of an anti-neuronal antibody from some children with TS induced striatal dysfunction and suggest a possible cause for the basal ganglia alterations observed in children with TS.


Asunto(s)
Cuerpo Estriado/inmunología , Neuronas/inmunología , Síndrome de Tourette/inmunología , Adolescente , Animales , Autoanticuerpos/farmacología , Conducta Animal , Niño , Cuerpo Estriado/citología , Modelos Animales de Enfermedad , Humanos , Inmunoglobulina G/farmacología , Masculino , Ratas , Ratas Endogámicas F344 , Conducta Estereotipada
18.
J Clin Endocrinol Metab ; 85(7): 2596-603, 2000 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10902813

RESUMEN

We recently demonstrated that three arcuate nucleus-derived peptides, neuropeptide Y (NPY), agouti-related protein (AGRP), and alphaMSH, are contained in axon terminals that heavily innervate hypophysiotropic TRH neurons in the rat brain and may contribute to the altered set-point of the hypothalamo-pituitary-thyroid axis during fasting. To determine whether a similar regulatory system exists in human brain, we performed a series of immunohistochemical studies using antisera against NPY, AGRP, alphaMSH, and TRH in adult hypothalami obtained within 15 h of death. Numerous small to medium-sized, fusiform and multipolar NPY-, AGRP-, and alphaMSH-immunoreactive (-IR) cells were widely distributed throughout the rostro-caudal extent of the infundibular (arcuate) nucleus. A similar distribution pattern was found for NPY- and AGRP-IR neurons in the arcuate nucleus, whereas alphaMSH-IR cells appeared to form a separate cell population. By double labeling fluorescent immunohistochemistry, 82% of NPY neurons cocontained AGRP, and 87% of AGRP neurons coexpressed NPY. No colocalization was found between alphaMSH- and AGRP-IR neurons. NPY-, AGRP-, and alphaMSH-containing axons densely innervated the hypothalamic paraventricular nucleus and were found in close juxtaposition to TRH-synthesizing cell bodies and dendrites. These studies demonstrate that in man, the NPY-, AGRP-, and alphaMSH-IR neuronal systems in the infundibular and paraventricular nuclei are highly reminiscent of that observed in the rat and may similarly be involved in regulating the hypothalamo-pituitary-thyroid axis in the human brain.


Asunto(s)
Hipotálamo/metabolismo , Neuronas/metabolismo , Neuropéptido Y/fisiología , Proteínas/fisiología , Hormona Liberadora de Tirotropina/biosíntesis , alfa-MSH/fisiología , Adulto , Proteína Relacionada con Agouti , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Hipotálamo/citología , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intercelular , Masculino , Persona de Mediana Edad , Fibras Nerviosas/metabolismo , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Hipotalámico Paraventricular/fisiología
19.
Neurobiol Aging ; 21(2): 349-55, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-10867220

RESUMEN

Heparan sulfate proteoglycans (HSPGs) are ubiquitously present within the perivascular basement membrane, and have been shown to be altered in patients with Alzheimer's Disease (AD). Although the HSPG agrin clearly orchestrates the differentiation of the neuromuscular junction, its role in the brain remains unclear. Growing evidence suggests that agrin may be an important vascular basement membrane (VBM)-associated HSPG. In previous studies, we demonstrated that agrin is present throughout the brain microvasculature, as well as in neuronal cell bodies. AD brains exhibited fragmentation of VBM-associated agrin. Agrin immunoreactivity was also seen within senile plaques and neurofibrillary tangles. These changes were accompanied by the appearance of an additional pool of insoluble agrin. In the present study, we provide further evidence for microvascular damage in AD, by examining the distribution of agrin and laminin within the VBM, and by measuring the agrin concentration within hippocampus and prefrontal cortex. Furthermore, we assessed blood-brain-barrier (BBB) leakage by examining the perivascular distribution of prothrombin immunoreactivity. Soluble agrin levels were increased approximately 30% in Braak stage III-VI AD patients relative to age-matched controls. Furthermore, agrin and laminin exhibited identical patterns of VBM fragmentation in AD and colocalized with beta-amyloid in senile plaques. Microvascular changes were associated with the appearance of perivascular prothrombin immunoreactivity. Our data suggest that agrin is an important VBM-associated HSPG in the brain and that agrin levels are altered in association with microvascular damage in AD.


Asunto(s)
Agrina/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/metabolismo , Química Encefálica/fisiología , Capilares/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Inmunohistoquímica , Laminina/metabolismo , Masculino , Persona de Mediana Edad , Protrombina/metabolismo
20.
Brain Res ; 856(1-2): 142-51, 2000 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-10677621

RESUMEN

The distribution of estrogen receptor protein-alpha (ER-alpha)-containing cells in the human hypothalamus and adjacent regions was studied using a monoclonal antibody (H222) raised against ER-alpha derived from MCF-7 human breast cancer cells. Reaction product was found in restricted populations of neurons and astrocyte-like cells. Neurons immunoreactive for ER-alpha were diffusely distributed within the basal forebrain and preoptic area, infundibular region, central hypothalamus, basal ganglia and amygdala. Immunoreactive astrocyte-like cells were noted within specific brain regions, including the lamina terminalis and subependymal peri-third-ventricular region. These data are consistent with the location of estrogen receptors in the basal forebrain of other species and the known effects of estrogens on the cellular functions of both neurons and supporting elements within the human hypothalamus and basal forebrain.


Asunto(s)
Astrocitos/citología , Encéfalo/citología , Hipotálamo/citología , Neuronas/citología , Prosencéfalo/citología , Receptores de Estrógenos/análisis , Amígdala del Cerebelo/citología , Anticuerpos Monoclonales , Neoplasias de la Mama , Receptor alfa de Estrógeno , Femenino , Globo Pálido/citología , Humanos , Inmunohistoquímica , Área Preóptica/citología , Sustancia Innominada/citología , Células Tumorales Cultivadas
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