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1.
Front Biosci ; 13: 3423-38, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18508444

RESUMO

We have long promulgated the idea that microglial cells serve an entirely beneficial role in the central nervous system (CNS), not only as immunological sentinels to fend off potentially dangerous infections, but also as constitutively neuroprotective glia that help sustain neuronal function in the normal and especially in the injured CNS when microglia become activated. In recent years, we have reported on the presence of degenerating microglial cells, which are prominent in the brains of aged humans and humans with neurodegenerative diseases, and this has led us to propose a hypothesis stating that loss of microglia and microglial neuroprotective functions could, at least in part, account for aging-related neurodegeneration. In the current review, we sum up the many aspects that characterize microglial activation and compare them to those that characterize microglial senescence and degeneration. We also consider the possible role of oxidative stress as a cause of microglial degeneration. We finish up by discussing the role microglial cells play in terms of amyloid clearance and degradation with the underlying idea that removal of amyloid constitutes a microglial neuroprotective function, which may become compromised during aging.


Assuntos
Encéfalo/patologia , Microglia/patologia , Degeneração Neural/patologia , Neurônios/patologia , Envelhecimento , Doença de Alzheimer/patologia , Animais , Encéfalo/crescimento & desenvolvimento , Lesões Encefálicas/patologia , Senescência Celular , Citosol/patologia , Humanos , Doença de Huntington/patologia , Peróxido de Hidrogênio/metabolismo , Lipofuscina/metabolismo , Modelos Animais , Doença de Parkinson/patologia
2.
J Biol Chem ; 283(28): 19489-98, 2008 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-18456655

RESUMO

Cerebral deposition of beta-amyloid (Abeta) peptides is a pathological hallmark of Alzheimer disease. Intramembranous proteolysis of amyloid precursor protein by a multiprotein gamma-secretase complex generates Abeta. Previously, it was reported that CD147, a glycoprotein that stimulates production of matrix metalloproteinases (MMPs), is a subunit of gamma-secretase and that the levels of secreted Abeta inversely correlate with CD147 expression. Here, we show that the levels and localization of CD147 in fibroblasts, as well as postnatal expression and distribution in brain, are distinct from those of integral gamma-secretase subunits. Notably, we show that although depletion of CD147 increased extracellular Abeta levels in intact cells, membranes isolated from CD147-depleted cells failed to elevate Abeta production in an in vitro gamma-secretase assay. Consistent with an extracellular source that modulates Abeta metabolism, synthetic Abeta was degraded more rapidly in the conditioned medium of cells overexpressing CD147. Moreover, modulation of CD147 expression had no effect on epsilon-site cleavage of amyloid precursor protein and Notch1 receptor. Collectively, our results demonstrate that CD147 modulates Abeta levels not by regulating gamma-secretase activity, but by stimulating extracellular degradation of Abeta. In view of the known function of CD147 in MMP production, we postulate that CD147 expression influences Abeta levels by an indirect mechanism involving MMPs that can degrade extracellular Abeta.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Basigina/metabolismo , Metaloproteinases da Matriz/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Basigina/genética , Linhagem Celular , Cerebelo/metabolismo , Cerebelo/patologia , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Receptor Notch1/genética , Receptor Notch1/metabolismo
3.
Glia ; 56(10): 1048-60, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18442088

RESUMO

Degeneration of microglial cells may be important for understanding the pathogenesis of aging-related neurodegeneration and neurodegenerative diseases. In this study, we analyzed the morphological characteristics of microglial cells in the nondemented and Alzheimer's disease (AD) human brain using ferritin immunohistochemistry. The central hypothesis was that expression of the iron storage protein ferritin increases the susceptibility of microglia to degeneration, particularly in the aged brain since senescent microglia might become less efficient in maintaining iron homeostasis and free iron can promote oxidative damage. In a primary set of 24 subjects (age range 34-97 years) examined, microglial cells immunoreactive for ferritin were found to constitute a subpopulation of the larger microglial pool labeled with an antibody for HLA-DR antigens. The majority of these ferritin-positive microglia exhibited aberrant morphological (dystrophic) changes in the aged and particularly in the AD brain. No spatial correlation was found between ferritin-positive dystrophic microglia and senile plaques in AD tissues. Analysis of a secondary set of human postmortem brain tissues with a wide range of postmortem intervals (PMI, average 10.94 +/- 5.69 h) showed that the occurrence of microglial dystrophy was independent of PMI and consequently not a product of tissue autolysis. Collectively, these results suggest that microglial involvement in iron storage and metabolism contributes to their degeneration, possibly through increased exposure of the cells to oxidative stress. We conclude that ferritin immunohistochemistry may be a useful method for detecting degenerating microglia in the human brain.


