Neuroprotective Effects of Quercetin in Alzheimer's Disease

Abstract

Quercetin is a flavonoid with notable pharmacological effects and promising therapeutic potential. It is widely distributed among plants and found commonly in daily diets predominantly in fruits and vegetables. Neuroprotection by quercetin has been reported in several in vitro studies. It has been shown to protect neurons from oxidative damage while reducing lipid peroxidation. In addition to its antioxidant properties, it inhibits the fibril formation of amyloid-β proteins, counteracting cell lyses and inflammatory cascade pathways. In this review, we provide a synopsis of the recent literature exploring the relationship between quercetin and cognitive performance in Alzheimer's disease and its potential as a lead compound in clinical applications.

Keywords: Alzheimer’s disease; clinical directions; mechanistic insights; polyphenols; quercetin.

Figure 1

(A) Flavan nucleus, (B) 4-oxo-flavonoid nucleus.

Figure 2

Chemical skeleton of quercetin and derivatives. (A) Quercetin glucoside, (B) quercetin-3-O-sulfate, (C) quercetin-3-O-glucuronide, and (D) 3-O-methyl quercetin.

Figure 3

Schematic presentation of the pathogenesis of Alzheimer’s disease. [1] Amyloid precursor protein (APP) is hydrolyzed by β and γ secretases to form β-amyloid (Aβ), which aggregates to form fibril Aβs. Fibril Aβs upregulate oxidative stress, the inflammatory cascade, and caspase activation, which results into the hyperphosphorylation of the Tau protein to form neurofibrillary tangles(NFTs), and the ultimate result is neuronal cells loss. Extensive fibrils along with activated microglia accumulated to form senile plaques, which lead to neuronal and synaptic loss. [2] Upstream regulating acetyl cholinesterase (AChE) enzyme promotes acetylcholine (Ach) degradation, resulting in neurotransmitter deficit, which leads to cognitive impairment. Amyloid precursor protein (APP), amyloid beta proteins (Aβ), neurofibrillary tangles (NFTs), acetylcholine (Ach), acetyl cholinesterase (AChE).

Figure 4

Anti-Alzheimer’s disease targets of quercetin. Quercetin may utilize several mechanistic targets for neuroprotection in Alzheimer’s disease such as the downstream regulation of oxidative stress and neuroinflammation, which leads to the direct protection of neurons, inhibiting AChE enzymes and resulting in increasing acetylcholine levels and reducing Tau phosphorylation and Aβ aggregation. Tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6), reactive oxygen species (ROS), nitric oxide (NO), acetyl cholinesterase (AChE), and amyloid beta protein (Aβ).

Figure 5

Mechanistic insights of quercetin in Alzheimer’s disease. Quercetin has inhibitory effects on JNK, PI3K/Akt pathways, acetyl cholinesterase (AChE), nuclear factor (erythroid-derived 2)-like 2 (Nrf-2), beta-secretase-1 (BACE-1) enzyme activity, and the hyperphosphorylation of tau proteins. On the other hand, it stimulates the expression of AMP-activated protein kinase (AMPK), which thereby decreases reactive oxygen species (ROS) generation by inhibiting NADPH oxidase activity or by increasing the antioxidant activity of enzymes such as superoxide dismutase-2 (SOD2).