Dietary Supplementation of Edible Mushroom Phallus atrovolvatus Aqueous Extract Attenuates Brain Changes in the AppNL−G−F Mouse Model of Alzheimer’s Disease

<b>Background/Objectives:</b> Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive dementia and brain accumulation of Aβ-peptide-containing plaques, gliosis, neuroimmune changes, and neurofibrillary tangles. Mushroom polysaccharides have been previously reported to have anti-neuroinflammation activity through the gut-brain axis. This study aimed to evaluate whether a dietary intervention with <i>Phallus atrovolvatus</i>, a recently identified edible mushroom in Thailand, could have a benefit on gut health and alleviate AD-related changes. <b>Methods:</b> Male and female 6-8-month-old littermate wild-type control (C57BL/6J) and <i>App^NL-G-F</i> mice were randomly assigned to either a control diet or a diet supplemented with mushroom aqueous extract (MAE) for 8 weeks to quantify changes in body weight, intestine, immune cells, short chain fatty acids, brain cytokines, amyloid-β (Aβ) levels, gliosis, and memory. <b>Results:</b> MAE had no adverse effects on gut leakiness and increased pyruvate levels in serum. Splenocyte immune profiling revealed a significant increase in the frequency of IgM⁺, IA_IE⁺, and CD14⁺ cells in MAE-administered <i>App^NL-G-F</i>female mice compared to their vehicle controls. <i>App^NL-G-F</i>male mice that received MAE showed a significant increase in the frequency of cytotoxic CD8 T cells within the cervical lymph nodes compared to their wild-type counterparts. Aβ deposition and gliosis were significantly reduced in the hippocampi of the MAE-supplemented <i>App^NL-G-F</i> groups. However, MAE feeding did not alter spatial recognition memory in either sex or genotype compared to their vehicle groups. <b>Conclusions:</b> Our findings demonstrated that the administration of <i>P. atrovolvatus</i> aqueous extract showed neuroprotective potential against AD-related changes in the brain with no adverse impact on gut health and memory.