Decreased Clearance of CNS -Amyloid in Alzheimer's Disease

Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Science (Impact Factor: 33.61). 12/2010; 330(6012):1774. DOI: 10.1126/science.1197623
Source: PubMed


Alzheimer’s disease is hypothesized to be caused by an imbalance between β-amyloid (Aβ) production and clearance that leads
to Aβ accumulation in the central nervous system (CNS). Aβ production and clearance are key targets in the development of
disease-modifying therapeutic agents for Alzheimer’s disease. However, there has not been direct evidence of altered Aβ production
or clearance in Alzheimer’s disease. By using metabolic labeling, we measured Aβ42 and Aβ40 production and clearance rates
in the CNS of participants with Alzheimer’s disease and cognitively normal controls. Clearance rates for both Aβ42 and Aβ40
were impaired in Alzheimer’s disease compared with controls. On average, there were no differences in Aβ40 or Aβ42 production
rates. Thus, the common late-onset form of Alzheimer’s disease is characterized by an overall impairment in Aβ clearance.

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    • "It is defined by two cardinal pathologic features: senile plaques and neurofibrillary degen- eration[1]. Inexplicably, most cases of AD are associated with decreased clearance and degradation of amyloid beta (Aβ)[2]and increased secretion of inflammatory mediators, both associated with the phenotypic activation of microglial cells. It is widely accepted that beneficial strategies against AD may be attributabled to the promotion of phagocytosis and inhibition of the pro-inflammatory response in microglia. "
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    ABSTRACT: Inflammatory activation of microglia and β amyloid (Aβ) deposition are considered to work both independently and synergistically to contribute to the increased risk of Alzheimer's disease (AD). Recent studies indicate that long-term use of phenolic compounds provides protection against AD, primarily due to their anti-inflammatory actions. We previously suggested that phenolic compound curcumin ameliorated phagocytosis possibly through its anti-inflammatory effects rather than direct regulation of phagocytic function in electromagnetic field-exposed N9 microglial cells (N9 cells). Here, we explored the prostaglandin-E2 (PGE2)-related signaling pathway that involved in curcumin-mediated phagocytosis in fibrillar β-amyloid peptide (1-42) (fAβ42)-stimulated N9 cells. Treatment with fAβ42 increased phagocytosis of fluorescent-labeled latex beads in N9 cells. This increase was attenuated in a dose-dependent manner by endogenous and exogenous PGE2, as well as a selective EP2 or protein kinase A (PKA) agonist, but not by an EP4 agonist. We also found that an antagonist of EP2, but not EP4, abolished the reduction effect of PGE2 on fAβ42-induced microglial phagocytosis. Additionally, the increased expression of endogenous PGE2, EP2, and cyclic adenosine monophosphate (AMP), and activation of vasodilator-stimulated phosphoprotein, cyclic AMP responsive element-binding protein, and PKA were depressed by curcumin administration. This reduction led to the amelioration of the phagocytic abilities of PGE2-stimulated N9 cells. Taken together, these data suggested that curcumin restored the attenuating effect of PGE2 on fAβ42-induced microglial phagocytosis via a signaling mechanism involving EP2 and PKA. Moreover, due to its immune modulatory effects, curcumin may be a promising pharmacological candidate for neurodegenerative diseases.
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    • "A protein complex including the protease, secretase , is required for this cleavage of APP to occur and to produce the pathogenic A peptide. In AD an imbalance exists in the production and clearance of -amyloid [58]. Mutations in the three genes encoding APP, presenilin-1, and presenilin-2 (needed for -secretase activity) lead to autosomal-dominant Alzheimer's disease, the least common type [78]. "
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    • "Results from current study suggest that chronic and early-onset dietary intake of EVOO reduces Aβ deposition on the microvessels of the brain of TgSwDI, which could provide a mechanistic explanation for improvement in the cerebrovascular function that was associated with the Mediterranean diet. Cerebral levels of Aβ are regulated by the balance of brain production and clearance[53]. Although production of Aβ increases significantly in early-onset familial AD, mounting evidence suggests that Aβ accumulation in the brains of late-onset AD patients is related to its impaired clearance from the brain[54]. "

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