The flavonoid quercetin ameliorates Alzheimer's disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer's disease model mice

Abstract

Alzheimer’s disease (AD) is the most common senile dementia in the world. Although important progress has been made in understanding the pathogenesis of AD, current therapeutic approaches provide only modest symptomatic relief. In this study, we evaluated the neuroprotective effect of quercetin (25 mg/kg) administration via i.p. injection every 48 hours for 3 months on aged (21–24 months old) triple transgenic AD model (3xTg-AD) mice. Our data show that quercetin decreases extracellular β-amyloidosis, tauopathy, astrogliosis and microgliosis in the hippocampus and the amygdala. These results were supported by a significant reduction in the paired helical filament (PHF), β-amyloid (βA) 1–40 and βA 1–42 levels and a decrease in BACE1-mediated cleavage of APP (into CTFβ). Additionally, quercetin induced improved performance on learning and spatial memory tasks and greater risk assessment behavior based on the elevated plus maze test. Together, these findings suggest that quercetin reverses histological hallmarks of AD and protects cognitive and emotional function in aged 3xTg-AD mice.

Quercetin ameliorates inflammation in CA1 hippocampal region in aged triple transgenic Alzheimer´s disease mice model.

“…The 3xTg-AD and non-Tg mice received 25 mg/ kg intraperitoneal injections of quercetin or 0.1% DMSO every 48 hours for three consecutive months, as previously described (17).…”

“…Animals were intracardially perfused using 4% paraformaldehyde, and 50 µm coronal sections were used for Nissl (toluidine blue) staining and immunohistochemistry evaluation as previously described (17). We assessed the CA1 region at bregma -1.82 and -2.06 mm.…”

“…The procedure was performed as described previously (17). Briefly, anti-NOS2, anti-COX2, and anti-Tubulin (1:10000, monoclonal anti-βIII tubulin, # G712A, Promega, AB_430874) were used as loading control, and CW IRDye 680 goat antimouse or rabbit 800 (LI-COR, diluted 1: 10000) were used as secondary antibodies.…”

“…In our previous studies, we have demonstrated that quercetin reduces histopathological hallmarks improving cognitive and emotional skills in a 3xTg-AD mice model (17). Given that the hippocampus CA1 region is a vulnerable area for excitotoxicity and neuronal death in Alzheimer's disease (18), in this study we evaluated the effect of quercetin on the pro-inflammatory response.…”

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

“…Quercetin also displays antiamyloidogenic properties, illustrated by its ability to reduce BACE1 and Aβ levels in mice (217), prevent Aβ aggregation (221,222), promote autophagy (221,223) and bind to BACE1 catalytic core as an inhibitor (224). On the other hand, quercetin enhances the effect of neurotrophic factors such as NGF (225) and BDNF (226) to foster neuronal survival and neurite outgrowth, with tangible amelioration of memory function in animal models of AD (227)(228)(229)(230)(231) and in In parallel, XBP1 can be locally synthetized within dendrites through SPRCs and transported into the nucleus to activate transcription of BDNF, Kalirin-7 and a myriad of other genes that are crucial for the survival and plasticity of neurons. mBDNF is released at synapses and activates TrkB receptors to recruit XBP1 and Kalirin-7, which controls spinogenesis through Rho-GTPases RAC1 and PAK1, resulting in a positive activation loop.…”