scholarly journals (-)-Oleocanthal Nutraceuticals for Alzheimer’s Disease Amyloid Pathology: Novel Oral Formulations, Therapeutic, and Molecular Insights in 5xFAD Transgenic Mice Model

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1702
Author(s):  
Afsana Tajmim ◽  
Areli K. Cuevas-Ocampo ◽  
Abu Bakar Siddique ◽  
Mohammed H. Qusa ◽  
Judy Ann King ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Virgin Olive Oil ◽  
Therapeutic Effects ◽  
Dissolution Profile ◽  
Amyloid Pathology ◽  
Oral Formulations ◽  
Aβ Amyloid ◽  
Anti Inflammatory ◽  
The Brain

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 (SEM) 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.

scholarly journals Aβ Amyloid Pathology Affects the Hearts of Patients With Alzheimer’s Disease

2016 ◽  
Vol 68 (22) ◽  
pp. 2395-2407 ◽  
Author(s):  
Luca Troncone ◽  
Marco Luciani ◽  
Matthew Coggins ◽  
Elissa H. Wilker ◽  
Cheng-Ying Ho ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Pathology ◽  
Aβ Amyloid

scholarly journals Systems Pharmacological Approach to Investigate the Mechanism of Acori Tatarinowii Rhizoma for Alzheimer’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-20 ◽  
Author(s):  
Zhenyan Song ◽  
Fang Yin ◽  
Biao Xiang ◽  
Bin Lan ◽  
Shaowu Cheng
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Enrichment Analysis ◽  
Pathway Enrichment Analysis ◽  
Therapeutic Effects ◽  
Biological Processes ◽  
Pathway Enrichment ◽  
Study Results ◽  
Target Network ◽  
Anti Inflammatory

In traditional Chinese medicine (TCM), Acori Tatarinowii Rhizoma (ATR) is widely used to treat memory and cognition dysfunction. This study aimed to confirm evidence regarding the potential therapeutic effect of ATR on Alzheimer’s disease (AD) using a system network level based in silico approach. Study results showed that the compounds in ATR are highly connected to AD-related signaling pathways, biological processes, and organs. These findings were confirmed by compound-target network, target-organ location network, gene ontology analysis, and KEGG pathway enrichment analysis. Most compounds in ATR have been reported to have antifibrillar amyloid plaques, anti-tau phosphorylation, and anti-inflammatory effects. Our results indicated that compounds in ATR interact with multiple targets in a synergetic way. Furthermore, the mRNA expressions of genes targeted by ATR are elevated significantly in heart, brain, and liver. Our results suggest that the anti-inflammatory and immune system enhancing effects of ATR might contribute to its major therapeutic effects on Alzheimer’s disease.

scholarly journals Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
T. Harach ◽  
N. Marungruang ◽  
N. Duthilleul ◽  
V. Cheatham ◽  
K. D. Mc Coy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Transgenic Mice ◽  
Intestinal Microbiota ◽  
Neurodegenerative Disorder ◽  
Wild Type ◽  
Germ Free ◽  
Amyloid Pathology ◽  
Aβ Amyloid

Abstract Alzheimer’s disease is the most common form of dementia in the western world, however there is no cure available for this devastating neurodegenerative disorder. Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer’s disease is not known. To this end we sequenced bacterial 16S rRNA from fecal samples of Aβ precursor protein (APP) transgenic mouse model and found a remarkable shift in the gut microbiota as compared to non-transgenic wild-type mice. Subsequently we generated germ-free APP transgenic mice and found a drastic reduction of cerebral Aβ amyloid pathology when compared to control mice with intestinal microbiota. Importantly, colonization of germ-free APP transgenic mice with microbiota from conventionally-raised APP transgenic mice increased cerebral Aβ pathology, while colonization with microbiota from wild-type mice was less effective in increasing cerebral Aβ levels. Our results indicate a microbial involvement in the development of Abeta amyloid pathology, and suggest that microbiota may contribute to the development of neurodegenerative diseases.

scholarly journals P1-434: Accumulation of Aβ starting with pyroglutamate at position 3 in the brain and its impact on amyloid pathology of Alzheimer's disease

