Acta Neuropathologica Communications

The choroid plexus epithelial cells (CPECs) at the blood-cerebrospinal fluid (CSF) interface possess an exceptionally high mitochondrial content to support CNS homeostasis. Oncocytic CPECs (O-CPECs), characterized by enlarged and granular eosinophilic cytoplasm composed of excessive abnormal mitochondria, likely contribute to an energetic failure of this energy-demanding tissue. The relationship between O-CPECs and other CPEC pathologies in humans, such as Biondi body (BB) amyloid inclusions, remains poorly defined. In the present study, using H&E-stained sections from 68 postmortem cases, we classified O-CPECs by quantitative size criteria and cytological features, and found an increase in the prevalence of O-CPECs with age after adjusting for sex and tissue source. After excluding two influential control cases, there was evidence for a further increase associated with Alzheimers disease. Using antibodies to ATP synthase beta chain to classify O-CPECs, and thioflavin-S to identify BBs, we revealed an increased prevalence of BBs in O-CPECs compared to neighboring non-oncocytic cells. Small multiple BB inclusions were responsible for the increase in O-CPECs, while the prevalence of larger inclusions was decreased in O-CPECs. Together, our data support a clear age-associated oncocytic transformation of CPECs and implicate mitochondrial dysfunction-amyloid interactions.

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron (MN) loss, muscle atrophy and paralysis. Although traditionally considered a MN-specific disease, accumulating evidence supports a crucial contribution of skeletal muscle pathology to disease onset and progression. Except for specific mutations, to date there is no effective treatment for ALS. FOXO transcription factors regulate programs of atrophy, metabolism and stress response in skeletal muscle, and their inhibition has shown beneficial effects in cellular and Drosophila models of ALS. MethodsIn this study, we investigated whether pharmacological FOXO inhibition (iFOXO) could modify disease progression and muscle pathology in female hSOD1G93A mice. Mice received daily oral administration of iFOXO starting at presymptomatic (P50; n=5 per group) or symptomatic (P90; n=9 mice per group) stages until end-stage. Body weight was monitored longitudinally, and motor performance was evaluated using grip strength and hanging-wire tests. Tibialis anterior and soleus muscles, representing fast- and slow-twitch muscles respectively, were analyzed by histology and immunofluorescence to assess fiber atrophy, fibrosis, lipid accumulation, satellite cell pool and fiber type composition. Quadriceps muscles (n=3 per group) were used for RNA-seq analysis. ResultsWhile histological analyses revealed severe fiber atrophy and increased fibrosis in hSOD1G93A mice, satellite cell numbers were preserved or mildly increased in a muscle and treatment onset dependent manner. iFOXO treatment did not improve motor performance, survival or attenuate muscle atrophy. Transcriptomic profiling indicated that genotype was the predominant driver of gene expression changes, while iFOXO produced only subtle, treatment onset dependent effects on pathways related to oxidative stress responses, mitochondrial function and adaptive metabolism. ConclusionOverall, FOXO inhibition alone showed limited therapeutic benefit in the hSOD1G93A ALS mouse model. These findings highlight the dominant influence of ALS driven molecular alterations over pharmacological modulation and emphasize the need for combinatorial therapeutic strategies targeting multiple disease mechanisms, including those preserving nerve health.

To resolve discrepancies in the literature regarding the association between Alzheimers disease (AD) and Biondi body (BB) amyloid in choroid plexus epithelial cells (CPECs), we investigated postmortem hippocampal paraffin blocks with and without a neuropathological diagnosis of AD (n=26-27 each). Similar to previous studies, age was associated with an increased fraction of hippocampal-associated CPECs bearing thioflavin S-positive BBs (p=0.004). In addition, we found that paraffin block storage time was associated with decreased BB detectability (p=0.038) while sex had no effect (p=0.577). Controlling for age, sex, and storage time, AD was associated with a near-significant increase in the BB-containing CPEC fraction (p=0.066) and a significantly greater load of BB-like amyloid in hippocampal-associated ependymal cells (p=0.032). The AD-BB association contrasts with our findings on choroid plexus from the atrium of the lateral ventricle, which lacked this association. We discuss potential explanations for the apparent discrepancy such as regional amyloid cross-seeding.

