Prosocial behaviour, as a facet of social behaviour across species, entails voluntary actions that benefit others, including helping and comforting behaviours. To explain how external sensory information is integrated to generate motivation and ultimately govern prosocial action, we organize its emergence into three interacting components: a social orientation process centered on the superior colliculus (SC), which selects and evaluates social cues and calibrates attention and arousal; a framework formed by the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC), which transforms perceived distress into internal representations, forming empathic memory that guides subsequent behavior; and neuromodulatory systems (e.g., oxytocin and dopamine) together with projections linking the insular cortex (IC), thalamus, and ventral tegmental area (VTA), that compose social motivation, assign value to prosocial acts and promote helping. Evidence across these processes suggests alignment and potential generalisation in autism spectrum disorder (ASD), which is marked by atypical attention to social signals and diminished responsiveness to social reward. We define prosocial neural network mapping as the characterisation of interregional projections and their neuromodulatory regulation to explain how social information is organised and transformed, offering new insights into circuit-level pathology in ASD and helping identify therapeutic targets aimed at restoring social salience and enhancing social motivation.

Olfactory dysfunction has emerged as a promising target for the early diagnosis and treatment of Alzheimer’s disease (AD). However, the mechanisms underlying neural circuit disruption associated with olfactory dysfunction in AD remain poorly understood. We conducted single-cell RNA sequencing (RNA-seq) and ex vivo electrophysiological studies to determine the link between olfactory memory in AD and dynamic synaptic transmission disorders in PCx-IL engram cell circuits. Clinical functional magnetic resonance imaging (fMRI) data revealed that connectivity between the piriform cortex (PCx) and the infralimbic cortex (IL) was impaired during the early mild cognitive impairment (MCI) stage of AD. Optogenetic stimulation of IL-projecting PCx engram neurons successfully improved olfactory memory retrieval in 5xFAD mice. In addition, single-cell RNA sequencing was employed to investigate the mechanisms of damage in IL engram cells, which revealed increased glutamate expression and impaired synaptic function as key alterations. Guided by single-cell sequencing data, we analyzed glutamatergic synaptic transmission in the PCx-IL engram cell circuit in 5xFAD mice. These results indicated dynamic impairments in AMPA receptor-associated synaptic transmission within this circuit. Optical long-term potentiation (LTP) of synaptic transmission restored directional engram synaptic transmission and prevented olfactory memory decline. Therefore, dynamic impairment of synaptic transmission in the PCx-IL engram cell circuit underlies the early decline in olfactory memory in AD. Impairment of PCx-IL functional connectivity may represent a new target for the diagnosis and treatment of early-stage AD.

Memory generalization is essential for adaption to novel circumstances through experiential learning, leading to behavioral flexibility and survival capability. However, its underlying neural mechanisms remain to be elucidated. This study designed 8-arm-maze-based tasks to reveal how the hippocampal CA3 associates with the generalization of spatial working memory. Mice successfully transferred the learned rule to novel task configurations, but the efficiency was inversely correlated with task difficulty. In vivo electrophysiological recordings of the CA3 showed that single-unit and population activity in the CA3 reflected this behavioral transition. On testing day 1, neuronal firing and population trajectories robustly distinguished in relatively simple tasks, but not in more difficult tasks. On testing day 2, as behavioral performance improved, the representational differences of the CA3 neuronal population across different tasks gradually decreased. Decoding analysis revealed that task discriminability based on population activity decreased over time, indicating CA3 neural coding is shifting toward a more generalized pattern. Feature elimination analysis further demonstrated that CA3 neurons employ a sparse but redundant coding scheme to support generalization. Together, the observed neural and behavioral changes are consistent with the emergence of generalized task representations, indicating experience-dependent reorganization of CA3 population activity during memory generalization across task configurations.