2008 ◽  
Vol 4 ◽  
pp. T346-T347
Author(s):  
Nobuhisa Iwata ◽  
Satoshi Tsubuki ◽  
Makoto Higuchi ◽  
Kaori Watanabe ◽  
Matthias Staufenbiel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Pathology ◽  
The Brain

scholarly journals BRAIN ENERGETICS EVALUATION IN EARLY STAGES OF AMYLOID PATHOLOGY IN A RAT MODEL OF ALZHEIMER’S DISEASE

2021 ◽  
Author(s):  
Carolina Soares ◽  
Débora G. Souza ◽  
Andreia Silva da Rocha ◽  
Luiza Machado ◽  
Bruna Bellaver ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rat Model ◽  
Respiratory Control ◽  
Transgenic Rat ◽  
Amyloid Pathology ◽  
Model Of Alzheimer’S Disease ◽  
Preclinical Ad ◽  
Similar Disease ◽  
The Brain

Background: Transgenic models of Alzheimer’s disease (AD) overexpress human APP, PS1 or PS2 mutations. These models present amyloid-beta pathology but do not recapitulate the complexity of AD. Interestingly, the transgenic rat model TgF344-AD, which overpresses human APP and PS1 mutations, seems to follow a more similar disease progression, manifesting progressive tau tangle-like pathology and late cognitive impairment. Yet, whether they develop energy metabolism changes as we see in AD remains unclear. Objective: Here, we investigated brain bioenergetics in 6-7 months F344-AD/WT rats, an age where animals present early amyloid pathology but no memory impairment - mimicking the human preclinical AD. Methods: We used high-resolution respirometry to assess mitochondrial oxidative phosphorylation capacity (OXPHOS), electron transfer capacity (ET), respiratory control ratio (RCR) and reserve capacity (R) in brain homogenates of male and female F344-AD and WT rats (n = 6-8, per group). Results: The results were analyzed by Welch’s t test: 1. Frontal cortex a)OXPHOS (p=0.307); b)ET (p=0.99); c)RCR (p=0.138); d)R (p=0.482). 2. Hippocampus a)OXPHOS (p=0.446); b)ET (p=0.409); c)RCR (p=0.952); d)R (p=0.503). Conclusion: In conclusion, at 6-7 months, changes in the respirometry in the brain of F344-AD rats were not observed. We hypothesize that these measures will be altered at older ages.

scholarly journals Neuroprotective and Anti-Inflammatory Effects of Low–Moderate Dose Ionizing Radiation in Models of Alzheimer’s Disease

2020 ◽  
Vol 21 (10) ◽  
pp. 3678 ◽  
Author(s):  
Sujin Kim ◽  
Yunkwon Nam ◽  
Chanyang Kim ◽  
Hyewon Lee ◽  
Seojin Hong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Ionizing Radiation ◽  
Pharmacological Intervention ◽  
Therapeutic Effects ◽  
Moderate Dose ◽  
Short Term ◽  
Anti Inflammatory ◽  
5Xfad Mice

Alzheimer’s disease (AD) is the most common cause of dementia. The neuropathological features of AD include amyloid-β (Aβ) deposition and hyperphosphorylated tau accumulation. Although several clinical trials have been conducted to identify a cure for AD, no effective drug or treatment has been identified thus far. Recently, the potential use of non-pharmacological interventions to prevent or treat AD has gained attention. Low-dose ionizing radiation (LDIR) is a non-pharmacological intervention which is currently being evaluated in clinical trials for AD patients. However, the mechanisms underlying the therapeutic effects of LDIR therapy have not yet been established. In this study, we examined the effect of LDIR on Aβ accumulation and Aβ-mediated pathology. To investigate the short-term effects of low–moderate dose ionizing radiation (LMDIR), a total of 9 Gy (1.8 Gy per fraction for five times) were radiated to 4-month-old 5XFAD mice, an Aβ-overexpressing transgenic mouse model of AD, and then sacrificed at 4 days after last exposure to LMDIR. Comparing sham-exposed and LMDIR-exposed 5XFAD mice indicated that short-term exposure to LMDIR did not affect Aβ accumulation in the brain, but significantly ameliorated synaptic degeneration, neuronal loss, and neuroinflammation in the hippocampal formation and cerebral cortex. In addition, a direct neuroprotective effect was confirmed in SH-SY5Y neuronal cells treated with Aβ1–42 (2 μM) after single irradiation (1 Gy). In BV-2 microglial cells exposed to Aβ and/or LMDIR, LMDIR therapy significantly inhibited the production of pro-inflammatory molecules and activation of the nuclear factor-kappa B (NF-κB) pathway. These results indicate that LMDIR directly ameliorated neurodegeneration and neuroinflammation in vivo and in vitro. Collectively, our findings suggest that the therapeutic benefits of LMDIR in AD may be mediated by its neuroprotective and anti-inflammatory effects.

