The amyloid beta protein has been identified as an important component of both cerebrovascular amyloid and amyloid plaques of Alzheimer's disease and Down syndrome. A complementary DNA for the beta protein suggests that it derives from a larger protein expressed in a variety of tissues. Overexpression of the gene in brain tissue from fetuses with Down syndrome (trisomy 21) can be explained by dosage since the locus encoding the beta protein maps to chromosome 21. Regional localization of this gene by both physical and genetic mapping places it in the vicinity of the genetic defect causing the inherited form of Alzheimer's disease.
"Aβ was isolated from meningovascular amyloid deposits in AD and Down’s syndrome [2,5]. These findings led to the cloning of the gene encoding amyloid precursor protein (APP) as one of the AD genes [6,7] and consequently, the further studies of APP processing and Aβ metabolism. "
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia. At the present time, however, AD still lacks effective treatments. Our recent studies showed that chronic treatment with anesthetic propofol attenuated brain caspase-3 activation and improved cognitive function in aged mice. Accumulation of beta-amyloid protein (Abeta) is a major component of the neuropathogenesis of AD dementia and cognitive impairment. We therefore set out to determine the effects of chronic treatment with propofol on Abeta levels in brain tissues of aged mice. Propofol (50 mg/kg) was administrated to aged (18 month-old) wild-type mice once a week for 8 weeks. The brain tissues of mice were harvested one day after the final propofol treatment. The harvested brain tissues were then subjected to enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Here we report that the propofol treatment reduced Abeta (Abeta40 and Abeta42) levels in the brain tissues of the aged mice. Moreover, the propofol treatment decreased the levels of beta-site amyloid precursor protein cleaving enzyme (the enzyme for Abeta generation), and increased the levels of neprilysin (the enzyme for Abeta degradation) in the brain tissues of the aged mice. These results suggested that the chronic treatment with propofol might reduce brain Abeta levels potentially via decreasing brain levels of beta-site amyloid precursor protein cleaving enzyme, thus decreasing Abeta generation; and via increasing brain neprilysin levels, thus increasing Abeta degradation. These preliminary findings from our pilot studies have established a system and postulated a new hypothesis for future research.
"Subsequently, other studies confirmed that this was the same peptide found in senile plaques of AD patients [18, 19]. Finally, the identification of both the protein precursor from which Aβ is originated (the APP) [20, 21] and the first mutation that was associated with AD development (located in the APP gene, precisely), inevitably led to suggest that this peptide has a central role in the disease origin . The amyloid hypothesis was proposed formally for the first time by Hardy and Allsop in 1991, and it still continues to be one of the etiologic hypotheses best scientifically supported nowadays. "
[Show abstract][Hide abstract] ABSTRACT: Amyloid beta (A β ) is a peptide of 39-43 amino acids found in large amounts and forming deposits in the brain tissue of patients with Alzheimer's disease (AD). For this reason, it has been implicated in the pathophysiology of damage observed in this type of dementia. However, the role of A β in the pathophysiology of AD is not yet precisely understood. A β has been experimentally shown to have a wide range of toxic mechanisms in vivo and in vitro, such as excitotoxicity, mitochondrial alterations, synaptic dysfunction, altered calcium homeostasis, oxidative stress, and so forth. In contrast, A β has also shown some interesting neuroprotective and physiological properties under certain experimental conditions, suggesting that both physiological and pathological roles of A β may depend on several factors. In this paper, we reviewed both toxic and protective mechanisms of A β to further explore what their potential roles could be in the pathophysiology of AD. The complete understanding of such apparently opposed effects will also be an important guide for the therapeutic efforts coming in the future.
Oxidative Medicine and Cellular Longevity 02/2014; 2014(2):795375. DOI:10.1155/2014/795375 · 3.36 Impact Factor
"Although the full significance of triplication of the APP gene in Alzheimer pathogenesis in DS is still under investigation, it is clear that there is a dramatic overexpression of the APP gene product in fetal DS , which is accompanied by a similarly dramatic increase in the levels of IL-1 and S100B , two neuroinflammation-promoting cytokines that are known to induce the overexpression of APP in vitro and in vivo. "
[Show abstract][Hide abstract] ABSTRACT: Down syndrome (DS) is the result of triplication of chromosome 21 (trisomy 21) and is the prevailing cause of mental retardation. In addition to the mental deficiencies and physical anomalies noted at birth, triplication of chromosome 21 gene products results in the neuropathological and cognitive changes of Alzheimer's disease (AD). Mapping of the gene that encodes the precursor protein (APP) of the beta-amyloid (Abeta) present in the Abeta plaques in both AD and DS to chromosome 21 was strong evidence that this chromosome 21 gene product was a principal neuropathogenic culprit in AD as well as DS. The discovery of neuroinflammatory changes, including dramatic proliferation of activated glia overexpressing a chromosome 2 gene product - the pluripotent immune cytokine interleukin-1 (IL-1) - and a chromosome 21 gene product - S100B - in the brains of fetuses, neonates, and children with DS opened the possibility that early events in Alzheimer pathogenesis were driven by cytokines. The specific chromosome 21 gene products and the complexity of the mechanisms they engender that give rise to the neuroinflammatory responses noted in fetal development of the DS brain and their potential as accelerators of Alzheimer neuropathogenesis in DS are topics of this review, particularly as they relate to development and propagation of neuroinflammation, the consequences of which are recognized clinically and neuropathologically as Alzheimer's disease.
Journal of Neuroinflammation 07/2013; 10(1):84. DOI:10.1186/1742-2094-10-84 · 5.41 Impact Factor
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