Binggui Sun

Bile acids emerge as multifunctional signaling molecules with dual hepatic and microbial origins, acting through farnesoid X receptor and Takeda G protein-coupled receptor 5 to influence inflammation and metabolism. Their dysregulation is consistently observed across various neurodegenerative diseases. The microbiota–gut–brain axis is a pivotal conduit for bile acids-driven neuromodulation, while sex-specific bile acid profiles and signaling pathways introduce critical biological heterogeneity. Emerging translational evidence indicates the promise of bile acids as biomarkers and therapeutic targets, yet highlights the critical hurdles that need to be addressed to realize precision interventions. Our core findings are: (1) Bile acids are far more than mere metabolic byproducts. They orchestrate core pathological processes such as neuroinflammation and energy metabolism. Their functions, whether neuroprotective or neurotoxic, are highly context-dependent, varying with cell type and disease-specific pathological backgrounds, thus exhibiting a potent “double-edged sword” effect. (2) The “microbiota–bile acids–brain axis” serves as a crucial bridge linking peripheral metabolic dysregulation to central nervous system pathology. (3) Sexual dimorphism emerges as a fundamental biological variable essential for understanding the heterogeneity in bile acid profiles and disease susceptibility. The primary contribution of this work is the proposal of an integrated “microbiota-bile acids-sex” framework that systematically describes the key scientific challenge of the context-dependent, dual roles of bile acids. Ultimately, this review champions a paradigm shift from a traditional brain-centric view to a systemic, metabolic perspective, establishing the bile acid system as a promising target for future precision therapeutic interventions.

Alzheimer’s disease (AD) is the most common neurodegenerative disease, and diverse factors contribute to its pathogenesis. Previous studies have suggested the dysregulation of m⁶A modification involves in AD, but the underlying mechanism and targets remain largely unknown. In the present study, we have shown that the levels of Mettl3 and m⁶A modification are increased in specific brain regions of 5xFAD mice and post-mortem AD patients, respectively. Heterozygous deletion of neuronal Mettl3 (AD::Mettl3^+/−) reduced Aβ plaques and inflammation, and improved learning and memory of AD mice, and vice versa for Mettl3 knock in (AD::Mettl3-KI). Mechanistically, we observed that the level of m⁶A modification of Lingo2 increased in 5xFAD mice and AD patients, which promoted the binding of Ythdf2 and enhanced the degradation of Lingo2 mRNA. The decreased level of Lingo2 promoted the interaction between APP and β-site amyloid precursor protein cleaving enzyme (Bace1), and subsequently enhanced Aβ production in AD mice, which can be inhibited by Mettl3 depletion. Both ectopic Lingo2 and the administration of Mettl3 inhibitor STM2457 significantly alleviated the neuropathology and behavioral deficits of AD mice. In summary, our study has revealed the important function of Mettl3 and m⁶A in the pathogenesis of AD and provided novel insight for the underlying mechanisms. Our study also suggests that m⁶A and Lingo2 could be potential therapeutic targets for AD.

Abnormal excitability of hippocampal neurons may lead to dysfunction of neural circuits and then causes cognitive impairments in Alzheimer’s disease (AD). However, the underlying mechanisms remain to be fully elucidated. Electrophysiology was performed to examine the intrinsic excitability of CA1 neurons and the activity of the hyperpolarization-activated cyclic nucleotide-gated ion channels (HCNs) of CA1 neurons in wild type (WT) and hAPP-J20 mice. The activity of CA1 pyramidal neurons (PNs) was modulated with chemogenetics. The activity of HCNs was regulated with nonselective facilitator (cAMP) or inhibitor (ZD7288) of HCNs. Immunohistochemical staining or western blotting were performed to examine the expression of HCN1 and HCN2 in the hippocampus of WT and hAPP-J20 mice, or AD patients and non-AD controls. AAVs were injected to specifically modulate the expression of HCN2 in dorsal CA1 (dCA1) PNs. Cognitive performance of mice was assessed with behavioral tests. dCA1 PNs were more excitable in hAPP-J20 mice, but the excitability of PNs in the ventral CA1 (vCA1) or PV neurons was comparable between WT and hAPP-J20 mice. The activity of the HCNs was reduced in dCA1 PNs of hAPP-J20 mice, and pharmacologically increasing the activity of HCNs attenuated the hyperexcitability of dCA1 PNs in hAPP-J20 mice, suggesting that the reduced activity of HCNs is associated with the hyperexcitability of dCA1 PNs in hAPP-J20 mice. The expression of HCN2 but not HCN1 was reduced in the hippocampus of hAPP-J20 mice, and the expression of HCN2 was also reduced in the hippocampus of AD patients, suggesting that dysregulation of HCN2 is associated with the reduced activity of HCNs in AD. Overexpressing HCN2 rescued the activity of HCNs, attenuated the hyperexcitability of dCA1 PNs and improved memory of hAPP-J20 mice, and knocking down HCN2 impaired the function of HCNs, increased the excitability of dCA1 PNs and led to memory deficits in WT mice. Our data suggest that dysregulation of HCNs, particularly HCN2, contributes to the abnormal excitability of CA1 PNs in AD mice and probably in AD patients as well, and thus provide new insights into the mechanisms underlying the aberrant activity or excitability of hippocampal neurons in AD.

