Alzheimer’s disease (AD) is characterized by the deposition of amyloid-β (Aβ) plaques, neuronal loss, and neurofibrillary tangles. In addition, neuroinflammatory processes are thought to contribute to AD pathophysiology. Maitake (Grifola frondosa), an edible/medicinal mushroom, exhibits high nutritional value and contains many health-beneficial, bioactive compounds. It has been reported that proteo-β-glucan, a polysaccharide derived from Maitake (PGM), possesses strong immunomodulatory activities.

In past decades, great efforts have been made to investigate the pathogenesis and therapies of AD. Current medications used to treat AD, which includes donepezil and memantine, are not highly effective. Therefore, further investigation into the effective interventions which could counteract AD is needed. Due to their multimodal effects and relatively low toxicities, functional foods have become highly potent drug candidates for treating AD. In the present study, we revealed that a bioactive polysaccharide component of Maitake (PGM) could significantly alleviate learning and memory deficits in APP/PS1 mice. The current findings highlighted the possibility of using PGM to treat AD.

Maitake (Grifola frondosa), the king of mushrooms, is one of the most valuably traditional medicines. It has been a healthy food in China for a long time. Polysaccharides extracted from Maitake have been reported to possess multiple effects, such as immunomodulatory, antitumor, and antioxidant effects. In a recent study, Oral administration of Grifola frondosa polysaccharides could improve memory impairment via antioxidant action in aged rats. Such polysaccharides exerted their biological activities mainly through immunomodulation; however, it remains unclear whether they improved learning and memory by mediating the immune pathway.

In addition, the role of PGM in Aβ deposition, the most iconic pathological marker of AD, remains unexplored. Nowadays, APP/PS1 double transgenic mice, which mimic the pathological hallmarks of AD in terms of Aβ deposition, have been widely used as an animal model of AD. This study further suggested that PGM could improve learning and memory impairment in APP/PS1 mice and provided clear evidence that PGM treatment could increase the number of surviving neurons and maintain the histomorphology of the hippocampus. Moreover, PGM could enhance microglial recruitment adjacent to the Aβ plaques and improve microglial phagocytic capacity, thereby promoting Aβ clearance in APP/PS1 mice.

In concert with the behavioral result, the neuronal cells of the cortex and hippocampus of APP/PS1 mice were significantly lost and shrinkage than those of the WT mice. The changes in neuronal cell density and morphology were inconsistent with the previous study, and several pathological modifications were observed in the brain of APP/PS1 mice. In the current study, the reduction of the shrunken neurons and ameliorative cell morphology were found by PGM (5 and 10 mg kg−1) treatment, indicating that PGM possessed a neuroprotective effect. Moreover, the Nissl positive cell numbers per mm2 in the DG region of the hippocampus in PGM (5 and 10 mg kg−1) treated mice showed a significant increase as compared with saline treated-APP/PS1 mice. The results indicated that PGM could protect neurons from damage and improve learning and memory impairment.

It has been reported that the accumulation and deposition of Aβ in the brain could drive the pathogenic cascades of AD. Microglia, the brain’s resident immune cells, are the first responders to Aβ accumulation and phagocytosis. During the disease progression of AD, microglia cluster around Aβ deposits and adopt a polarized morphology with hypertrophic processes extending toward plaques. Microglia exerted a potentially protective impact on AD progression by regulating the degree of amyloid deposition by phagocytosis of amyloid aggregates.

Recently, it has been reported that multi-sensory gamma stimulation can ameliorate Alzheimer’s-associated pathology and improves cognition, enhancing microglial recruitment around the plaques and promoting the Aβ phagocytosis and clearance played important roles in this process. Moreover, the depletion of microglia in an AD mouse model led to an overproduction of plaque. Also, an AD mouse model observed dendritic spine loss and shaft atrophy in adjacent neurons. However, chronic and sustained microglial activation could cause the overproduction of neurotoxic inflammatory cytokines and reactive oxygen species, which aggravated the disease progression of AD.

Unfortunately, AD patients who accepted anti-inflammatory therapy showed no cognitive benefits, suggesting that neuroinflammation was not a major driver of AD. Inflammation in neurodegenerative disease is a double-edged sword. Therefore, the activated status of glial cells and their roles in AD pathology were related to the disease progression of AD and the type, intensity, and duration of the medication used to treat AD. Thus, the specific mechanisms and the corresponding outcomes should be explored.

Furthermore, several pieces of evidence showed that a β-glucan, which was extracted from Grifola frondosa, not only directly activated various immune effector cells (macrophages, killer T cells, and natural killer cells) but also potentiated the activities of various mediators, including lymphokines and IL-1 (the first mediator in the activation of T cell lines). Remarkably, polysaccharides derived from Grifola frondosa were more likely to activate the immune system under pathological conditions and thereby exerted multiple biological activities. However, like most immunomodulators, PGM showed a double-edged sword effect on the regulation and subsequent effect of immunity; it has a beneficial impact with reasonable concentration and intensity. Otherwise, it might be difficult to exert its effect or show adverse effects.

In the current study, the results suggested that PGM possessed the most satisfactory effect on the learning ability of APP/PS1 mice and the most significant protective effect on the hippocampus at the medium dosage (10 mg kg−1). In addition, the clearance of Aβ deposits and regulation of glial cells were most effective by PGM treatment at this dosage. At the same time, the high dosage of PGM (20 mg kg−1) did not show the above effects.

Therefore, the follow-up study of PGM, especially the dose-effect relationship on glial cells and the corresponding role in AD, should be applied. In addition, it is imperative to study the therapeutic basis of PGM, including exploring whether other immune effector molecules and key signaling pathways are involved.