RESUMEN
Elevated expression of interleukin-1 (IL-1beta), a pro-inflammatory cytokine secreted by activated microglia, is a pathogenic marker of numerous neurodegenerative processes including Alzheimer's disease (AD). We have characterized a link between IL-1beta and the 68-kDa neurofilament light (NF-L) protein, which is a major component of the neuronal cytoskeleton. Using human brain aggregate cultures, we found that IL-1beta treatment significantly increased NF-L expression in primary neurons. Analysis of mRNA levels demonstrated elevated NF-L expression within 72 h while imaging of neurons by immunofluorescent staining for NF-L confirmed IL-1beta-induced NF-L protein expression. These observations suggest a potential inflammatory-induced mechanism for deregulation of an important cytoskeletal protein, NF-L, possibly leading to neuronal dysfunction.
Asunto(s)
Interleucina-1/farmacología , Proteínas de Neurofilamentos/metabolismo , Neuronas/metabolismo , Enfermedad de Alzheimer/metabolismo , Células Cultivadas , Medio de Cultivo Libre de Suero , Regulación de la Expresión Génica , Humanos , Immunoblotting , Microscopía Fluorescente , Proteínas de Neurofilamentos/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Individuals infected with the human immunodeficiency virus (HIV) often experience a dementia characterized by mental slowing and memory loss. Motor dysfunction may also accompany this condition. The pathogenesis of the dementia is not known, but microscopic examination of brain tissue from those afflicted shows evidence of chronic inflammation, reactive gliosis and cell death. Neurotoxic factors produced from activated macrophage or microglial cells such as tumor necrosis factor-alpha (TNFalpha), gp120 and quinolinic acid have been implicated as agents for the cell death which often appears to occur by an apoptotic mechanism. CPI-1189, a drug currently undergoing clinical evaluation as a treatment for the dementia associated with AIDS, is shown in this paper to mitigate apoptosis induced by TNFalpha, gp120, and necrosis induced by quinolinic acid. In addition, CPI-1189 mitigates the cell death produced by supernatants from cultured macrophages obtained from patients with AIDS dementia. The exact mechanism by which CPI-1189 prevents neurotoxicity is not known; however, protection from TNFalpha and supernatant-induced toxicity does not appear to involve NFkappaB translocation, and appears to be associated with an increase in activated ERK-MAP kinase. These findings may have implications for other neurological diseases where apoptotic cell death contributes to neurodegeneration.
Asunto(s)
Complejo SIDA Demencia/metabolismo , Encéfalo/metabolismo , Butanos/farmacología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neurotoxinas/antagonistas & inhibidores , Óxidos de Nitrógeno/farmacología , Complejo SIDA Demencia/etiología , Apoptosis/efectos de los fármacos , Encéfalo/citología , Encéfalo/efectos de los fármacos , Butanos/antagonistas & inhibidores , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Flavonoides/farmacología , Proteína gp120 de Envoltorio del VIH/farmacología , Humanos , Macrófagos/citología , Macrófagos/metabolismo , Macrófagos/virología , Monocitos/citología , Monocitos/metabolismo , FN-kappa B/metabolismo , Necrosis , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Óxidos de Nitrógeno/antagonistas & inhibidores , Fosforilación/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Ácido Quinolínico/metabolismo , Ácido Quinolínico/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
BACKGROUND: The cause of dementia in subcortical ischemic vascular disease (SIVD) is controversial. OBJECTIVES: To determine whether cognitive impairment in SIVD 1) correlates with measures of ischemic brain injury or brain atrophy, and/or 2) is due to concomitant AD. METHODS: Volumetric MRI of the brain was performed in 1) elderly subjects with lacunes (L) and a spectrum of cognitive impairment-normal cognition (NC+L, n = 32), mild cognitive impairment (CI+L, n = 26), and dementia (D+L, n = 29); 2) a comparison group with probable AD (n = 28); and 3) a control group with normal cognition and no lacunes (NC). The authors examined the relationship between the severity of cognitive impairment and 1) volume, number, and location of lacunes; 2) volume of white matter signal hyperintensities (WMSH); and 3) measures of brain atrophy (i. e., hippocampal, cortical gray matter, and CSF volumes). RESULTS: Among the three lacune groups, severity of cognitive impairment correlated with atrophy of the hippocampus and cortical gray matter, but not with any lacune measure. Although hippocampal atrophy was the best predictor of severity of cognitive impairment, there was evidence for a second, partially independent, atrophic process associated with ventricular dilation, cortical gray matter atrophy, and increase in WMSH. Eight autopsied SIVD cases showed variable severity of ischemic and neurofibrillary degeneration in the hippocampus, but no significant AD pathology in neocortex. The probable AD group gave evidence of only one atrophic process, reflected in the severity of hippocampal atrophy. Comparison of regional neocortical gray matter volumes showed sparing of the primary motor and visual cortices in the probable AD group, but relatively uniform atrophy in the D+L group. CONCLUSIONS: Dementia in SIVD, as in AD, correlates best with hippocampal and cortical atrophy, rather than any measure of lacunes. In SIVD, unlike AD, there is evidence for partial independence between these two atrophic processes. Hippocampal atrophy may result from a mixture of ischemic and degenerative pathologies. The cause of diffuse cortical atrophy is not known, but may be partially indexed by the severity of WMSH.
Asunto(s)
Isquemia Encefálica/patología , Corteza Cerebral/patología , Demencia Vascular/patología , Hipocampo/patología , Accidente Cerebrovascular/patología , Anciano , Atrofia/patología , Encéfalo/patología , Femenino , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
In this report, we examined the presence of the activation marker, CD69, on monocytes derived from patients with Alzheimer's disease (AD). We have previously shown that patients with AIDS dementia had an elevated percentage of a CD14+/CD69+ subset and that conditioned media from these M/M phi cultures were toxic to neural cultures. We therefore postulated that patients with AD might likewise have a higher monocyte subset and that this would be associated with neural toxicity. Flow analysis showed that AD patients (n = 13) had a higher percentage of CD69+ M/M phi over age matched controls (n = 14); this trend was statistically significant (p = 0.006). Side scatter (SSC), a measure of cellular granularity was also elevated in AD patients (p = 0.02). The elevated expression of human leukocyte antigen (HLA-DR) was not found to be significant between age-matched controls and AD patients. When conditioned media from M/M phi from five AD and two control patients were evaluated for neurotoxicity, three of the five culture supernatants from AD patients induced apoptosis in neural cell aggregate cultures. Electrophoretic mobility shift assays revealed that these three supernatants also triggered NF-kappaB translocation to the nucleus. Surprisingly, in vitro neurotoxicity was induced by M/M phi supernatants having a lower percentage of CD14+/CD69+ cells. Elevation of the CD14+/CD69+ subset in AD patients may therefore represent a manifestation in the peripheral blood of the pathological events occurring in the brain but may not be directly involved in neural cell toxicity.