Ischemic stroke is a complex and heterogeneous neurological disorder with high mortality and long-term disability rates, yet effective clinical biomarkers and targeted therapies remain elusive. Despite extensive research, the molecular mechanisms driving ischemic stroke pathophysiology are still not fully understood. Cathepsins, a family of endo/lysosomal proteases, play a crucial role in modulating neuronal protein activation and degradation, thereby exerting both neuroprotective and neurotoxic effects. This review synthesizes current findings on the neuropharmacological roles of cathepsins in ischemic stroke, highlighting their dual functions and potential as therapeutic targets. By providing an integrated perspective, this article aims to uncover novel molecular pathways implicated in stroke progression and identify innovative therapeutic strategies centered on cathepsin modulation. Furthermore, this review explores the potential of cathepsins as biomarkers, paving the way for more precise, personalized interventions that could ultimately improve patient outcomes and mitigate long-term disability in ischemic stroke survivors.

Background Microglia undergo extensive transcriptional remodeling in Alzheimer’s disease (AD), particularly within plaque-associated environments enriched in lipid-rich debris and phagocytic cargo. Although lipid handling and lysosomal processing are prominent features of disease-associated microglia, whether these processes constitute a coordinated remodeling program associated with neuropathological severity and plaque-associated spatial niches remains challenging. We investigated the cellular, pathological, and spatial organization of coupled lipid–lysosome remodeling in AD. Methods The study analyzed 236,044 Microglia/PVM-lineage single-nucleus transcriptomic profiles from 84 donors across 10 brain regions in the Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD). Lipid–lysosome (LL) remodeling was characterized using continuous module scores and a Context-Aware Dual-Graph Lipid–Lysosome Remodeling framework (CA-DGLLR) integrating cellular context and biologically structured gene features. Robustness was evaluated using label-free clustering, canonical-program adjustment, threshold and gene-set sensitivity analyses, alternative scoring methods, strict microglial filtering, and held-out validation. Independent validation included four external transcriptomic datasets, human GeoMx plaque-zone transcriptomics, and mouse STARmap plaque-distance data. Statistical analyses included Spearman correlations, rank-based comparisons, Cohen’s d effect sizes, predictive performance metrics, and false-discovery-rate correction for multiple testing. Results LL remodeling comprised 13.34% of the primary discovery compartment and formed a continuous transcriptional landscape. Donor-level LL scores correlated with cognitive and neuropathological severity, including CERAD (ρ = 0.357, FDR = 0.00295) and Braak stage (ρ = 0.321, FDR = 0.00685). The LL-remodeled fraction remained similar across five transcriptomic datasets (12.47–15.22%), with strong human–mouse program-level conservation ( r = 0.96, P = 4.8×10⁻⁴). Spatial analyses further localized this conserved program to plaque-associated tissue environments. Human GeoMx analysis showed strong plaque-core LL enrichment (Cohen’s d = 1.25, FDR = 4.41×10⁻¹⁰), while independent STARmap analysis demonstrated a corresponding spatial gradient, with LL scores decreasing with plaque distance (Spearman ρ=−0.388, FDR = 8.79×10⁻⁹³). Conclusions LL remodeling defines a reproducible microglial response landscape that tracks AD severity and localizes preferentially to plaque-associated niches. By linking lipid handling and lysosomal processing within a shared cellular and spatial framework, these findings provide a cross-platform and cross-species view of microglial metabolic remodeling in AD and nominate candidates for future mechanistic and therapeutic investigation.