Background: Despite epidemiological interest in aspirin's chemopreventive potential against glioma, the underlying multi-layered molecular mechanisms -- spanning COX-2/PGE2 signaling, iron metabolism, ferroptosis, epigenetic regulation, and the NEO1/hepcidin regulatory axis -- have not been systematically characterized at the multi-omics level. Methods: We conducted an integrative multi-omics analysis leveraging TCGA-GBM (n=172) and TCGA-LGG (n=534) transcriptomes, CPTAC GBM proteomics (n=99), TCGA HM450K DNA methylation data (GBM n=140, LGG n=516), GEO aspirin perturbation datasets, IEU OpenGWAS summary statistics, and independent single-cell RNA-seq data (GSE131928, 28 GBM patients). Eight analytical tracks were executed: (1) COX-2/PGE2 pathway profiling, (2) BBB tight junction characterization, (3) GEO-derived aspirin response signature projection, (4) gut-brain axis evaluation, (5) Mendelian randomization (MR) using PTGS2 cis-SNPs, (6) iron metabolism and ferroptosis pathway analysis, (7) NEO1/HFE2/BMP6/HAMP regulatory axis characterization with multi-omics validation, and (8) single-cell transcriptomic validation across GBM malignant cell states. Results: Transcriptomic analysis revealed profound reprogramming of the NEO1/hepcidin iron regulatory axis in GBM: HAMP (hepcidin) was massively upregulated (log2FC=+2.92, P=5.0e-37), accompanied by TFRC upregulation (log2FC=+1.38, HR=2.30, P=3.6e-42) and NEO1 downregulation (log2FC=-0.57, HR=0.59, P=4.6e-6). De novo HM450K methylation analysis revealed HAMP as the dominant epigenetic target in the iron network, exhibiting the strongest hypomethylation signal (DeltaBeta=-0.265, P=1.4e-48), while NEO1 and TFRC showed constitutively low baseline methylation (Beta<0.05). Gene set enrichment analysis identified ferroptosis driver genes (NES=+1.861, P=0.030) and the iron deficiency response pathway (NES=+1.698, P=0.010) as the most significantly enriched pathways in GBM. Molecular subtype analysis revealed that the mesenchymal GBM subtype exhibits the highest iron metabolism gene expression. Mendelian randomization established a causal relationship between PTGS2 expression and glioma risk (IVW OR=1.31, P=1.1e-4). Single-cell RNA-seq analysis validated that iron metabolism gene expression is heterogeneously distributed across malignant cell states, with the mesenchymal state exhibiting the highest HAMP expression and elevated ferroptosis vulnerability. GPX4 was universally highly expressed across all cell states, indicating pan-GBM dependence on GPX4-mediated ferroptosis suppression. Conclusions: This multi-omics investigation reveals that the NEO1/hepcidin iron regulatory axis is epigenetically reprogrammed in glioma, driving iron-dependent vulnerability that bridges COX-2 signaling with ferroptosis susceptibility. The convergent evidence from transcriptomics, proteomics, epigenomics, and causal inference provides a comprehensive mechanistic framework for aspirin's protective effects against glioma and identifies the NEO1/HAMP/TFRC axis as a promising therapeutic target.

