In tauopathies, such as Alzheimer’s disease (AD), oligomeric tau (oTau) can induce tau hyperphosphorylation and further oligomerization, contributing to dendrite and dendritic spine degeneration. The p75 neurotrophin receptor (p75NTR), which regulates signaling that overlaps with tauopathy-related degenerative pathways, is a promising therapeutic target. LM11A-31, a small-molecule p75NTR modulator, downregulates p75NTR’s degenerative signaling and upregulates signaling that promotes dendritic and synaptic integrity. In a tauopathy mouse model, LM11A-31 reversed spine loss in hippocampal pyramidal neurons and improved performance on behavioral tests of hippocampal function. In a Phase 2a randomized, placebo-controlled AD clinical trial, LM11A-31 slowed the progression of synaptic degeneration biomarkers. In the present study, we tested the hypothesis that LM11A-31 enhances resilience of spines and dendrites to pathological forms of tau and/or inhibits the formation and accumulation of pathological tau species. We found that LM11A-31 prevented degeneration of spines and dendrites in cultured hippocampal neurons exposed to recombinant oTau or oTau-containing hippocampal extract fractions from PS19 tauopathy mice. Treating PS19 mice with LM11A-31 reduced the degeneration-promoting activity in oTau-containing hippocampal extract fractions. In cultured hippocampal neurons, LM11A-31 inhibited excess tau phosphorylation and aggregation induced by oTau and counteracted oTau-induced abnormalities in RhoA, PKC, LIMK1, and cofilin signaling, a signaling module known to regulate spine integrity. The ability of LM11A-31 to confer resilience to dendritic spines was partially dependent on LIMK1 activity. These findings demonstrate that small-molecule modulation of p75NTR by LM11A-31 both reduces the accumulation of pathological tau species and promotes resilience against oTau-induced dendritic spine degeneration, exemplifying a “dual-mechanism” therapeutic approach for tauopathies.

BackgroundAmyotrophic lateral sclerosis (ALS) is a movement disorder lacking effective diagnostics and therapeutics, largely due to its clinical and etiological heterogeneity. The unifying hallmark of TDP-43 pathology is found in approximately 97% of ALS patients, and 50% of frontotemporal dementia (FTD) patients. Indeed, TDP-43 has a central role in ALS/FTD disease mechanisms. An mRNA target of TDP-43 loss of function, KIAA1324/ELAPOR1, is consistently upregulated in various RNA-sequencing datasets from systems with TDP-43 depletion.MethodsThis study sought to investigate the TDP-43 target gene, KIAA1324, in the context of human brain tissue. We performed immunohistochemistry and image analysis on 10 ALS and 10 control brains to quantify the protein levels of KIAA1324 in TDP-43 pathology-affected cells. We then used immunocytochemistry of iPSC-derived neurons and mass spectroscopy of SH-SY5Y cells to investigate the relationship between KIAA1324 mRNA and the function of its cognate protein KIAA1324.ResultsKIAA1324 expression was enriched in neurons in the human brain. While KIAA1324 mRNA increased in iPSC-derived neurons with TDP-43 depleted from the nucleus in vitro, in human post-mortem brain neurons, KIAA1324 protein was significantly decreased (p < 0.05) in cells with pathological TDP-43 (nuclear-cleared TDP-43 and cytoplasmic, phosphorylated TDP-43). This may be due to the alternative polyadenylation of KIAA1324 detected with TDP-43 depletion from iPSC-derived neurons, hypothesised to affect translation efficiency. Mass spectrometry of SH-SY5Y cells revealed that overexpression of KIAA1324 protein affects a network of mitochondrial proteins.ConclusionsThe clear inverse relationship between KIAA1324 mRNA levels and TDP-43 function, and the near complete absence of KIAA1324 protein from neurons with pathological TDP-43 in post-mortem brain tissue, suggests KIAA3142 function is impaired in TDP-43 proteinopathies. Therefore, in addition to there being various disease mechanisms implicated in ALS, and TDP-43 being a challenging disease target to restore, KIAA1324 emerges as another of the many targets downstream of TDP-43 that may need to be addressed to demonstrate a therapeutic effect in ALS/FTD.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40478-026-02237-7.

The LIM domain only 2 (LMO2) is a nuclear transcriptional regulator that influences cell fate in hematopoiesis and vasculogenesis. Recent evidence indicates that LMO2 also functions as a signaling molecule in the cytoplasm of cancer cells. However, its role in tumor endothelial cells (ECs) and angiogenesis remains unclear. In this study, we explored the cytoplasmic role of LMO2 in tumor angiogenesis using a three-dimensional microfluidic sprouting model. LMO2 was found to be enriched in the cytoplasm of migrating ECs, along with increased expression of vascular endothelial growth factor (VEGF) receptor 2. VEGF stimulation elevated cytoplasmic LMO2 levels, and LMO2 was enriched at tumor margins in vivo. Proteomic screening identified integrin β1 (ITGB1) as a potential interactor with LMO2, and their interaction was confirmed through co-immunoprecipitation and proximity ligation assays. Overexpressing LMO2 enhanced focal adhesion signaling, as indicated by increased activation of FAK, Src, and ERK, and promoted EC migration without altering total ITGB1 levels. Knocking down ITGB1 reversed these effects, suggesting that the LMO2–ITGB1 interaction is essential for focal adhesion signaling and EC migration. Importantly, these effects depended on cytoplasmic, not nuclear, LMO2. Our findings reveal a previously unknown cytoplasmic role of LMO2 in regulating focal adhesion dynamics and endothelial behavior. Targeting the LMO2-ITGB1 pathway could be a promising strategy for anti-angiogenic therapy.