Assuntos
Envelhecimento/imunologia , Doença de Alzheimer/patologia , Encéfalo/patologia , Ferritinas/imunologia , Ferritinas/metabolismo , Microglia/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/metabolismo , Encéfalo/imunologia , Encéfalo/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Microglia/imunologia , Microglia/metabolismo , Pessoa de Meia-Idade
4.
J Biol Chem ; 278(5): 3446-54, 2003 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-12435726

RESUMO

Presenilins (PS1/PS2) play a critical role in proteolysis of beta-amyloid precursor protein (beta APP) to generate beta-amyloid, a peptide important in the pathogenesis of Alzheimer's disease. Nevertheless, several regulatory functions of PS1 have also been reported. Here we demonstrate, in neuroblastoma cells, that PS1 regulates the biogenesis of beta APP-containing vesicles from the trans-Golgi network and the endoplasmic reticulum. PS1 deficiency or the expression of loss-of-function variants leads to robust vesicle formation, concomitant with increased maturation and/or cell surface accumulation of beta APP. In contrast, release of vesicles containing beta APP is impaired in familial Alzheimer's disease (FAD)-linked PS1 mutant cells, resulting in reduced beta APP delivery to the cell surface. Moreover, diminution of surface beta APP is profound at axonal terminals in neurons expressing a PS1 FAD variant. These results suggest that PS1 regulation of beta APP trafficking may represent an alternative mechanism by which FAD-linked PS1 variants modulate beta APP processing.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Complexo de Golgi/metabolismo , Proteínas de Membrana/metabolismo , Rede trans-Golgi/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Biotinilação , Membrana Celular/metabolismo , Permeabilidade da Membrana Celular/fisiologia , Retículo Endoplasmático/metabolismo , Humanos , Cinética , Proteínas de Membrana/genética , Camundongos , Microscopia Confocal , Modelos Biológicos , Neuroblastoma , Presenilina-1 , Transporte Proteico , Proteínas Recombinantes/metabolismo , Transfecção , Células Tumorais Cultivadas
5.
J Biol Chem ; 277(21): 19236-40, 2002 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-11943765

RESUMO

Proteolytic processing of amyloid precursor protein generates beta-amyloid (Abeta) peptides that are deposited in senile plaques in brains of aged individuals and patients with Alzheimer's disease. Presenilins (PS1 and PS2) facilitate the final step in Abeta production, the intramembranous gamma-secretase cleavage of amyloid precursor protein. Biochemical and pharmacological evidence support a catalytic or accessory role for PS1 in gamma-secretase cleavage, as well as a regulatory role in select membrane protein trafficking. In this report, we demonstrate that PS1 is required for maturation and cell surface accumulation of nicastrin, an integral component of the multimeric gamma-secretase complex. Using kinetic labeling studies we show that in PS1(-/-)/PS2(-/-) cells nicastrin fails to reach the medial Golgi compartment, and as a consequence, is incompletely glycosylated. Stable expression of human PS1 restores these deficiencies in PS1(-/-) fibroblasts. Moreover, membrane fractionation studies show co-localization of PS1 fragments with mature nicastrin. These results indicate a novel chaperone-type role for PS1 and PS2 in facilitating nicastrin maturation and transport in the early biosynthetic compartments. Our findings are consistent with PS1 influencing gamma-secretase processing at multiple steps, including maturation and intracellular trafficking of substrates and component(s) of the gamma-secretase complex.


Assuntos
Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/fisiologia , Secretases da Proteína Precursora do Amiloide , Animais , Ácido Aspártico Endopeptidases , Membrana Celular/metabolismo , Endopeptidases/metabolismo , Camundongos , Presenilina-1 , Transporte Proteico , Frações Subcelulares/metabolismo , Células Tumorais Cultivadas
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