scholarly journals Infusion of blood from mice displaying cerebral amyloidosis accelerates amyloid pathology in animal models of Alzheimer’s disease

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Rodrigo Morales ◽  
Claudia Duran-Aniotz ◽  
Javiera Bravo-Alegria ◽  
Lisbell D. Estrada ◽  
Mohammad Shahnawaz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prion Diseases ◽  
Amyloid Β ◽  
Cerebral Amyloidosis ◽  
Amyloid Pathology ◽  
Tissue Extracts ◽  
The Brain ◽  
New Strategies

AbstractPrevious studies showed that injection of tissue extracts containing amyloid-β (Aβ) aggregates accelerate amyloid deposition in the brain of mouse models of Alzheimer’s disease (AD) through prion-like mechanisms. In this study, we evaluated whether brain amyloidosis could be accelerated by blood infusions, procedures that have been shown to transmit prion diseases in animals and humans. Young transgenic mice infused with whole blood or plasma from old animals with extensive Aβ deposition in their brains developed significantly higher levels brain amyloidosis and neuroinflammation compared to untreated animals or mice infused with wild type blood. Similarly, intra-venous injection of purified Aβ aggregates accelerated amyloid pathology, supporting the concept that Aβ seeds present in blood can reach the brain to promote neuropathological alterations in the brain of treated animals. However, an amyloid-enhancing effect of other factors present in the blood of donors cannot be discarded. Our results may help to understand the role of peripheral (amyloid-dependent or -independent) factors implicated in the development of AD and uncover new strategies for disease intervention.

scholarly journals PLCG2 as a Risk Factor for Alzheimer's Disease

2020 ◽  
Author(s):  
Andy Po-Yi Tsai ◽  
Chuanpeng Dong ◽  
Christoph Preuss ◽  
Miguel Moutinho ◽  
Peter Bor-Chian Lin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Missense Variant ◽  
Parahippocampal Gyrus ◽  
Carrier Status ◽  
Eqtl Analysis ◽  
Expression Levels ◽  
Amyloid Pathology ◽  
The Brain

Abstract Background Alzheimer's disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Indeed, genetic variants in microglial genes are linked to risk for late-onset AD (LOAD). Phospholipase C 𝛾 2 (PLCG2) participates in the transduction of signals emanating from immune cell-surface receptors that regulate the inflammatory response and is selectively expressed by microglia in the brain. A rare variant in PLCG2 (P522R) was previously found to be protective against LOAD. Here, we performed association analysis to identify a new genetic variation in PLCG2 that is associated with elevated risk for LOAD.Methods Using whole genome sequencing (N=1,894) and RNA-Seq (N=1,077) data from the AMP-AD cohort, we investigated whether a missense variant in PLCG2 (M28L) was associated with risk for LOAD. We have examined the homology model and space-filling model of PLCG2 generated with PyMOL to investigate the protein structure of PLCG2 with substitutions of LOAD risk and protective variants in PLCG2 . Gene expression analysis and expression quantitative trait loci (eQTL) of PLCG2 were conducted. We also evaluated the relationship between PLCG2 expression levels and amyloid plaque density and expression levels of microglia specific markers ( AIF1 and TMEM119 ). Age, sex, and APOE ε4 carrier status were used as covariates. Finally, we investigated the longitudinal changes PLCG2 expression in the 5XFAD mouse model of AD and it relationship to amyloid pathology progression.Results A rare missense variant in PLCG2 (M28L) confers increased AD risk ( p =0.047; OR=1.164 [95% CI=1.002-1.351]). PLCG2 is highly expressed in the brain and was significantly up-regulated in the parahippocampal gyrus, superior temporal gyrus, and inferior temporal gyrus in LOAD. Higher PLCG2 expression levels were associated with increased brain amyloid deposition. The findings were validated in 5xFAD mice, showing a disease progression-dependent increase in Plcg2 expression with amyloid pathology. Furthermore, eQTL analysis identified several variants as associated with increased PLCG2 expression levels in the brain and other organs.Conclusions Our results provide further evidence that PLCG2 and the M28L variant confers increase risk for LOAD and may play an important role in AD pathophysiology.

