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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    • "Pglycoprotein (P-gp) is highly expressed on the luminal surface of brain capillary endothelial cells and contributes to the BBB. The recent two independent clinical studies [4] [5] observed that AD patients have decreased clearance of CNS amyloid-b compared to healthy volunteers. The rate of Ab production is same as that in healthy volunteers; whereas rate of clearance is impaired by 25e30%. "
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    ABSTRACT: The screening of IIIM natural products repository for P-gp modulatory activity in P-gp over-expressing human adenocarcinoma LS-180 cells led to the identification of 7 natural products viz. withaferin, podophyllotoxin, 3-demethylcolchicine, agnuside, reserpine, seseberecine and fascaplysin as P-gp inducers. Fascaplysin (6a), a marine-derived bis-indole alkaloid, was the most potent among all of them, showing induction of P-gp with EC50 value of 25 nM. P-gp induction is one of the recently targeted strategy to increase amyloid-β clearance from Alzheimer brains. Thus, we pursued a medicinal chemistry of fascaplysin to establish its structure-activity relationship for P-gp induction activity. Four series of analogs viz. substituted quaternary fascaplysin analogs, D-ring opened quaternary analogs, D-ring opened non-quaternary analogs, and β-carbolinium analogs were synthesized and screened for P-gp induction activity. Among the total of 48 analogs screened, only quaternary nitrogen containing analogs 6a-g and 10a, 10h-l displayed promising P-gp induction activity; whereas non-planar non-quaternary analogs 9a-m, 13a-n, 15a-h were devoid of this activity. The P-gp induction activity of best compounds was then confirmed by western-blot analysis, which indicated that fascaplysin (6a) along with 4,5-difluoro analog of fascaplysin 6f and D-ring opened analog 10j displayed 4-8 fold increase in P-gp expression in LS-180 cells at 1 μM. Additionally, compounds 6a and 6f also showed inhibition of acetylcholinestease (AChE), an enzyme responsible for neuronal loss in Alzheimer's disease. Thus, fascaplysin and its analogs showing promising P-gp induction along with AChE inhibition at 1 μM, with good safety window (LS-180: IC50 > 10 μM, hGF: 4 μM), clearly indicates their promise for development as an anti-Alzheimer agent.
    European Journal of Medicinal Chemistry 11/2015; 107:1-11. DOI:10.1016/j.ejmech.2015.10.049 · 3.45 Impact Factor
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    • "Recently, studies in humans have corroborated the hypothesis that inefficient amyloid-b clearance mechanisms may lead to abnormal amyloid-b accumulation in the brain (Mawuenyega et al., 2010). Within individual cortical arterioles, the accumulation of amyloid can be relatively heterogeneous with dense regions of CAA occurring adjacent to sections within the same vessel that are more sparsely affected. "
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    ABSTRACT: Prominent cerebral amyloid angiopathy is often observed in the brains of elderly individuals and is almost universally found in patients with Alzheimer's disease. Cerebral amyloid angiopathy is characterized by accumulation of the shorter amyloid-β isoform(s) (predominantly amyloid-β40) in the walls of leptomeningeal and cortical arterioles and is likely a contributory factor to vascular dysfunction leading to stroke and dementia in the elderly. We used transgenic mice with prominent cerebral amyloid angiopathy to investigate the ability of ponezumab, an anti-amyloid-β40 selective antibody, to attenuate amyloid-β accrual in cerebral vessels and to acutely restore vascular reactivity. Chronic administration of ponezumab to transgenic mice led to a significant reduction in amyloid and amyloid-β accumulation both in leptomeningeal and brain vessels when measured by intravital multiphoton imaging and immunohistochemistry. By enriching for cerebral vascular elements, we also measured a significant reduction in the levels of soluble amyloid-β biochemically. We hypothesized that the reduction in vascular amyloid-β40 after ponezumab administration may reflect the ability of ponezumab to mobilize an interstitial fluid pool of amyloid-β40 in brain. Acutely, ponezumab triggered a significant and transient increase in interstitial fluid amyloid-β40 levels in old plaque-bearing transgenic mice but not in young animals. We also measured a beneficial effect on vascular reactivity following acute administration of ponezumab, even in vessels where there was a severe cerebral amyloid angiopathy burden. Taken together, the beneficial effects ponezumab administration has on reducing the rate of cerebral amyloid angiopathy deposition and restoring cerebral vascular health favours a mechanism that involves rapid removal and/or neutralization of amyloid-β species that may otherwise be detrimental to normal vessel function.
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    • "With regard to SAD, our data reveal a heterogeneous group in terms of γ-secretase activity, suggesting that subpopulations of late-onset patients may present alterations in Aβ production, which could be of relevance for future " personalized " treatment strategies. However, the fact that most patients do not show altered γ-secretase activity supports the view that accumulation of Aβ peptides in the central nervous system of SAD patients is more frequently caused by impaired Aβ peptide clearance (Mawuenyega et al., 2010). "
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