Thrombosis and bacterial infections pose critical challenges for blood-contacting implants, inducing serious morbidity and mortality. Inspired by the vascular endothelium, we present an eco-friendly and facile strategy to construct a structurally enhanced, integrated offensive-defensive coating with exceptional hemocompatibility, biocompatibility, and antibacterial activity. Hierarchical cobblestone-like micro/nanostructures are fabricated on the pyrolytic carbon via femtosecond laser ablation. Subsequently, copper ions (offensive component) are immobilized onto the structured surface through dopamine-mediated adhesion, enabling the catalytic generation of endogenous nitric oxide to actively interrupt the thrombosis cascade and bactericidal action by disrupting their membranes. Following this, a zwitterionic polymer is grafted onto the surface to form a hydration layer (defensive component), which passively inhibits the adhesion of biofoulants. The pre-engineered hierarchical structures effectively enhance copper ion loading capacity, stabilize the interfacial hydration layer, and simultaneously reduce the availability of anchoring sites for biofoulants. The resulting biomimetic coating exhibits excellent biocompatibility, with an ultralow hemolysis rate (0.1%, below ISO 10993-4 standards) and nearly 100% endothelial cell viability after 48 h of coincubation. It also demonstrates robust defensive performance, markedly reducing the adhesion of platelets (by 99.6%), fibrin (by 69.8%), and bacteria (by 99.1% for S. aureus and 95.5% for E. coli) compared to the pristine surface. Additionally, the coating achieves outstanding offensive functionality, with negligible platelet activation and high bactericidal efficiencies of 92.8% and 77.1% against S. aureus and E. coli, respectively. This endothelium-mimicking, drug-free strategy provides a versatile platform for durable, biocompatible cardiovascular implants, potentially reducing clinical complications and improving patient outcomes.

While amyloid-β (Aβ) has historically dominated the research landscape of Alzheimer’s disease (AD), the limited clinical success of Aβ-centric therapies has redirected focus toward tau pathology, which correlates more robustly with cognitive deterioration and synaptic dysfunction. Transcending the traditional linear pathological model, this review reframes tau phosphorylation as a dynamic hub within a multi-scale regulatory network. We first synthesize recent breakthroughs in molecular mechanisms, detailing how the kinase-phosphatase equilibrium, cross-regulation of diverse post-translational modifications (PTMs), nuclear envelope damage, iron metabolism and ferroptosis collectively drive the transition from soluble tau species to neurofibrillary tangles (NFTs). Beyond neuronal boundaries, we elucidate how pathological tau orchestrates systemic neurotoxicity by synergizing with Aβ deposition to trigger neuroinflammation, blood-brain barrier breakdown, and gut-brain axis dysregulation. Finally, we bridge these mechanistic insights with translational advancements, evaluating next-generation biofluid biomarkers and innovative therapeutic modalities—ranging from small-molecule inhibitors to Dephosphorylation-Targeting Chimeras (DEPTACs)—currently under clinical investigation. This integrated perspective offers a holistic framework for understanding AD pathogenesis and provides a roadmap for the development of precision medicine strategies targeting the tau interactome.

Neuroinflammation has emerged as a crucial factor in the pathogenesis of Alzheimer's disease (AD), paving the way for promising therapeutic interventions. Increasing evidence highlights the interplay between the peripheral immune system and the central nervous system (CNS) in driving neuroinflammation, with T lymphocytes playing a vital role in both regulatory and effector functions. Aberrant activation of T cells during the early stages of neuroinflammation perpetuates inflammatory responses by interacting with CNS glial cells and releasing pro-inflammatory mediators, such as IFN-γ, TNF-α, and IL-17. Studies have documented significant T cell activation and infiltration into the brain parenchyma in AD, contributing to disease progression. However, the specific mechanisms by which T cells mediate AD pathogenesis remain unclear. This comprehensive review synthesizes the current understanding of T cell involvement in AD pathology, emphasizing their aberrant activation, interactions with microglia, tau protein pathology, and the influence of gut microbiota. Finally, we propose potential treatment modalities for AD, highlighting the promise of T cellbased therapies currently under investigation in clinical trials. Understanding the critical role of T cells in intercellular communication and disease progression may enhance our comprehension of the pathophysiology of AD.

