Natural Dietary Supplementation of Anthocyanins via PI3K/Akt/Nrf2/HO-1 Pathways Mitigate Oxidative Stress, Neurodegeneration, and Memory Impairment in a Mouse Model of Alzheimer’s Disease

Abstract

Well-established studies have shown an elevated level of reactive oxygen species (ROS) that induces oxidative stress in the Alzheimer's disease (AD) patient's brain and an animal model of AD. Herein, we investigated the underlying anti-oxidant neuroprotective mechanism of natural dietary supplementation of anthocyanins extracted from Korean black beans in the amyloid precursor protein/presenilin-1 (APP/PS1) mouse model of AD. Both in vivo (APP/PS1 mice) and in vitro (mouse hippocampal HT22 cells) results demonstrated that anthocyanins regulate the phosphorylated-phosphatidylinositol 3-kinase-Akt-glycogen synthase kinase 3 beta (p-PI3K/Akt/GSK3β) pathways and consequently attenuate amyloid beta oligomer (AβO)-induced elevations in ROS level and oxidative stress via stimulating the master endogenous anti-oxidant system of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (Nrf2/HO-1) pathways and prevent apoptosis and neurodegeneration by suppressing the apoptotic and neurodegenerative markers such as activation of caspase-3 and PARP-1 expression as well as the TUNEL and Fluoro-Jade B-positive neuronal cells in the APP/PS1 mice. In vitro ApoTox-Glo™ Triplex assay results also showed that anthocyanins act as a potent anti-oxidant neuroprotective agent and reduce AβO-induced neurotoxicity in the HT22 cells via PI3K/Akt/Nrf2 signaling. Importantly, anthocyanins improve memory-related pre- and postsynaptic protein markers and memory functions in the APP/PS1 mice. In conclusion, our data suggested that consumption and supplementation of natural-derived anti-oxidant neuroprotective agent such as anthocyanins may be beneficial and suggest new dietary-supplement strategies for intervention in and prevention of progressive neurodegenerative diseases, such as AD.

Isoflavone biochanin A, a novel nuclear factor erythroid 2‐related factor 2 (Nrf2)‐antioxidant response element activator, protects against oxidative damage in HepG2 cells

“…Similarly, ERK1/2 was also found to be involved in the activation of Nrf2 signaling induced by genistin. 15 According to many recent studies, the activation of Nrf2 signaling induced by natural antioxidant agents can also be regulated by other upstream signaling pathways, such as AMP-activated protein kinase (AMPK), 40,41 phosphorylated-phosphatidylinositol 3-kinase-Akt (PI3K/Akt), 42 and glycogen-synthase kinase-3β (GSK-3β). 43 Thus, in addition to MAPK pathways suggested in our study, whether aforementioned molecular mechanisms are responsible for the activation of Nrf2 pathway mediated by BCA requires more study.…”

Microglia Mediated Neuroinflammation: Focus on PI3K Modulation

“…The PI3K pathway is involved in many common diseases, such as cancer, diabetes, cardiovascular disease, and neurological diseases [48]. In particular, its dysregulation has a role in brain pathologies such as developmentally associated brain malformations [76,77], epilepsy [78], aging associated neurodegeneration [79] and brain cancer [80].…”

Pharmacological Mechanisms Underlying the Neuroprotective Effects of Alpinia oxyphylla Miq. on Alzheimer’s Disease

“…Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by brain atrophy, progressive cognitive dysfunction, and behavioral disturbances [1]. The cardinal neuropathological features of AD include extracellular accumulations of amyloid beta (Aβ) peptide [2], neurofibrillary tangles (NFTs) of hyper-phosphorylated tau proteins [3], neuropil threads, dystrophic neuritis [4,5], astrogliosis, microglial activation [6], and overall neurodegeneration of the brain [6][7][8]. Several hypotheses about cholinergic system dysfunction [9], Aβ deposits, oxidative stress [10], inflammatory pathways [11], calcium signaling dysfunction [12], hormone imbalance [13], and genetic components [14] have been considered to play important roles in the occurrence and development of AD, although the etiology of this disease is still not precisely known [15].…”