This Is AuburnElectronic Theses and Dissertations

Targeting Neuroinflammation as a Therapeutic Approach in Alzheimer’s Disease Mouse Model

Date

2020-08-24

Author

Abdallah, Ihab

Type of Degree

PhD Dissertation

Department

Pharmacy

Restriction Status

EMBARGOED

Restriction Type

Full

Date Available

08-31-2022

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder and the most common form of dementia that affects people in their middle age, in the case of familial cases, and the elderly causing significant losses to the health and economic sectors of countries. Several hallmarks have been associated with AD, including but not limited to extracellular amyloid-beta (Aβ) plaques, neurofibrillary tangle (NFT), compromised blood-brain barrier (BBB) and neuroinflammation. Thus, targeting multiple pathways could be a novel therapeutic approach to prevent and/or treat AD. In the last few decades, olive oil and olive leaf extract (OLE) containing polyphenols have shown a beneficial health effect in experimental and clinical studies. The major bioactive phenol enriched in OLE, named oleuropein, showed a beneficial effect in memory and Aβ accumulation in AD transgenic mice, but the mechanism of these positive effect were not fully elucidated. In the current study, we sought first to test the effect of OLE consumption at advanced disease stage in homozygous 5xFAD mice, starting at the age of 3 months for 3 months treatment. The treatment group was compared to vehicle-treated mice with refined oil. Next, we identified mechanism(s) by which OLE exerts the beneficial effect. Our findings showed that long-term consumption of OLE enhanced the cognitive performance and enhanced the brain function. In addition, OLE shifted the amyloid precursor protein (APP) processing pathway toward the non-amyloidogenic pathway and reduced Aβ-related pathology by reducing neuroinflammation through inhibition of NLRP3 inflammasomes activation. This effect was associated with reduced release of pro-inflammatory cytokines by the inactivation of the NF-κB signaling pathway. In conclusion, our results suggested diet supplementation with OLE enriched with oleuropein, and a mixture of polyphenols could provide a beneficial effect to slow and/or halt AD progression.