Efficient cerebrovasculature is vital to neuronal health and cognition and evidence shows most dementia patients have cerebrovascular abnormalities. Brain vasculature is regulated by Vascular Endothelial Growth Factors (VEGFs) binding VEGF receptor2 (VEGFR2) and stimulating angiogenesis, and neuroprotection. Presenilin1 (PS1) is the main proteolytic component of {gamma}-secretase and PS1 mutants are the most common cause of Familial Alzheimer Disease (FAD). Here we show that an ADAM17 cleavage of extracellular VEGFR2 produces the membrane-bound {gamma}-secretase substrate VEGFR2/CTF1 (called VCTF1), comprising the transmembrane and intracellular domains of VEGFR2. PS1 FAD mutants and {gamma}-secretase inhibitors both accumulate VCTF1 and suppress VEGF-A-induced brain angiogenesis. Moreover, PS1 FAD mutants, {gamma}-secretase inhibitors, and PS1 downregulation, all decrease {gamma} secretase processing of VCTF1, thereby increasing its accumulation and impairing VEGF-A-induced VEGFR2 dimerization/activation, signaling, and endothelial cell (EC) functions. Importantly, VCTF1 binds fulllength VEGFR2 monomers suppressing VEGFR2 dimerization/activation, signaling, and EC functions. These data show that VCTF1 suppresses VEGFR2 dimerization and downstream signaling and functions of the brain VEGF-A-/VEGFR2 system. PS1 FAD mutants increase vulnerability of brain neurons to ischemic stress and exert antimorphic effects on {gamma}-secretase cleavage of VCTF1, increasing its concentration and abolishing VEGF-A-induced VEGFR2 dimerization/activation, signaling, neuroprotection and cognition. Importantly, we detected molecular markers of decreased VEGFR2 dimerization and angiogenic dysfunction in human brain tissue from PS1 FAD mutant genotypes. Together, our data suggest a pathway through which FAD mutants promote dementia by increasing VCTF1 and decreasing brain angiogenesis and neuroprotection, suggesting that PS1 FAD patients may benefit from therapeutic methods that decrease brain VCTF1.

The temporal coupling between cortical blood-oxygen-level-dependent (BOLD) activity and CSF inflow has recently been proposed as a non-invasive marker of glymphatic function, a brain-wide clearance system closely linked to sleep, neuromodulatory regulation and neurodegeneration. Reduced BOLD-CSF coupling has been previously reported in Parkinsons disease but its characterization in dementia with Lewy bodies, regional specificity and relevance to shared neuropsychiatric symptoms remain unclear. Using resting-state functional MRI, we quantified global and regional BOLD-CSF coupling in 39 participants, including 17 with Parkinsons disease (mean age 61.4 years), 10 with dementia with Lewy bodies (mean age 72.8 years) and 12 healthy controls (mean age 66.2 years), and examined the relationship with clinical and cognitive measures, as well as volumetric measures of the subcortical ascending arousal network. Parkinsons disease and dementia with Lewy bodies patients both demonstrated weaker global BOLD-CSF coupling compared to controls, with no detectable difference between patient groups. Coupling reductions were most pronounced within the unimodal and attentional networks, encompassing regions that are particularly vulnerable in Lewy body disease. Weaker coupling was associated with the severity of hallucinations and cognitive fluctuations, poorer nocturnal sleep quality and impaired attentional working memory, but not overall motor symptom burden. Associations between BOLD-CSF coupling and basal forebrain and brainstem volumes were observed, though partially age-dependent, suggesting a complex interaction between neuromodulatory system degeneration, ageing and brain-fluid dynamics. Our results provide preliminary evidence that disrupted temporal coordination between cerebrovascular activity and CSF inflow may contribute to the fluctuating neuropsychiatric features of Lewy body disease and highlight the utility of BOLD-CSF coupling as a dynamic in vivo proxy of glymphatic function. Replication in larger cohorts incorporating multimodal imaging and biomarkers of pathology will be essential to validate these findings and determine whether brain-fluid dysregulation represents a potentially modifiable therapeutic target.