Cognitive impairments are common clinical manifestation of Alzheimer’s disease, vascular dementia, type 2 diabetes mellitus, and autoimmune diseases. Emerging evidence has suggested a strong correlation between peripheral chronic inflammation and cognitive impairments. For example, nearly 40

Abstract Background Cerebral amyloid angiopathy (CAA) is observed in more than 80% of Alzheimer’ s disease (AD) patients and receptor for advanced glycation end products (RAGE) mediates amyloid β (Aβ) influx into brain (Deane et al. 2003). We have found that cathepsin B (CatB) involves peripheral Aβ production during Porphyromonas gingivalis (P.g ) infection (Nie et al., 2019). Aims & Objectives In the present study, we explored the roles of CatB in Aβ transportation from periphery into the brain, known as “Aβ influx” during P.g infection. Method Fifteen-month-old female mice C57BL/6J were intraperitoneally injected with P.g (1×108 CFU/mouse) every 3 days and last for 3 consecutive weeks. The step-through passive avoidance test was used to test learning and memory function. Culture hCMEC/D3 cell line was infected by P. gingivalis (ATCC33277, MOI: multiplicity of infection=5). Real-time quantitative PCR, immunofluorescent staining and immunoblotting were used for gene and protein analysis Results In comparison to non-infection mice, systemic P. gingivalis infection for 3 consecutive weeks significantly increased the RAGE expression in the CD31-positive endothelial cells (2-fold increase) and the Aβ loads around the CD31-positive cells in the parenchyma of mice’ s brains (11-fold, increase). The RAGE expression in the CD31-positive cells was positively correlated with the Aβ loads. In addition, learning and memory function was significantly decreased in the P.g-infected mice than that of in PBS-injected mice. In compassion to uninfected hCMEC/D3 cells, RAGE expression was significantly increased in the P.g-infected hCMEC/D3 cells which was inhibited by pretreating with NFκ B inhibitor. On the other hand, CatB expression was increased in the P.g-infected hCMEC/D3 cells, and CatB specific inhibitor suppressed both Iκ Bα degradation and RAGE expression in the P.g-infected hCMEC/D3 cells. Using fluorescently labeled Aβ1-42, the amount of Aβ1-42 in basolateral medium of the P.g-infected hCMEC/D3 cells was 16-fold higher than that in uninfected cells, the P.g-increased Aβ1-42 in basolateral medium of culture hCMEC/D3 cells was inhibited by pretreating with RAGE specific inhibitor. Discussion & Conclusion These observations demonstrate that NF-κ B activation-dependent RAGE upregulation in cerebral endothelial cells mediates Aβ influx during P. gingivalis infection. CatB plays a critical role in Aβ influx via up-regulating RAGE expression and NF-κ B activation. Taking together with our previous findings of the involvements of CatB in Aβ generation in peripheral inflammatory macrophages during P.g infection (Nie et al. 2019), CatB would be a therapeutic target for preventing the Porphyromonas gingivalis infection-associated amyloidogenesis in AD. References 1.Deane, R., Du Yan, S., Submamaryan, R. K. et al. (2003) RAGE mediates amyloid β peptide transport across the blood-brain barrier and accumulation in brain. Nature edicine 9, 907-913.2. 2.Nie R, Wu Z, Ni J, Zeng F, Yu W, Zhang Y, Kadowaki T, Kashiwazaki H, Teeling JL,Yanmin Zhou Y. (2019) Porphyromonas gingivalis Infection Induces Amyloid β Accumulation in Monocytes/Macrophages. J. Alzheimer's Dis. 72 (2):479-494.

