Screening of plant-based natural products for reactive astrogliosis in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, that involves the deposition of extracellular amyloid-beta (Aβ) plaques, the intracellular aggregation of hyperphosphorylated tau as well as the onset of chronic neuroinflammation along with synaptic dysfunction. Despite extensive research, effective treatment options remain elusive. Astrocytes, key regulators of neuroinflammation and Aβ processing, are emerging as promising therapeutic targets. The accumulation of pyroglutamylated Aβ (Aβ3(pE)-42) in astrocytes triggers glial activation and the release of pro-inflammatory cytokines, ultimately contributing to early synaptic dysfunction in AD. However, the mechanisms of Aβ3(pE)-42 uptake to astrocytes are unknown and pharmacological interventions interfering with this process are lacking. Plant-based natural products, such as polyphenols, hold promise for AD therapy due to their anti-inflammatory and antioxidant properties. This study aimed to identify plant substances modulating astrocytic responses to Aβ3(pE)-42. Optimal culture conditions for primary astrocytes were established, and astrocytic Aβ3(pE)-42 uptake was confirmed without significant changes in reactivity markers. A screening assay identified five polyphenols (quercetin, epicatechin, rutin, apigenin, resveratrol) that reduce Aβ3(pE)-42 uptake, with quercetin showing protective effects against early synaptic loss in neuron-glia co-cultures and long-term potentiation impairment in acute mouse hippocampal slices. Taken together, this work highlights the potential of plant-derived polyphenols in mitigating astrocyte-related cellular dysfunctions in AD.