Alzheimer’s disease (AD) is a progressive neurodegenerative disorder; it is the most common cause of dementia and has no treatment. It is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aβ) and the intraneuronal deposits of Neurofibrillary tangles (NFTs). Yet, those two hallmarks do not explain the full pathology seen with AD, suggesting the involvement of other mechanisms. Neuroinflammation could offer another explanation for the progression of the disease. This review provides an overview of recent advances on the role of the immune cells’ microglia and astrocytes in neuroinflammation. In AD, microglia and astrocytes become reactive by several mechanisms leading to the release of proinflammatory cytokines that cause further neuronal damage. We then provide updates on neuroinflammation diagnostic markers and investigational therapeutics currently in clinical trials to target neuroinflammation.

Alzheimer's disease (AD) is the most common form of dementia among several neurodegenerative disorders afflicting the elderly. AD is characterized by the deposition of extracellular amyloid-β (Aβ) plaques, disrupted blood−brain barrier (BBB), and neuroinflammation. Several studies have demonstrated the health benefits of olive oil and olive leaf extract (OLE) due to their polyphenolic content. The main phenolic compound in OLE is glycosylated oleuropein (OLG), while the aglycon form of oleuropein (OLA) exists in much lower amounts. This work aimed to evaluate the effect of a low dose of OLG-rich OLE and the mechanism(s) that contributed to the observed beneficial effects against Aβ pathology in the homozygous 5xFAD mouse model. Mice were fed with OLE-enriched diet (695 μg/kg body weight/day) for 3 months, starting at 3 months old. Overall findings demonstrated that OLE reduced neuroinflammation by inhibiting the NF-κB pathway and suppressing the activation of NLRP3 inflammasomes and RAGE/HMGB1 pathways. In addition, OLE reduced total Aβ brain levels due to increased clearance and reduced production of Aβ and enhanced BBB integrity and function, which collectively improved the memory function. Thus, the consumption of OLE as a dietary supplement is expected to stop and/or slow the progression of AD.

In Alzheimer’s disease (AD), several studies have reported blood-brain barrier (BBB) breakdown with compromised function. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are transport proteins localized at the BBB luminal membrane and play an important role in the clearance of amyloid-β (Aβ). The purpose of this study was to investigate the effect of pharmacological inhibition of Aβ efflux transporters on BBB function and Aβ accumulation and related pathology. Recently, we have developed an in vitro high-throughput screening assay to screen for compounds that modulate the integrity of a cell-based BBB model, which identified elacridar as a disruptor of the monolayer integrity. Elacridar, an investigational compound known for its P-gp and BCRP inhibitory effect and widely used in cancer research. Therefore, it was used as a model compound for further evaluation in a mouse model of AD, namely TgSwDI. TgSwDI mouse is also used as a model for cerebral amyloid angiopathy (CAA). Results showed that P-gp and BCRP inhibition by elacridar disrupted the BBB integrity as measured by increased IgG extravasation and reduced expression of tight junction proteins, increased amyloid deposition due to P-gp, and BCRP downregulation and receptor for advanced glycation end products (RAGE) upregulation, increased CAA and astrogliosis. Further studies revealed the effect was mediated by activation of NF-κB pathway. In conclusion, results suggest that BBB disruption by inhibiting P-gp and BCRP exacerbates AD pathology in a mouse model of AD, and indicate that therapeutic drugs that inhibit P-gp and BCRP could increase the risk for AD.

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Aging is a major risk factor for Alzheimer’s disease (AD). AD mouse models are frequently used to assess pathology, behavior, and memory in AD research. While the pathological characteristics of AD are well established, our understanding of the changes in the metabolic phenotypes with age and pathology is limited. In this work, we used the Promethion cage systems® to monitor changes in physiological metabolic and behavioral parameters with age and pathology in wild-type and 5xFAD mouse models. Then, we assessed whether these parameters could be altered by treatment with oleocanthal, a phenolic compound with neuroprotective properties. Findings demonstrated metabolic parameters such as body weight, food and water intake, energy expenditure, dehydration, and respiratory exchange rate, and the behavioral parameters of sleep patterns and anxiety-like behavior are altered by age and pathology. However, the effect of pathology on these parameters was significantly greater than normal aging, which could be linked to amyloid-β deposition and blood–brain barrier (BBB) disruption. In addition, and for the first time, our findings suggest an inverse correlation between sleep hours and BBB breakdown. Treatment with oleocanthal improved the assessed parameters and reduced anxiety-like behavior symptoms and sleep disturbances. In conclusion, aging and AD are associated with metabolism and behavior changes, with the changes being greater with the latter, which were rectified by oleocanthal. In addition, our findings suggest that monitoring changes in metabolic and behavioral phenotypes could provide a valuable tool to assess disease severity and treatment efficacy in AD mouse models.

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Background Transient Receptor Potential Ankyrin 1 (TRPA1) is a cation channel receptor that regulate calcium homeostasis among other cations. Calcium dyshomeostasis known to disrupt the blood‐brain barrier (BBB). In the brains of Alzheimer's disease (AD) transgenic mice, increased levels of TRPA1 was associated with increased levels of amyloid‐β (Aβ) and neuroinflammation. TRPA1 expressed in the endothelial cells of the BBB. The objective of this work is to investigate the effect of BBB‐endothelium TRPA1 activation on the BBB tightness and function. Method We performed in vitro and in vivo studies, Western blot, calcium assay, immunostaining. Result We performed in vitro studies using the mouse brain endothelial cell line bEnd3. First, we determined the expression of TRPA1 in bEnd3 by western blot and immunocytochemistry. Results confirmed TRPA1 expression in bEnd3. In addition, TRPA1 function was evaluated by monitoring calcium influx; the addition of the TRPA1 antagonist A‐967079 significantly reduced calcium influx in bEnd3, while the addition of Aβ42 oligomers to the cells increased intracellular calcium levels, which was blocked by the co‐addition of the TRPA1 antagonist suggesting that Aβ induces calcium influx via TRPA1. When tested in vivo in 5XFAD mouse model for AD by western blot, we found that TRPA1 levels were significantly higher in brain homogenates when compared to wild‐type (WT) mouse brains. Furthermore, the cerebrovascular levels of TRPA1 were significantly higher in 5XFAD compared to WT, which were also associated with BBB disruption as determined by increased IgG extravasation. Conclusion Our data suggests that endothelium‐TRPA1 could contribute to BBB disruption by increasing calcium influx.