Alzheimer's disease (AD) poses a significant challenge to modern healthcare, impacting over 55 million people worldwide as the aging population grows [1,2]. This neurodegenerative condition is characterized by cognitive decline, memory impairment, and behavioural changes, carrying profound societal and economic implications [3]. One of the hallmark features of AD is the aggregation of amyloid-beta (Aβ) peptides into insoluble plaques within the brain, a process linked with AD's pathogenesis [3]. Aβ is a protein fragment derived from the amyloid precursor protein and is typically produced and metabolized harmlessly in the brain [4]. However, examination of the postmortem brains of individuals with AD reveals an abnormal Aβ accumulation, leading to the formation of amyloid plaques. These plaques disrupt normal brain function and represent a prominent pathological feature of AD [5].

The aggregation of Aβ peptides involves several stages, beginning with individual, soluble monomers that can aggregate to form small, soluble oligomers. These Aβ oligomers are more toxic than monomers or larger fibrils, making them more detrimental to neurons [5]. Over time, Aβ oligomers can further assemble into insoluble fibrils, which constitute a major component of amyloid plaques. Therefore, inhibiting Aβ oligomer formation might prevent neurodegeneration, and Aβ oligomer inhibitors could be developed as disease-modifying treatments for AD [6,7].

This escalating concern over Aβ aggregation and its neurotoxic effects has led to a growing interest in exploring natural compounds that may mitigate these processes. Several studies have indicated that phenolic-containing natural products such as those found in olive oil and green tea reduce Aβ aggregation, providing a treatment approach for AD [[8], [9], [10]]. Mangosteen (Garcinia mangostana L.) has recently been discovered to be a rich source of xanthones, a class of polyphenols. Xanthones have been found to have a wide range of biological activities, including anti-cancer [11,12], antioxidant [13], anti-inflammatory [14], anti-cholinesterase [15,16], and anti-Aβ neurotoxicity [13,17], due to their varied structure and chemical properties. A study by Huang et al. [18] reported that Aβ deposition is lowered in AD mice after feeding them with a mangosteen pericarp diet as it exerted neuroprotective, antioxidative, and anti-inflammatory effects in the hippocampus of the mice. Mangosteen extract was seen to exhibit protective effects against increased reactive oxygen species (ROS), Aβ-induced cytotoxicity, and increased caspase activity in human neuroblastoma cells [13].

Previous studies have extensively investigated the neuroprotective effects of specific xanthones found in mangosteen against AD, particularly α-mangostin (α-M), γ-mangostin (γ-M), and gartanin. These compounds exhibit anti-AD properties through various mechanisms, including antioxidant effects, anti-apoptotic mediated neuroprotection, and modulation of inflammatory responses. Oxidative stress, a key factor in AD, is associated with the overproduction of ROS, leading to cellular damage [18]. α-M has been shown to possess significant antioxidant properties by reducing ROS levels and preserving antioxidant enzyme activity through the activation of the SIRT1/3-FOXO3a pathway [19]. α-M, γ-M, and gartanin have also demonstrated neuroprotective effects against apoptosis. They have been found to preserve mitochondrial function, inhibit caspase activation, and conserve Bcl-2 protein levels, thereby preventing neuronal cell death [[19], [20], [21]]. Neuroinflammation also plays a crucial role in AD progression. α-M has shown anti-inflammatory effects by modulating the TLR4/TAK1/NF-κB signaling pathway and inhibiting the release of pro-inflammatory cytokines [22]. γ-M has been reported to modulate the MAPK signaling pathway to ameliorate Aβ-induced neuroinflammation [23]. A further study has shown that mangostanaxanthone IV, another xanthone found in mangosteen, upregulates the phosphorylation of P13K, Akt and glycogen synthase kinase-3β, implying its protective effect in neuroinflammation [24]. Moreover, xanthones have been investigated for their potential to reduce amyloid plaque deposition, another hallmark of AD. α-M has been found to inhibit β- and γ-secretase activity, reducing Aβ formation and neurotoxicity caused by Aβ oligomers [25,26].

While α-M, γ-M, and gartanin have garnered significant attention, it is noteworthy that other xanthones, such as garcinone C (GC) and garcinone D (GD), remain relatively unexplored in the context of AD. Despite their potential therapeutic relevance, the inhibitory effects of GC and GD on Aβ42 oligomer formation have not been comprehensively researched. In this study, we aim to bridge this knowledge gap by examining the inhibitory effects of GC and GD, contributing novel insights to the expanding field of xanthone research for neurodegenerative disorders.