BackgroundLipopolysaccharides from Porphyromonas gingivalis (P.gLPS) are involved in the pathology of Alzheimer's disease (AD). However, the effect of P.gLPS on synaptic defects remains unclear.ObjectiveIn this study, we tested our hypothesis that P.gLPS induces synaptic defects in a low-amyloid-beta (Aβ)-concentration environment.MethodsMG6 microglia or N2a neurons was treated with P.gLPS (0.1 μg/mL), soluble Aβ42 (0.1 μM) or AL (combined P.gLPS and soluble Aβ42 at 0.1 μM).ResultsIn cultured MG6 microglia, increased the mRNA expression of TNF-α, IL-1β and IL-6 and the TNF-α release in parallel with increased NF-κB activation. In cultured N2a neurons, treatment with Aβ42, P.gLPS, and AL did not affect the mRNA expression of synapsin1 (SYN1) or post-synaptic density protein-95 (PSD-95). However, the treatment with conditioned medium from AL-exposed MG6 microglia (AL-MCM) significantly reduced the mRNA and protein expression of SYN1, PSD-95, and nuclear translocation of repressor element-1 silencing transcription factor (REST) but significantly increased the mRNA expression of TNF receptor type I (at 48 h) and glycogen synthase kinase (GSK)3β (at 24 h). TWS119 pretreatment (5 μM), a GSK3β specific inhibitor, significantly reversed the AL-MCM-induced reduction in the mRNA expression of SYN1 and PSD-95 and nuclear translocation of REST in cultured N2a neurons. In APPNL-F/NL-F mice, the immunofluorescence intensity of SYN1 and PSD-95 in cortical neurons was positively correlated with the index of the memory test but negatively correlated with that of TNF-α-positive microglia.ConclusionsThese observations demonstrate that P.gLPS induces neuronal GSK3β-dependent synaptic defects in a low-Aβ concentration environment via microglial activation.

Abstract Regulation of microglial activation and neuroinflammation are critical factors in the pathogenesis of ischemic brain injury. Interest in protease-activated receptor 2 (PAR2) as a pharmaceutical target for various diseases is creasing. However, it is unclear the expression and functions of PAR2 in hypoxia- ischemic (HI) brain injury. Mice with HI and cells with oxygen– glucose deprivation and reoxygenation (OGD/R) were studied. Immunoblot and qRT-PCR were used to study the differential gene expression in cultured microglia and neurons. Immunofluorescent staining was used to study the expression pattern of PAR2 in the HI brain and phagocytotic activity of microglia after OGD/R. In neonatal mice brain after HI, we found PAR2 expression was abundant in neurons, but barely in microglia from the contralateral side of cortex and hippocampus. Conversely, PAR2 expression was barely in neurons while significantly increased in activated microglia from the ipsilateral side of cortex and hippocampus. The activations of PAR2 were increased in both microglia and neuron in a cell model of OGD/R. PAR2 activation mediated the cross-talk between microglia and neurons including the following: microglial PAR2 mediated inflammatory responses that induced neuronal damage; neuronal PAR2 regulated chemokines that recruited activated microglia to damage area; microglia PAR2 controlled the phagocytosis of degenerating neurons. These data suggested differential expression and distinct roles of PAR2 in microglia and neurons after HI injury; thereby, interventions targeting PAR2 may provide insights into the inflammatory-related diseases.

The complex pathogenesis of Alzheimer’s disease (AD) has resulted in limited current biomarkers for its classification and diagnosis, necessitating further investigation into reliable universal biomarkers or combinations. In this work, we collect multiple CSF proteomics datasets and build a universal diagnose model by SVM-RFECV method combined with equal sample size and standard normalization design. The model was training in 297_CSF and then test the effect in other datasets. Utilizing machine learning, we identify a 12-protein panel from cerebrospinal fluid proteomic datasets. The universal diagnosis model demonstrated strong diagnostic capability and high accuracy across ten different AD cohorts across different countries and different detection technologies. These proteins involved in various biological processes related to AD and shows a tight correlation with established AD pathogenic biomarkers, including amyloid-β, tau/p-tau, and the Montreal Cognitive Assessment score. The high accuracy in the model may due to multiple protein combination based on comprehensive pathogenesis and different AD progress. Furthermore, it effectively differentiates AD from mild cognitive impairment (MCI) and other neurodegenerative disorders, especially the frontotemporal dementia (FTD), which share similar pathogenesis as AD. This study highlights a high accuracy, robustness and compatibility model of 12-protein panel whose detection is even based on label-free, TMT and DIA mass spectrometry or ELISA technologies, implicating its potential prospect in clinical application.