Retinal Changes in Transgenic Mouse Models of Alzheimer’s Disease

2021 ◽  
Vol 18 ◽  
Author(s):  
Li Guo ◽  
Nivedita Ravindran ◽  
Daniel Hill ◽  
M. Francesca Cordeiro
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Neurodegenerative Disorder ◽  
Neuronal Loss ◽  
Immunohistochemical Analysis ◽  
Therapeutic Effects ◽  
The Central Nervous System ◽  
New Treatments ◽  
The Brain

: Alzheimer’s disease (AD) is a neurodegenerative disorder, the most common form of dementia. AD is characterized by amyloid-ß (Aß) plaques and neurofibrillary tangles (NFT) in the brain, in association with neuronal loss and synaptic failure, causing cognitive deficits. Accurate and early diagnosis is currently unavailable in lifespan, hampering early intervention of potential new treatments. Visual deficits have been well-documented in AD patients, and the pathological changes identified in the brain are also believed to be found in the retina, an integral part of the central nervous system. Retinal changes can be detected by real-time non-invasive imaging due to the transparent nature of the ocular media, potentially allowing an earlier diagnosis as well as monitoring disease progression and treatment outcome. Animal models are essential for AD research, and this review has a focus on retinal changes in various transgenic AD mouse models with retinal imaging and immunohistochemical analysis as well as therapeutic effects in those models. We also discuss the limitations of transgenic AD models in clinical translations.

Dimethyl Fumarate is a Potential Therapeutic Option for Alzheimer’s Disease

2021 ◽  
pp. 1-14
Author(s):  
Xiaodi Sun ◽  
Xinjun Suo ◽  
Xianyou Xia ◽  
Chunshui Yu ◽  
Yan Dou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Antioxidant Enzymes ◽  
Therapeutic Option ◽  
Amyloid Β ◽  
Dimethyl Fumarate ◽  
Therapeutic Effects ◽  
Embryonic Mouse ◽  
Nrf2 Pathway ◽  
Anti Inflammatory

Background: Dimethyl fumarate (DMF) has been approved for clinical treatment of multiple sclerosis based on its antioxidant and anti-inflammatory effects by activating the Nrf2 pathway. Since both oxidative stress and inflammation are involved in Alzheimer’s disease (AD), DMF is a potential therapeutic option for AD. Objective: This study aims to test the therapeutic effects of DMF on AD model mice and to reveal its underlying molecular mechanisms. Methods: Cell viability assay and in vitro immunofluorescence imaging were used to evaluate the antioxidant effect of DMF on embryonic mouse hippocampal neurons. Behavioral test and brain magnetic resonance imaging were used to assess the therapeutic effects of DMF on spatial learning and memory as well as hippocampal volume in AD model mice with and without Nrf2 knockdown. Western blotting was used to analyze the expression of antioxidant enzymes and molecules associated with AD-related pathological pathways. Results: DMF inhibits reactive oxygen species overproduction and protects neurons without Nrf2 knockdown from death. DMF reduces amyloid-β induced memory impairment and hippocampal atrophy in AD model mice rather than in Nrf2 knockdown AD mice. DMF delays the progression of AD by activating the Nrf2 pathway to enhance the expression of downstream antioxidant enzymes and inhibits lipid peroxidation, apoptosis, inflammation, mitochondrial dysfunction and amyloid-β deposition. Conclusion: These results indicate that DMF is a potential therapeutic option for AD through its antioxidant, anti-inflammatory, anti-apoptotic, and other anti-AD effects by activating the Nrf2 pathway.

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