Gossypetin ameliorates 5xFAD spatial learning and memory through enhanced phagocytosis against Aβ

Abstract

Background Microglia are the resident immune cells found in our brain. They have a critical role in brain maintenance. Microglia constantly scavenge various waste materials in the brain including damaged or apoptotic neurons and Aβ. Through phagocytosis of Aβ, microglia prevent the accumulation of Aβ plaque in the brain. However, in Alzheimer’s disease (AD) patients, chronic exposure to Aβ makes microglia to become exhausted, which reduces their phagocytic activity against Aβ. Since microglia play an important role in Aβ clearance, enhancing microglial phagocytic activity against Aβ is a promising target for AD treatment. Therefore, there is a great need for therapeutic candidate that enhances microglial Aβ clearance while inhibiting microglia’s pathogenic properties. Methods In vivo studies were conducted with 5xFAD AD model mice by treating gossypetin for 13 weeks through intragastric administration. Their spatial learning and memory were evaluated through behavior tests such as Y-maze and Morris Water Maze test. Hippocampus and cortex were acquired from the sacrificed mice, and they were used for histological and biochemical analysis. Also, mouse tissues were dissociated into single cells for single-cell RNA sequencing (scRNA-seq) analysis. Transcriptome of microglial population was analyzed. Mouse primary microglia and BV2 mouse microglial cell line were cultured and treated with fluorescent recombinant Aβ to evaluate whether their phagocytic activity is affected by gossypetin. Results Gossypetin treatment improved the spatial learning and memory of 5xFAD by decreasing Aβ deposition in the hippocampus and cortex of 5xFAD. Gossypetin induced transcriptomic modulations in various microglial subpopulations, including disease-associated microglia. Gossypetin enhanced phagocytic activity of microglia while decreasing their gliosis. Gossypetin also increased MHC II+ microglial population. Conclusions Gossypetin showed protective effects against AD by enhancing microglial Aβ phagocytosis. Gossypetin appears to be a novel promising therapeutic candidate against AD.

Behavioral and neuropathological features of Alzheimer’s disease are attenuated in 5xFAD mice treated with intranasal GHK peptide

“…Specifically, in the Y-maze spatial alternation test, GHK-Cu-treated transgenic mice of both sexes exhibited more spontaneous alternations, indicative of rescued working memory and prefrontal cortical functions (Kraeuter et al, 2018). Similar levels of spontaneous alternations were observed i both sexes of GHK-Cu-treated mice compared to other studies involving AD-related drug interventio (Cai et al, 2019;Jo et al, 2022;Morello et al, 2018). In the Box Maze task, GHK-Cu-treated 5xFAD mice of both sexes displayed decreased escape latencies, consistent with other reports on AD-related drug interventions (Mukherjee et al, 2019).…”

Gamma-Flicker Light Reinforces MHC-II Mediated Antigen Processing and Presentation of Microglia in the Mouse Retina under Aging

“…In conclusion, γFL treatment can effectively orchestrate microglia activity, inducing MHC-II mediated antigen presentation in the retina under aging in mice. The clearance of aging-related proteins depends on the recruitment and phagocytosis of MHC-II positive microglia [33,34,36]. Yet, aging-related proteins inhibit antigen-presenting cells including astrocytes, dendritic cells, and microglia in the central nervous system to varying degrees [54].…”

“…Recently, MHC-II + microglia population becomes the therapeutic target for aging-related neural diseases, arousing more and more research attention [11,12,33]. In the future, further studies are needed to reveal more systemic-overall, precise mechanisms underlying γFL-induced MHC-II-expressing microglial subpopulation, and more expansions are necessary to apply the treatment of γFL to various aging-related disease situations.…”

“…Additionally, considering the possible protective role of subretinal microglia in rodent retinal aging [7], we also assessed the subretinal MHC-II expression and showed that γFL increased the microglia number in the subretinal space, the microglia whose cell body was larger versus the control and whose MHC-II expression was high positive. The MHC II has been regarded as an indispensable condition for microglial phagocytosis, which is a promising target to clear waste materials when treating aging-related nervous diseases [11,12,33]. A recent report showed that a de ciency in MHC II induced an increased Aβ aggravation and decreased microglial phagocytic activity in the agedmouse brain [34].…”

Transcranial Magneto-Acoustic Stimulation Protects Synaptic Rehabilitation from Amyloid-Beta Plaques via Regulation of Microglial Functions

“…Amyloid plaques play an important role in the pathogenesis of Alzheimer's disease [26,27]. Microglial phagocytosis is essential for diminishing the accumulation of amyloid plaques [28,29].…”