Ellagic acid-loaded nanovesicles rescue LTP impairment and neuroinflammation in an AD ex-vivo model

Neurodegenerative diseases, such as Alzheimer's disease (AD), cause progressive neurological decline and major healthcare challenges. AD is marked by deterioration in learning, memory, and cognition, leading to dementia. Early-stage AD brains show accumulation of amyloid-beta (Aβ) protofibrils and plaques, particularly in the hippocampus, associated with chronic neuroinflammation and impaired synaptic plasticity that drive cognitive decline. Current AD treatments primarily relieve symptoms without slowing disease progression, and existing monoclonal antibodies targeting Aβ plaques have controversial side effects. This has driven interest in natural compounds like polyphenols for their broad biological activities. Ellagic acid (EA), a natural polyphenol, exhibits antioxidant, anti-inflammatory, and neuroprotective properties. Experimental models of neurodegenerative diseases have shown EA's potential to improve memory and cognition by modulating synaptic plasticity. This study has evaluated EA's impact on hippocampal synaptic plasticity and its neuroprotective effects against Aβ_1-42-mediated impairments using electrophysiological recordings and immunofluorescence analysis, evaluating microglial morphological normalization as well as interleukins expression. It has been found that, in ex vivo brain slices, EA modulated synaptic plasticity at high concentration, while at the dose that per se does not alter neurotransmission it rescued LTP and basal neurotransmission impairment Aβ_1-42 mediated, and normalized neuroinflammation by reducing interleukins expression released by activated microglia. However, EA's poor water solubility and extensive first-pass metabolism limit its clinical use. Here, EA has been encapsulated in non-ionic surfactant vesicles (NSVs), and the formulation (EA-NSVs) has demonstrated a neuroprotective effect at a lower dose compared to free EA, effectively rescuing synaptic impairment induced by Aβ_1-42.