Alzheimer's disease (AD) is an imperceptible, progressive, and incurable neuro-degenerative disorder, that occurs most commonly in elderly individuals over the age of 65 years, and accounts for 60–80 % of all cases of dementia [1]. AD is clinically distinguished by impaired learning and memory abilities, and its pathogenesis has been attributed to the formation of extracellular senile plaques made up of amyloid β (Aβ) fibrils and intracellular phosphorylated tau-containing neurofibrillary tangles (NFTs) [2]. Over the past few decades, multiple hypotheses regarding the pathology of AD have been proposed, including Aβ cascade, tau protein phosphorylation, cholinergic deficits, mitochondrial dysfunction, and intestinal flora imbalance [3]. The main reason for the repeated failures targeting anti-Aβ drugs is the complicated nature of AD aetiology, as single-targeted therapies cannot meet all of the pathogenetic routes associated with neurological diseases [4]. In contrast, traditional Chinese medicines have natural advantages in the prevention and intervention of neurodegenerative disorders, such as multiple targets, components, pathways, and few side effects.

Despite the predominance of the Aβ cascade hypothesis in AD pathogenesis, an increasing number of studies have indicated the critical role of gut microbiota in AD progression, acting via the “gut-brain axis”, while its interaction with microglial identity and function has been highlighted [5]. Remodelling of the gut microbiota can ameliorate AD pathology and improve cognitive function [6,7]. A stable intestinal flora microenvironment benefits the intestinal immune system, whereas gut flora disturbances lead to peripheral inflammation, and are probably conducive to pathological advancement and cognitive deficits in AD [8]. Microglia are categorised into classical M1 or alternative M2 phenotypes, whereas astrocytes are classified as neurotoxic A1 and neuroprotective A2 phenotypes, both of which play crucial roles in the onset and development of AD [9]. Disturbances in the intestinal flora disrupt the ontogeny and function of microglia via the gut-brain axis, thus triggering neuroinflammation. Activated neurotoxic M1 microglia provoke A1 astrocyte activity by secreting C1q, Il-1α, and TNFα, leading to further deterioration of central nervous system disease, and aggravating AD [10,11]. Given the emerging role of the intestinal flora in AD, it is possible that nutritional intervention may regulate the phenotype of microglia and astrocytes via the gut-brain axis, thereby providing an efficient way to treat neurodegenerative diseases.

Pseudostellaria heterophylla is a traditional Chinese medicinal herb used for thousands of years in China, which has been authorised by the National Health Commission of the People's Republic of China as one of the “Health Food Commodities” [12]. Modern pharmacological studies have shown that P. heterophylla exerts an assortment of biological activities, including anti-inflammatory [13], antidiabetic [14], antitumour [15], and immunomodulatory [16] effects. Cyclopeptides and polysaccharides are representative constituents of P. heterophylla, and we have previously shown in our research that P. heterophylla aqueous extracts can promote axonal regrowth and regulate neurotransmitters, thus enhancing cognitive memory function [17]. Moreover, a cyclopeptide from P. heterophylla, heterophyllin B, has been shown to attenuate cognitive deficits through immunoregulation and axonal regeneration in an intracerebral Aβ-induced AD mice model [18]. However, whether P. heterophylla polysaccharides (PH-PS) exert neuroprotective and memory-improving effects in AD has not yet been investigated.

In this study, we investigated the cognitive effects of PH-PS in 5 × FAD model mice. To further examine the signalling underlying the PH-PS-induced effects, we investigated brain and serum physiological indicators, microglial and astrocyte phenotypes, and intestinal flora composition. Our study suggests that PH-PS could be used as a potential nutritional supplement for therapeutic interventions in AD.