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The molecular genetics of Alzheimer's disease 总被引:1,自引:0,他引:1
The major pathological characteristic of Alzheimer's disease (AD) is the abnormal deposition of β-amyloid peptide (Aβ) in
the brain. In some early onset cases, the disease develops because of mutations in the gene coding for β-amyloid precursor
protein (βAPP). However, the majority of AD families in the early onset subgroup are linked to a locus on chromosome 14. The genetic analysis
and age of onset correlates of both the βAPP gene and the chromosome 14 locus are discussed. We speculate on the mechanisms by which the βAPP mutations cause the disease and discuss recent advances in βAPP processing that may be relevant to the pathogenesis of the late-onset (common) form of the disease. In addition, we review
the association of theAPOE locus with late-onset familial and nonfamilial disease. Further work is required to establish the effects of this locus on
disease occurrence, age of onset, and progression. The molecular pathology of ApoE in relation to AD development and the identification
of the chromosome 14 gene will greatly contribute to a general pathogenic model of AD, and will clarify the role of βAPP and its derivatives. 相似文献
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mtDNA diversity in rhesus monkeys reveals overestimates of divergence time and paraphyly with neighboring species 总被引:4,自引:0,他引:4
Reconstructions of the human-African great ape phylogeny by using
mitochondrial DNA (mtDNA) have been subject to considerable debate. One
confounding factor may be the lack of data on intraspecific variation. To
test this hypothesis, we examined the effect of intraspecific mtDNA
diversity on the phylogenetic reconstruction of another Plio- Pleistocene
radiation of higher primates, the fascicularis group of macaque (Macaca)
monkey species. Fifteen endonucleases were used to identify 10 haplotypes
of 40-47 restriction sites in M. mulatta, which were compared with similar
data for the other members of this species group. Interpopulational,
intraspecific mtDNA diversity was large (0.5%- 4.5%), and estimates of
divergence time and branching order incorporating this variation were
substantially different from those based on single representatives of each
species. We conclude that intraspecific mtDNA diversity is substantial in
at least some primate species. Consequently, without prior information on
the extent of genetic diversity within a particular species, intraspecific
variation must be assessed and accounted for when reconstructing primate
phylogenies. Further, we question the reliability of hominoid mtDNA
phylogenies, based as they are on one or a few representatives of each
species, in an already depauperate superfamily of primates.
相似文献
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The analysis of clinical breast samples using biomarkers is integral to current breast cancer management. Currently, a limited number of targeted therapies are standard of care in breast cancer treatment. However, these targeted therapies are only suitable for a subset of patients and resistance may occur. Strategies to prevent the occurrence of invasive lesions are required to reduce the morbidity and mortality associated with the development of cancer. In theory, application of targeted therapies to pre-invasive lesions will prevent their progression to invasive lesions with full malignant potential. The diagnostic challenge for pathologists is to make interpretative decisions on early detected pre-invasive lesions. Overall, only a small proportion of these pre-invasive lesions will progress to invasive carcinoma and morphological assessment is an imprecise and subjective means to differentiate histologically identical lesions with varying malignant potential. Therefore differential biomarker analysis in pre-invasive lesions may prevent overtreatment with surgery and provide a predictive indicator of response to therapy. There follows a review of established and emerging potential druggable targets in pre-invasive lesions and correlation with lesion morphology. 相似文献
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Tan J Town T Saxe M Paris D Wu Y Mullan M 《Journal of immunology (Baltimore, Md. : 1950)》1999,163(12):6614-6621
Recently, it has been demonstrated that the CD40 receptor is constitutively expressed on cultured microglia at low levels. Ligation of CD40 by CD40 ligand on these cells results in microglial activation, as measured by TNF-alpha production and neuronal injury. However, the intracellular events mediating this effect have yet to be investigated. We report that ligation of microglial CD40 triggers activation of p44/42 mitogen-activated protein kinase (MAPK). This effect is evident 30 min posttreatment, and progressively declines thereafter (from 30 to 240 min). Phosphorylated p38 MAPK is not observed in response to ligation of microglial CD40 across the time course examined. Inhibition of the upstream activator of p44/42 MAPK, mitogen-activated protein/extracellular signal-related kinase kinase 1/2, with PD98059, decreases phosphorylation of p44/42 MAPK and significantly reduces TNF-alpha release following ligation of microglial CD40. Furthermore, cotreatment of microglial cells with CD40 ligand and TGF-beta1 or IL-10, or both, inhibits CD40-mediated activation of p44/42 MAPK and production of TNF-alpha in a statistically interactive manner. Taken together, these data show that ligation of microglial CD40 triggers TNF-alpha release through the p44/42 MAPK pathway, an effect that can be opposed by TGF-beta1 and IL-10. 相似文献
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