CA2 pyramidal neurons (PNs) are associated with social behaviors. The mechanisms, however, remain to be fully investigated. Here, we report that Efr3b, a protein essential for phospholipid metabolism at the plasma membrane, is widely expressed in the brain, especially in the hippocampal CA2/CA3 areas. To assess the functional significance of Efr3b in the brain, we generated Efr3b ^f/f mice and crossed them with Nestin-cre mice to delete Efr3b specifically in the brain. We find that Efr3b deficiency in the brain leads to deficits of social novelty recognition and hypoexcitability of CA2 PNs. We then knocked down the expression of Efr3b specifically in CA2 PNs of C57BL/6J mice, and our results showed that reducing Efr3b in CA2 PNs also resulted in deficits of social novelty recognition and hypoexcitability of CA2 PNs. More interestingly, restoring the expression of Efr3b in CA2 PNs enhances their excitability and improves social novelty recognition in Efr3b-deficient mice. Furthermore, direct activation of CA2 PNs with chemogenetics improves social behaviors in Efr3b-deficient mice. Together, our data suggest that Efr3b is essential for social novelty by modulating the excitability of CA2 PNs.

Alzheimer's disease (AD) is a neurodegenerative disorder, and its strongest risk factor is aging. A few studies have explored the relationship between aging and AD, while the underlying mechanism remains unclear. We assembled data across multi‐omics (i.e., epigenetics, transcriptomics, and proteomics, based on frozen tissues from the dorsolateral prefrontal cortex) and neuropathological and clinical traits from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). Aging was assessed using six DNA methylation clocks (including the Horvath clock, Hannum clock, Levine clock, HorvathSkin clock, Lin clock, and Cortical clock) that capture mortality risk in literature. After accounting for age, we first identified a gene module (including 263 genes) that was related to the integrated aging measure of six clocks, as well as three neuropathological traits of AD (i.e., β‐amyloid, Tau tangles, and tangle density). Interestingly, among 20 key genes with top intramodular connectivity of the module, PBXIP1 was the only one that was significantly associated with all three neuropathological traits of AD at the protein level after Bonferroni correction. Furthermore, PBXIP1 was associated with the clinical diagnosis of AD in both ROSMAP and three independent datasets. Moreover, PBXIP1 may be related to AD through its role in astrocytes and hippocampal neurons, and the mTOR pathway. The results suggest the critical role of PBXIP1 in AD and support the potential and feasibility of using multi‐omics data to investigate mechanisms of complex diseases. However, more validations in different populations and experiments in vitro and in vivo are required in the future.

Previous studies have shown that Ogt-mediated O-GlcNAcylation is essential for neuronal development and function. However, the function of O-GlcNAc transferase (Ogt) and O-GlcNAcylation in astrocytes remains largely unknown. Here we show that Ogt deficiency induces inflammatory activation of astrocytes in vivo and in vitro, and impairs cognitive function of mice. The restoration of O-GlcNAcylation via GlcNAc supplementation inhibits the activation of astrocytes, inflammation and improves the impaired cognitive function of Ogt deficient mice. Mechanistically, Ogt interacts with NF-κB p65 and catalyzes the O-GlcNAcylation of NF-κB p65 in astrocytes. Ogt deficiency induces the activation of NF-κB signaling pathway by promoting Gsk3β binding. Moreover, Ogt depletion induces the activation of astrocytes derived from human induced pluripotent stem cells. The restoration of O-GlcNAcylation inhibits the activation of astrocytes, inflammation and reduces Aβ plaque of AD mice in vitro and in vivo. Collectively, our study reveals a critical function of Ogt-mediated O-GlcNAcylation in astrocytes through regulating NF-κB signaling pathway.

Hippocampal neurogenesis declines with aging. Wnt ligands and antagonists within the hippocampal neurogenic niche regulate the proliferation of neural progenitor cells and the development of new neurons, and the changes of their levels in the niche mediate aging-associated decline of neurogenesis. We found that RNA-binding protein Lin28a remained existent in neural progenitor cells and granule neurons in the adult hippocampus, and decreased with aging. Loss of Lin28a inhibited the responsiveness of neural progenitor cells to niche Wnt agonist and reduced neurogenesis, thus impairing pattern separation. Overexpression of Lin28a increased the proliferation of neural progenitor cells, promoted the functional integration of newborn neurons, restored neurogenesis in Wnt-deficient dentate gyrus, and rescued the impaired pattern separation in aging mice. Our data suggest that Lin28a regulates adult hippocampal neurogenesis as an intracellular mechanism by responding to niche Wnt signals, and its decrease is involved in aging-associated decline of hippocampal neurogenesis as well as related cognitive functions.