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Dual Targeting of Amyloid-beta Clear...
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Batarseh, Yazan S.
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Dual Targeting of Amyloid-beta Clearance and Neuroinflammation as a Novel Therapeutic Approach against Alzheimer's Disease.
紀錄類型:
書目-電子資源 : Monograph/item
正題名/作者:
Dual Targeting of Amyloid-beta Clearance and Neuroinflammation as a Novel Therapeutic Approach against Alzheimer's Disease./
作者:
Batarseh, Yazan S.
出版者:
Ann Arbor : ProQuest Dissertations & Theses, : 2017,
面頁冊數:
141 p.
附註:
Source: Dissertation Abstracts International, Volume: 78-10(E), Section: B.
Contained By:
Dissertation Abstracts International78-10B(E).
標題:
Pharmaceutical sciences. -
電子資源:
http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10263948
ISBN:
9781369800357
Dual Targeting of Amyloid-beta Clearance and Neuroinflammation as a Novel Therapeutic Approach against Alzheimer's Disease.
Batarseh, Yazan S.
Dual Targeting of Amyloid-beta Clearance and Neuroinflammation as a Novel Therapeutic Approach against Alzheimer's Disease.
- Ann Arbor : ProQuest Dissertations & Theses, 2017 - 141 p.
Source: Dissertation Abstracts International, Volume: 78-10(E), Section: B.
Thesis (Ph.D.)--University of Louisiana at Monroe, 2017.
Amyloid-beta (Abeta) cascade hypothesis suggests that Alzheimer's disease (AD) is related to an imbalance between the production and clearance of Abeta peptide. Sporadic AD has been related to faulty clearance of Abeta. Accumulation of Abeta oligomers (Abetao) has been linked to several downstream toxic effects including neuroinflammation, synaptic loss, and cellular death. Abeta transport across the blood-brain barrier (BBB) is one of the primary pathways for reducing Abeta load in the brain, which work hand in hand with other parenchymal mechanisms to reduce Abeta levels including intra and extracellular degradation by a family of Abeta degrading enzymes. Established AD drugs, such as the cholinesterase inhibitor donepezil, have been reported to have several additional non-cholinergic effects that alter Abeta pathology; reduce Abeta load, anti-inflammatory response, and attenuate synaptic loss. However, their limited effect only lead to minor improvements in AD symptoms without improving the prognosis of the disease. The lack of effective medical treatment for AD led to several studies focusing on establishing new therapeutic approaches to reduce Abeta pathology. We aimed to identify and characterize natural products that are capable of enhancing the BBB clearance of Abeta in addition to reducing neuroinflammation.
ISBN: 9781369800357Subjects--Topical Terms:
3173021
Pharmaceutical sciences.
Dual Targeting of Amyloid-beta Clearance and Neuroinflammation as a Novel Therapeutic Approach against Alzheimer's Disease.
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Thesis (Ph.D.)--University of Louisiana at Monroe, 2017.
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Amyloid-beta (Abeta) cascade hypothesis suggests that Alzheimer's disease (AD) is related to an imbalance between the production and clearance of Abeta peptide. Sporadic AD has been related to faulty clearance of Abeta. Accumulation of Abeta oligomers (Abetao) has been linked to several downstream toxic effects including neuroinflammation, synaptic loss, and cellular death. Abeta transport across the blood-brain barrier (BBB) is one of the primary pathways for reducing Abeta load in the brain, which work hand in hand with other parenchymal mechanisms to reduce Abeta levels including intra and extracellular degradation by a family of Abeta degrading enzymes. Established AD drugs, such as the cholinesterase inhibitor donepezil, have been reported to have several additional non-cholinergic effects that alter Abeta pathology; reduce Abeta load, anti-inflammatory response, and attenuate synaptic loss. However, their limited effect only lead to minor improvements in AD symptoms without improving the prognosis of the disease. The lack of effective medical treatment for AD led to several studies focusing on establishing new therapeutic approaches to reduce Abeta pathology. We aimed to identify and characterize natural products that are capable of enhancing the BBB clearance of Abeta in addition to reducing neuroinflammation.