Lens epithelium-derived growth factor (LEDGF), encoded by the Psip1 gene, exists in two splice variants, LEDGF/p75 and LEDGF/p52. Although little is known about its role in the brain, LEDGF has been proposed to play a role in neurogenesis. Since known LEDGF binding partners, such as PogZ, CDA7L, MLL1 and MeCP2 are implicated in neurological dysfunction, we investigated the role of LEDGF in mouse brain. We developed a conditional Psip1 knock-out (cKO) mouse model by crossbreeding Psip1fl/fl mice with NestinCre mice, resulting in neuronal depletion of both isoforms in the central nervous system. In wild-type (WT) animals, brain region-dependent alternative splicing was evidenced, with more p75 over p52 in the cerebellum and more p52 over p75 in the hippocampus. Behavioral phenotyping revealed that already at a young age, Psip1 cKO mice show motor deficits. In cerebellar neurons, LEDGF depletion results in more and smaller MeCP2 condensates. Bulk and comparative RNA sequencing of cerebellar extracts revealed downregulation of genes involved in synaptic transmission. Moreover, transcription factor network analysis showed that the differentially expressed genes are mainly regulated by the Polycomb repressive complex 2 (PRC2). Since the LEDGF/p75 binding partner MLL1 is part of the Trithorax Complex, the counterpart of PRC2 in gene regulation, our data highlight the importance of LEDGF/p75-mediated regulation of synaptic gene expression in the cerebellum through Trithorax.

Alzheimer’s disease (AD) progression is closely linked to the accumulation of amyloid-$$\upbeta $$ (A$$\upbeta $$), with impaired clearance mechanisms playing a key role. The meningeal lymphatic (mLym) system, which drains cerebrospinal fluid (CSF) and waste from the brain to peripheral lymph nodes, has emerged as a critical pathway for A$$\upbeta $$ removal. While physical exercise is known to improve cognitive function and reduce AD risk, its effect on the mLym system and downstream AD pathology have not been fully elucidated. Three-month-old 5xFAD mice underwent a 3-month wheel-running exercise regimen. The function of the mLym system was assessed before and after exercise using high-frequency ultrasound imaging with nanoparticle tracers to monitor CSF drainage to deep cervical lymph nodes. The study evaluated changes in mLym vessel structure, A$$\upbeta $$ deposition, and cognitive performance. Additionally, the effects of serum and extracellular vesicles (EVs) from exercised rats on the expression of lymphatic vessel-related genes (LYVE-1, VEGFR3, and VEGF-C) were examined in lymphatic endothelial and microglial cell lines. Compared to 3-month-old 5xFAD mice and age-matched wild-type controls, 6-month-old 5xFAD mice displayed progressive decline in mLym function, reduced vessel integrity, and increased amyloid plaque burden, accompanied by impaired learning and memory. These changes were associated with decreased expression of LYVE-1 and VEGFR3 in the meninges and VEGF-C in the brain. Exercise intervention reversed these deficits, restoring mLym function and vessel structure, enhancing A$$\upbeta $$ clearance, and improving cognitive performance. Surgical ligation of mLym vessels accelerated amyloid accumulation and removed the exercise-induced benefits, underscoring the system’s importance in A$$\upbeta $$ removal. In vitro, A$$\upbeta $$ oligomers suppressed VEGFR3 and VEGF-C expression, while serum and EVs from exercised rats counteracted this effect. Proteomic analysis of EVs from exercised animals revealed upregulation of CD9, suggesting a link to VEGFR3 signaling. This study demonstrates that A$$\upbeta $$ oligomers impair mLym function, exacerbating amyloid pathology. Exercise preserves the structure and function of the mLym system, promoting A$$\upbeta $$ clearance and mitigating AD progression. These findings highlight the therapeutic potential of targeting the meningeal lymphatic system to slow or prevent AD.

Currently there are no therapeutic agents that are effective against both vestibular schwannoma and meningioma, the two most common tumour types affecting patients with the rare tumour predisposition syndrome NF2-related schwannomatosis. This study aimed to characterise the similarities and differences in the tumour immune microenvironments of meningioma and vestibular schwannoma to identify potential therapeutic targets viable for both tumour types. Publicly available bulk Affymetrix expression data for both meningioma (n = 22) and vestibular schwannoma (n = 31) were used to compare gene expression and signalling pathways, and deconvolved to predict the abundance of the immune cell types present. Publicly available single cell RNA sequencing data for both meningioma (n = 6) and vestibular schwannoma (n = 15) was used to further investigate specific T cell and macrophage subtypes for their signalling pathways, gene expression, and drug targets for predicted drug repurposing in both tumour types. Immune cells comprised a larger proportion of the vestibular schwannoma tumour microenvironment compared to meningioma and included a significantly higher abundance of alternatively activated macrophages. However, these alternatively activated macrophages, alongside other immune cell subtypes such as CD8 + T cells and classically activated macrophages, were predicted to be more active in meningioma than vestibular schwannoma. Despite these differences, T cells and tumour associated macrophages of both vestibular schwannoma and meningioma shared drug-target kinases amenable to drug repurposing with Food and Drug Administration (FDA) drugs approved for other conditions. These include bosutinib, sorafenib, mitoxantrone, and nintedanib which are yet to be clinically investigated for vestibular schwannoma or meningioma. Drug repurposing may offer an expedited route to the clinical translation of approved drugs effective for treating both meningioma and vestibular schwannoma to benefit NF2-related schwannomatosis patients.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40478-025-02176-9.