A Synergistic Combination of DHA, Luteolin, and Urolithin A Against Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common form of dementia worldwide. The classical AD brain is characterized by extracellular deposition of amyloid-ß (Aß) protein aggregates as senile plaques and intracellular neurofibrillary tangles (NFTs), composed of hyper-phosphorylated forms of the microtubule-associated protein Tau. There has been limited success in clinical trials for some proposed therapies for AD, so attention has been drawn toward using alternative approaches, including prevention strategies. As a result, nutraceuticals have become attractive compounds for their potential neuroprotective capabilities. The objective of the present study was to derive a synergistic nutraceutical combination in vitro that may act as a potential preventative therapy for AD. The compounds of interest were docosahexaenoic acid (DHA), luteolin (LUT), and urolithin A (UA). The cell viability and cytotoxicity assays MTS and LDH were used to evaluate the compounds individually and in two-compound combinations, for their ability to inhibit Aß1-42-induced toxicity in human neuroblastoma BE(2)-M17 cells. The LDH-derived% protection values were used in the program CompuSyn v.1.0 to calculate the combination index (CI) of the two-compound combinations. The software-predicted potentially synergistic (CI < 1) two-compound combinations were validated using CellTiter Glo assay. Finally, a three-compound combination was predicted (D5L5U5) and shown to be the most effective at inhibiting Aß1-42-induced toxicity. The synergistic combination, D5L5U5 warrants further research for its mechanism of action; however, it can serve as a basis to develop an advanced functional food for the prevention or co-treatment of AD.

Mitoprotective Effects of a Synergistic Nutraceutical Combination: Basis for a Prevention Strategy Against Alzheimer's Disease.

Evidence to date suggests the consumption of food rich in bioactive compounds, such as polyphenols, flavonoids, omega-3 fatty acids may potentially minimize age-related cognitive decline. For neurodegenerative diseases, such as Alzheimer's disease (AD), which do not yet have definitive treatments, the focus has shifted toward using alternative approaches, including prevention strategies rather than disease reversal. In this aspect, certain nutraceuticals have become promising compounds due to their neuroprotective properties. Moreover, the multifaceted AD pathophysiology encourages the use of multiple bioactive components that may be synergistic in their protective roles when combined. The objective of the present study was to determine mechanisms of action underlying the inhibition of Aß1-42-induced toxicity by a previously determined, three-compound nutraceutical combination D5L5U5 for AD. In vitro experiments were carried out in human neuroblastoma BE(2)-M17 cells for levels of ROS, ATP mitophagy, and mitobiogenesis. The component compounds luteolin (LUT), DHA, and urolithin A (UA) were independently protective of mitochondria; however, the D5L5U5 preceded its single constituents in all assays used. Overall, it indicated that D5L5U5 had potent inhibitory effects against Aß1-42-induced toxicity through protecting mitochondria. These mitoprotective activities included minimizing oxidative stress, increasing ATP and inducing mitophagy and mitobiogenesis. However, this synergistic nutraceutical combination warrants further investigations in other in vitro and in vivo AD models to confirm its potential to be used as a preventative therapy for AD.

Targeting Mitophagy in Alzheimer's Disease.

Mitochondria perform many essential cellular functions including energy production, calcium homeostasis, transduction of metabolic and stress signals, and mediating cell survival and death. Maintaining viable populations of mitochondria is therefore critical for normal cell function. The selective disposal of damaged mitochondria, by a pathway known as mitophagy, plays a key role in preserving mitochondrial integrity and quality. Mitophagy reduces the formation of reactive oxygen species and is considered as a protective cellular process. Mitochondrial dysfunction and deficits of mitophagy have important roles in aging and especially in neurodegenerative disorders such as Alzheimer's disease (AD). Targeting mitophagy pathways has been suggested to have potential therapeutic effects against AD. In this review, we aim to briefly discuss the emerging concepts on mitophagy, molecular regulation of the mitophagy process, current mitophagy detection methods, and mitophagy dysfunction in AD. Finally, we will also briefly examine the stimulation of mitophagy as an approach for attenuating neurodegeneration in AD.

Activate or Inhibit? Implications of Autophagy Modulation as a Therapeutic Strategy for Alzheimer's Disease.

Neurodegenerative diseases result in a range of conditions depending on the type of proteinopathy, genes affected or the location of the degeneration in the brain. Proteinopathies such as senile plaques and neurofibrillary tangles in the brain are prominent features of Alzheimer's disease (AD). Autophagy is a highly regulated mechanism of eliminating dysfunctional organelles and proteins, and plays an important role in removing these pathogenic intracellular protein aggregates, not only in AD, but also in other neurodegenerative diseases. Activating autophagy is gaining interest as a potential therapeutic strategy for chronic diseases featuring protein aggregation and misfolding, including AD. Although autophagy activation is a promising intervention, over-activation of autophagy in neurodegenerative diseases that display impaired lysosomal clearance may accelerate pathology, suggesting that the success of any autophagy-based intervention is dependent on lysosomal clearance being functional. Additionally, the effects of autophagy activation may vary significantly depending on the physiological state of the cell, especially during proteotoxic stress and ageing. Growing evidence seems to favour a strategy of enhancing the efficacy of autophagy by preventing or reversing the impairments of the specific processes that are disrupted. Therefore, it is essential to understand the underlying causes of the autophagy defect in different neurodegenerative diseases to explore possible therapeutic approaches. This review will focus on the role of autophagy during stress and ageing, consequences that are linked to its activation and caveats in modulating this pathway as a treatment.

Alterations and Interchange of Morphometric Characters in Different Life Cycle Stages with Reference to Genomic Variations of Anopheles subpictus (Diptera; Culicidae) Sibling Species Complex in Sri Lanka.

The species complex of the mosquito Anopheles subpictus is designated by the sibling species A⁻D, depending on morphological characters of life cycle stages and variations in polytene chromosomes. However, morphological aberrations in the life cycle stages make the identification of sibling species uncertain and imprecise. The objective of the present study is to determine the suitability of morphological variations of sibling species and their genomic variations to identify the sibling species status of an An. subpictus population in Sri Lanka. Life cycle stages of larvae, pupal exuviae, and adults were examined for previously reported distinctive morphological features. Five nuclear and mitochondrial genome regions, including the Internal transcribed spacer 2 (ITS2) region, D3 region, white gene, cytochrome c oxidase I (COI), and Cytochrome b (Cyt-b), were sequenced and analyzed for variations. The eggs changed their distinct sibling morphological characters during metamorphosis (89.33%). The larvae, pupal exuviae, and adult stages showed deviation from their sibling characters by 26.10%, 19.71%, and 15.87%, respectively. However, all the species from the analysis shared two distinct sequence types for all regions, regardless of the morphological variations. In conclusion, the An. subpictus sibling species complex in Sri Lanka is not identifiable using morphological characters due to variations, and the genomic variations are independent from the morphological variations.