Abstract
Alzheimer’s disease (AD) is a complex progressive neurodegenerative disorder affecting humans mainly through the deposition of Aβ-amyloid (Aβ) fibrils and accumulation of neurofibrillary tangles in the brain. Currently available AD treatments only exhibit symptomatic relief but do not generally intervene with the amyloid and tau pathologies. The extra-virgin olive oil (EVOO) monophenolic secoiridoid S-(–)-oleocanthal (OC) showed anti-inflammatory activity through COX system inhibition with potency comparable to the standard non-steroidal anti-inflammatory drug (NSAID) like ibuprofen. OC also showed positive in vitro, in vivo, and clinical therapeutic effects against cardiovascular diseases, many malignancies, and AD. Due to its pungent, astringent, and irritant taste, OC should be formulated in acceptable dosage form before its oral use as a potential nutraceutical. The objective of this study is to develop new OC oral formulations, assess whether they maintained OC activity on the attenuation of β-amyloid pathology in a 5xFAD mouse model upon 4-month oral dosing use. Exploration of potential OC formulations underlying molecular mechanism is also within this study scope. OC powder formulation (OC-PF) and OC-solid dispersion formulation with erythritol (OC-SD) were prepared and characterized using FT-IR spectroscopy, powder X-ray diffraction, and scanning electron microscopy (ScEM) analyses. Both formulations showed an improved OC dissolution profile. OC-PF and OC-SD improved memory deficits of 5xFAD mice in behavioral studies. OC-PF and OC-SD exhibited significant attenuation of the accumulation of Aβ plaques and tau phosphorylation in the brain of 5xFAD female mice. Both formulations markedly suppressed C3AR1 (complement component 3a receptor 1) activity by targeting the downstream marker STAT3. Collectively, these results demonstrate the potential for the application of OC-PF as a prospective nutraceutical or dietary supplement to control the progression of amyloid pathogenesis associated with AD.
Highlights
Powder X-ray Diffraction (PXRD) of OC powder formulation (OC-PF), placebo-PF, OC-solid dispersion formulation with erythritol (OC-SD), and placebo-SD were carried out to assess the changes of these formulation crystalline forms through the alteration of their diffraction pattern and phase purity (Figure 1B)
The PXRD pattern of OC-SD demonstrated the crystalline nature with several prominent high intensity peaks observed at approximately 2 h 1/4 24.6, 28.5, 32.5, 40, 52.6, 53.8 and other less prominent peaks at 2 h 1/4 14.5, 29.6, 37.3, 57.5, 68.8, 71.5, 74.5, and 75.5
Our study demonstrated that over a 4-month oral administration of OC-SD or OC-PF, there was no significant change in 5xFAD mice body weight compared to vehicle control group (Supplementary Figure S1A)
Summary
Alzheimer’s disease (AD) is manifested as a progressive, multifactorial neurodegenerative brain disorder attributed by the deposition of β-amyloid (Aβ) plaques and the accumulation of neurofibrillary tangles (NFTs) in brains of diseased individuals [1,2]. 5.8 million Americans aged 65 and older have been affected with Alzheimer’s disease in 2020 [1,3]. Pathogenesis of AD involves a couple of defined pathways, amyloid-β (Aβ) and tau-related neuropathology [3,4,5]. Amyloid-related brain pathogenesis caused by accumulation and precipitation of Aβ peptides (mainly Aβ40 and Aβ42 ) produced by proteolytic degradation of amyloid-β precursor protein (APP) [3,4,5].
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