Alcohol use disorder (AUD) is a global public health problem and is frequently comorbid with mental disorders, including anxiety and depression. Ferroptosis is an iron-dependent cell death, which is involved in the pathological process of various diseases such as neurodegenerative diseases, but the role of ferroptosis in the mediation of AUD and its induced mental disorders is unclear. In this study, we aimed to investigate whether ferroptosis was involved in alcohol-induced depressive and anxiety-like behaviors in mice. Following an 8-week period of intermittent alcohol exposure, the alcohol group showed noticeable depressive and anxiety-like behaviors. In addition, nissl staining revealed that alcohol exposure induced neuron damage in the hippocampus (Hip) and prefrontal cortex (PFC) of mice. The levels of synapse-related proteins were significantly reduced in the alcohol group. Iron staining demonstrated that alcohol increased the number of iron-positive staining cells. The protein expression of the transferrin receptor (TFRC) was increased, and the expression of glutathione peroxidase 4 (GPX4) was decreased, respectively, in the alcohol group. Furthermore, the ferroptosis inhibitor ferrostatin-1 significantly prevented alcohol-induced neuron damage and enhanced the expression of N-methyl-d-aspartic acid (NMDA) receptor 2B (NR2B), α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor 1 (GluA1) and GPX4 in vitro. These results indicated that alcohol exposure could induce depressive and anxiety-like behaviors, and that this effect may occur via activating ferroptosis.

Alzheimer’s disease (AD) pathogenesis involves progressive synaptic degeneration, a process potentially driven by maladaptive microglial pruning activity. While synaptic loss is a hallmark of AD, the molecular signals triggering pathological microglia-mediated synaptic engulfment remain elusive. Clec7a—a key marker of disease-associated microglia (DAM)—is known to activate spleen tyrosine kinase (SYK) signaling, enhancing Aβ phagocytosis and neuroprotective functions in 5×FAD models. However, its role in regulating synapse–microglia interactions under tauopathic conditions remains undefined. Our analysis revealed a progressive activation of the Clec7a–SYK signaling axis in the hippocampus of PS19 tauopathy mice, correlating with disease progression. Spatial mapping demonstrated a significant co-localization of Clec7a with hippocampal microglia, suggesting cell-autonomous signaling. The pharmacological inhibition of Clec7a achieved multimodal therapeutic effects by attenuating microglial hyperreactivity, suppressing neuroinflammatory cytokine release, and restoring physiological synaptic turnover. Mechanistically, we identified MD2 as a synaptic “eat-me” signal on tauopathy-related synapses, recruiting Clec7a+ microglia to drive aberrant synaptic elimination in PS19 mice. Strikingly, Clec7a blockade rescued hippocampal-dependent memory deficits in behavioral tests. These findings position Clec7a as a context-dependent therapeutic target, with inhibition strategies showing particular promise for tauopathy-related synaptic degeneration.

Intermediate filament protein vimentin (Vim) is a well-established marker for reactive astrocytes and has been closely associated with Alzheimer’s disease (AD). RNA sequencing data reveal elevated expression of Vim in AD brains, with its aggregation frequently observed around amyloid-β (Aβ) plaques. However, the precise mechanisms by which Vim influences the aggregation or propagation of Aβ plaques remain unclear. In this study, we detected the upregulation of astrocytic Vim in AD brain tissue, with its co-localization around Aβ plaques. Asparagine endopeptidase (AEP), another molecule implicated in AD, was found to cleave Vim both in vitro and in vivo, including within human brain tissue. Mass spectrometry analysis confirmed that the AEP cleavage site on Vim is located at N283. We further investigated the in vivo cellular localization of Vim and observed that fragmented Vim, particularly the C-terminal fragment Vim 284–466, promotes apoptosis and disrupts the network structure that is essential for interaction with glial fibrillary acidic protein (GFAP). This disruption impairs astrocytic phagocytosis of exogenous Aβ, which is attributed to the reduced release of apolipoprotein E (ApoE) by astrocytes. The decrease in ApoE levels, in turn, diminishes the transport and clearance of Aβ. Conversely, mutation of the Vim N283 site (N283A) prevents AEP-mediated cleavage of Vim, preserves the GFAP network structure, restores ApoE levels, and reverses the effects on Aβ aggregation. Collectively, our findings elucidate the role of Vim fragmentation in Aβ plaque deposition and propose a potentially novel therapeutic strategy for Alzheimer’s disease.