Surface engineering is an effective strategy for addressing thrombosis and bacterial infection associated with blood-contacting implants (BCIs). However, most functional surfaces rely on a single mechanism and surface engineering poses substantial processing challenges for chemically inert and difficult-to-process materials such as pyrolytic carbon. Herein, a multifunctional bio-metasurface (LDT surface) synergizing liquid-repellent (L), drag-reduction (D), and turbulence-attenuation (T) strategies is proposed. The LDT surface is achieved through the synergistic interplay of surface texture-mediated flow control and interfacial lubrication effects. The textured LDT surface with microgrooves exhibits a hemodynamic modulation capability, exhibiting an effective turbulence-attenuation effect. The slippery coating on the LDT surface exhibits liquid-repellent and drag-reduction effects, regulating bio (blood and bacteria)-material interfacial interactions. The complex, hierarchical micro-groove, micro-hole, and nano-ripples/gaps/protrusions structures on the surface are fabricated on pyrolytic carbon via temporally shaped femtosecond laser texturing, followed by functional coating. The LDT surface exhibits excellent stability under continuous turbulent flow, with no toxic byproducts generated during processing. The computational fluid dynamics simulation results confirm that the streamwise microgrooves on the wall significantly attenuate turbulence. Compared to the pristine sample surface, the experimental results reveal a 98.2% reduction in platelet adhesion on the LDT surface, with a platelet adhesion rate of only 0.22% and no detected activated platelets, while denatured fibrinogen adhesion decreases by 55.3%. Moreover, the antiadhesion capacities of the LDT surface against Staphylococcus aureus and Escherichia coli improve by 99.4% and 98.4%, respectively, relative to the pristine sample surface, without viable residual bacteria or biofilm formation. The study offers a promising strategy to mitigate BCI-associated thrombosis and bacterial infection on BCIs, particularly those made from difficult-to-machine materials.

Cathepsin B (CatB), a protease in endosomal and lysosomal compartments, plays a key role in neuronal protein processing and degradation, but its function in brain development remains unclear. In this study, we found that CatB is highly expressed in the cortex of E12.5-E16.5 mice. Morphological analysis revealed significant defects in cortical development in CatB knockout (KO) mice, particularly in layer 6. In vitro experiments showed that CatB deficiency notably impaired neuronal migration and development. Behaviorally, CatB KO mice displayed prominent depressive-like behaviors, and electrophysiological recordings demonstrated significantly reduced neuronal activity in layer 6 of the medial prefrontal cortex. Mechanistically, proteomics analysis revealed that CatB KO affected neuronal migration and axonal growth, and decreased the expression of key transcription factors involved in neuronal development, particularly PEG3. Deficiency of PEG3 also significantly impaired neuronal migration and development. Our findings uncover a role for CatB in cortical development and suggest a mechanism linking CatB deficiency with depression and developmental defects through the destabilization of PEG3.

Hippocampus (HPC)-associated spatial memory deficits are one of the earliest symptoms of Alzheimer’s disease (AD). Current pharmacological treatments only alleviate the symptoms but do not prevent disease progression. The emergence of neuromodulation technology suggests that specific neural circuits are potential therapeutic targets for AD. Current studies have analyzed the medial septum (MS)–HPC and the HPC–lateral septum (LS) circuitries separately. A comprehensive understanding of their synergistic effects and overall dysregulation in AD remains limited. In this review, we will integrate anatomical and functional evidence to give an overview of the role of the MS–HPC–LS circuitry in spatial memory, the mechanisms of AD-related dysregulation, and therapeutic strategies targeting the circuitry, specially focusing on molecular interventions (receptor modulation) and bioengineering strategies (circuit-specific stimulation).