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Our first project was to investigate the role of oleocanthal (one of the active ingredients in extra-virgin olive oil; EVOO) on attenuating Abeta toxic effects on neurons and astrocytes. We developed Abeta oligomers (Abetao) induced inflammatory environment by exposing neurons and astrocytes to accumulative doses of Abetao to investigate oleocanthal effect on modulating Abetao pathological changes in neurons and astrocytes. Our findings demonstrated oleocanthal prevented Abetao-induced synaptic proteins, SNAP-25 and PSD-95, down-regulation in neurons, attenuated Abetao-induced inflammation, and restored glutamine transporter (GLT1) and glucose transporter (GLUT1) expressions in astrocytes. Results from this study support the protective effect of the EVOO-derived phenolic secoiridoid oleocanthal against AD pathology.
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Next, we evaluated the role of EVOO in enhancing donepezil's effect on increasing Abeta clearance and reducing neuroinflammation in AD transgenic model, namely 5XFAD mice. The long-term consumption of EVOO in combination with donepezil is expected to enhance and expand donepezil protective mechanisms against Abeta pathology. EVOO consumption in combination with donepezil treatment significantly reduced Abeta load and related pathology; EVOO consumption with donepezil up-regulated synaptic proteins, enhanced BBB tightness and reduced neuroinflammation associated with Abeta pathology. Long-term consumption of EVOO significantly reduced Abeta pathological manifestations in addition to enhancing and expanding donepezil protective mechanisms against Abeta pathology when given concomitantly. Therefore, EVOO consumption as a medical food combined with donepezil offers an effective therapeutic approach by enhancing the non-cholinergic mechanisms of donepezil and by providing additional mechanisms to attenuate Abeta related pathology in AD patients.
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In the third project, the effect of Crocus sativus extract on Abeta clearance across the BBB and related pathology were evaluated in vitro and in vivo in wild-type and AD transgenic models. Available studies reported Crocus sativus exerts a positive effect against AD, however, the mechanism(s) for such effect is unknown. Therefore, here, we investigated its effect on enhancing Abeta clearance and reducing neuroinflammation. Findings from in vitro studies demonstrated that Crocus sativus extract increased the tightness and enhanced Abeta transport in our cell-based BBB model. Followed in vivo studies confirmed the effect of Crocus sativus extract on the BBB integrity and function that was associated with reduced Abeta load and related pathology in 5XFAD mice. Furthermore, Crocus sativus extract up-regulated synaptic proteins and reduced neuroinflammation associated with Abeta pathology in the brains of 5XFAD mice. Crocin, one of the major active compounds in Crocus sativus, known for its antioxidant and anti-inflammatory effect, was also tested separately in vivo. Crocin was able to reduce Abeta load and related pathologies but to a lesser extent when compared to Crocus sativus extract, which could be explained, at least in part, by the lack of crocin's ability in enhancing Abeta clearance and reducing neuroinflammation. Findings from this project support the positive effect of Crocus sativus against AD by reducing Abeta pathological manifestations.
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In conclusion, in this work, the therapeutics potential of oleocanthal, EVOO, and Crocus sativus extracts was in vitro and in vivo evaluated for their effect on Abeta clearance, BBB integrity and function, neuroprotective and neuroinflammation. Oleocanthal, EVOO, and Crocus sativus extract enhanced the clearance of Abeta by inducing its transport across the BBB and enhancing its enzymatic degradation and reduced neuroinflammation, which collectively led to Abeta brain levels reduction associated with inflammation reduction and neuroprotection. Therefore, we suggest that natural products such as EVOO, oleocanthal, and Crocus sativus may have a high potential therapeutic role against AD pathology.
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http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10263948
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