Ellagic acid ameliorates learning and memory impairment in APP/PS1 transgenic mice via inhibition of β‑amyloid production and tau hyperphosphorylation

Abstract

β-amyloid (Aβ) aggregation and tau hyperphosphorylation are considered to be the primary pathological hallmarks of Alzheimer's disease (AD). Targeted inhibition of these pathological processes may provide effective treatments for AD. Accumulating evidence has demonstrated that ellagic acid (EA) exerts neuroprotective effects in several diseases. The present study investigated the effects of EA on AD-associated learning and memory deficits on APP/PS1 double transgenic mice and the underlying mechanisms. APP/PS1 mice or wild-type C57BL/6 mice were intragastrically administered EA (50 mg/kg/day) or vehicle for 60 consecutive days. The learning and memory abilities of mice were investigated using the Morris water maze test. Hippocampal regions were examined for the presence of amyloid plaques, neuronal apoptosis and tau phosphorylation. Expression levels of APP, Aβ, RAC-αserine/threonine-protein kinase and glycogen synthase kinase (GSK)3β in the hippocampus were determined by western blot analysis and ELISA. The results demonstrated that EA treatment ameliorated spatial learning and memory impairment in APP/PS1 mice and significantly reduced neuronal apoptosis and Aβ deposition in the hippocampus (P<0.05 and P<0.01). In addition, EA significantly inhibited the hyperphosphorylation of tau and significantly decreased the activity of glycogen synthase kinase (GSK)3β (P<0.01), which is involved in tau phosphorylation. Overall, these findings indicated that the beneficial effects of EA on AD-associated cognitive impairments may be attributed to the inhibition of Aβ production and tau hyperphosphorylation, and its beneficial action may be mediated in part, by the RAC-α serine/threonine-protein kinase/GSK3β signaling pathway.

Alteration of the Wnt/GSK3β/β‑catenin signalling pathway by rapamycin ameliorates pathology in an Alzheimer's disease model

“…Notably, it has been demonstrated that different lengths of Tau may be degraded through different autophagic pathways; the full-length Tau is preferentially degraded through macroautophagy, whereas truncated Tau (for one, TauRdΔK280) is cleared through chaperone-mediated autophagy (30). Although the APP/PS1/Tau tri-transgenic Ad mouse model is an ideal model with which to study the pathology of Aβ and Tau, the tau-induced pathology in the APP/PS1 double-transgenic Ad mouse model was also found in our previous study and in other reports (31)(32)(33). This study examined the effects of rapamycin on Tau clearance.…”

Dietary Phenolic Acids and Their Major Food Sources Are Associated with Cognitive Status in Older Italian Adults

“…Ellagic acid, which belongs to hydroxybenzoic acids, has been shown to exert neuroprotective effects by modulating neuroinflammation is a promising constituent for improving cognitive impairment [ 55 ] and alleviating memory impairment [ 56 ]. The neuroprotective activity of ellagic acid has been also validated in APP/PS1 mice, a validated transgenic animal model of Alzheimer’s disease, where it prevents neuronal apoptosis in the hippocampus and rescues memory deficits through the inhibition of beta-amyloid production and tau hyperphosphorylation [ 57 ].…”

Bioaccessible Raspberry Extracts Enriched in Ellagitannins and Ellagic Acid Derivatives Have Anti-Neuroinflammatory Properties

“…A previous study has shown that EA inhibits human platelet activation upon stimulation with hydrogen peroxide, by inhibiting phosphorylation events of MAPK p38, Akt, phospholipase C, and protein kinase C [ 49 ]. In addition, EA was reported to inhibit tau phosphorylation, one of the prime suspects involved in AD pathology, leading to learning and memory improvements in a mice model of AD [ 50 ]. In a more recent study, EA revealed a strong binding affinity for sphingosine kinase 1, repressing phosphorylation by restricting ATP accessibility [ 51 ].…”