Alzheimer's disease (AD) is less prevalent in men than in women, although mechanisms remain unclear. Microglia degrade aggregated amyloid β (Aβ) through the lysosomal system, including autophagy. G protein-coupled receptor family C group 6 member A (GPRC6A), predominantly expressed in mouse microglial MG6 cells, is a primary mediator of testosterone signaling. This study examines testosterone's role in modulating Aβ-induced autophagy in microglia. Testosterone promotes Aβ-induced autophagy leading to Aβ clearance in MG6 cells by suppressing extracellular signal-regulated kinase (ERK) phosphorylation and subsequently inhibiting mammalian target of rapamycin (mTOR) activation, which is abrogated by shRNA knockdown of GPRC6A. In in vivo experiments with male 5xFAD AD model mice, Aβ clearance activity is associated with autophagy in microglia and is reduced by orchiectomy, but restored by testosterone supplementation. ERK phosphorylation in the brains of male AD model mice is upregulated by orchiectomy. Therefore, testosterone is involved in autophagy-mediated Aβ clearance in microglia. Aβ accumulation in human brain samples from patients with AD is significantly lower in men than in women, with less pronounced colocalization of Aβ with p62 aggregates, suggesting enhanced autophagic activity in men. In conclusion, testosterone enhances Aβ-induced autophagy in microglia, possibly contributing to lower susceptibility to AD in men.

Wound dressings play crucial roles in clinical wound management, serving as integral components repairing of damaged skin barriers. Herein, a curcumin-loaded asymmetric-wettability Janus polydimethylsiloxane wound dressing with surface microstructures is developed via a combined approach involving femtosecond laser technology and template replication. The prepared dressing has a hydrophobic outer surface, which offers antifouling and anticontamination characteristics, and an inner surface featuring groove-like micro/nanostructures with a hydrophilic coating, which collectively improve in vitro NIH/3T3 cell proliferation. Furthermore, the structures significantly increase the loading efficiency of curcumin and decrease its release rate, improving the antibacterial properties of the dressing. In vivo evaluation showed that the dressing effectively accelerates wound healing and epithelial tissue regeneration, achieving a wound healing rate of 95.89% within after 13 days of treatment. This study provides valuable insights into the design and development of drug-loaded Janus wound dressings, which have promising potential for improving wound healing outcomes.

Abstract The approval of anti-Amyloid β (Aβ) monoclonal antibodies (lecanemab) in the treatment of patients with early Alzheimer’ s disease by FDA, suggests the reliability and importance of clearance of brain Aβ in AD therapy. Microglia are the main phagocytes in the brain to clean up Aβ, but the regulatory mechanism has not been fully clarified. Here, we investigated the critical role of cathepsin B (CatB) in modulating microglial clearance of Aβ in the mouse brain. We stereotaxically injected Aβ into the hippocampus of mice to assess the effect of CatB on Aβ clearance. CatB deficiency significantly reduced the Aβ clearance efficiency and aggravated the cognitive decline in mice after Aβ administration for 3 weeks. Exogenous Aβ increase CatB expression majorly in activated microglia. Transcriptomic analysis indicated that CatB is associated with gene clusters of migration, phagocytosis, and inflammation, which were validated by in vitro cell culture experiments. In addition, KEGG analysis and immunoblotting suggested that CatB modulates microglial Aβ clearance depending on PI3K-AKT activation. These findings indicate that CatB regulated microglial Aβ clearance activity, highlighting CatB as a therapeutic target for AD targeting Aβ clearance.

The deposition of toxic aggregated amyloid-β (Aβ), resulting from continuous cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase, is a key pathogenic event in Alzheimer's disease (AD). Small interfering RNAs (siRNA) have shown great potential for disease treatment by specifically silencing target genes. However, the poor brain delivery efficiency of siRNAs limits their therapeutic efficacy against AD. We designed a simplified and effective BACE1 siRNA (siBACE1) delivery system, namely, dendritic polyamidoamine modified with the neurotropic virus-derived peptide RVG29 and polyethylene glycol (PPR@siBACE1). PPR@siBACE1 crossed the blood–brain barrier efficiently and entered brain parenchyma in large amount, with subsequent neurotropism and potential microglia-targeting ability. Both in vitro and in vivo studies validated the effective brain delivery of siBACE1 and strong BACE1 silencing efficiency. Treatment of AD mice with PPR@siBACE1 inhibited the production of Aβ, potentiated Aβ phagocytosis by microglia, improved the memory deficits and reduced neuroinflammatory response in AD mice. This study provides a reliable delivery platform for gene therapies for AD.