Background: Vascular contributions to cognitive impairment and dementia (VCID) are thought to arise from distributed neurovascular unit (NVU) dysfunction rather than focal pathology, yet the transcriptional architecture of human VCID brain tissue and the status of endogenous counter-regulatory signaling within it remain incompletely characterized. Defining whether protective pathways are engaged and why they may be insufficient is critical for identifying therapeutic entry points in a disease lacking approved treatments. Methods: We performed differential gene expression analysis (DESeq2 v1.38.0) and pre-ranked gene set enrichment analysis (fgsea v1.24.0) on bulk RNA-sequencing data from superior parietal lobe tissue (GEO:GSE303449; n = 40; 19 VCID, 21 controls; model: age_scaled + Sex + condition), followed by Spearman correlation analysis, PI3K-Akt pathway level, leading-edge decomposition, and single-nucleus RNA-seq endothelial cell characterization (GEO:GSE282111). Results: No individual gene reached FDR < 0.05 for differential expression between VCID and control across 51,962 genes tested. Gene set enrichment analysis nonetheless identified eight significantly enriched pathway programs (all FDR < 0.05) that were upregulated, encompassing inflammatory, stress-response, cytoskeletal, and apoptotic signaling, consistent with distributed network-level dysregulation rather than dominant single-gene effects. The MAS1/ANG1-7 associated signaling gene set (54 genes) was the only counter-regulatory pathway achieving significance (NES = 1.381, FDR = 0.0127). MAS1 receptor expression was strongly (absolute Spearman's rho >= 0.64) and inversely associated with NF-kB pathway drivers TLR4 (Spearman's rho = -0.804) and IKBKB (Spearman's rho = -0.797; both FDR = 4.73 x 10^-9). Further, 9 of 12 correlations between MAS1 downstream effectors and endothelial activation markers were FDR-significant and positive, indicating that the downstream protective effector program is co-activated by inflammatory stress rather than directed by its receptor. Single-nucleus RNA-seq supports endothelial enrichment of the MAS1 pathway enrichment signal in VCID brain tissue. PI3K-Akt leading-edge decomposition revealed 96% gene-level non-overlap between inflammatory and vasoprotective arms. Conclusions: Human VCID brain tissue exhibits coordinated pathway-level dysregulation in the absence of dominant individual-gene effects, consistent with a disease driven by distributed transcriptional network stress. The MAS1/ANG1-7 vasoprotective axis is transcriptionally engaged and endothelially enriched, yet receptor expression is inversely associated with inflammatory signaling while downstream effectors remain transcriptionally engaged. This pattern suggests a failed compensatory state in the VCID superior parietal lobe. This architecture is consistent with a transcriptionally primed but receptor-constrained protective program. These findings suggest that therapeutic strategies restoring MAS1 receptor-level input to an already engaged downstream program may represent a plausible therapeutic strategy for VCID, pending experimental validation.

The TREM2 R47H variant increases the risk of Alzheimers disease (AD), yet its functional impact in aged mouse models remains incompletely understood. We generated a humanized Trem2 R47H knock-in (KI) line on the AppNL-F background and compared it with a Trem2 knockout (KO) line to assess the degree of TREM2 functional impairment. Accumulation of amyloid {beta} 42 and formation of dystrophic neurites were increased in Trem2 KO mice but not in Trem2 R47H KI mice at 18 or 24 months. qPCR and transcriptomic analyses revealed Trem2 KO mice showed deficits in upregulation of microglial genes while Trem2 R47H KI mice showed a response similar to control mice. Differential gene expression analysis identified altered expressions of genes responsible for ER stress/unfolded protein response and intracellular signalling in Trem2 R47H KI mice. Among the differentially expressed genes, Pmel and Gpnmb were or tended to be downregulated in Trem2 R47H KI as well as in Trem2 KO mice indicating their involvement in AD pathogenesis. These results clearly indicate that the TREM2 R47H variant confers a mild, rather than null, effect on microglial alterations during AD development and that Trem2 R47H KI mice should be used to understand pathological mechanism elicited by TREM2. Further identification and characterization of genes differentially expressed in Trem2 R47H KI mice will provide important insights into how the TREM2 risk variant modulates Alzheimers disease-related pathology. HighlightsO_LIExon2-humanized Trem2 R47H knock-in mice are established, which will serve as a platform to study the role of TREM2 in Alzheimers disease development. C_LIO_LITrem2 knockout mice exhibit deficits in clearance of highly aggregated A{beta}42, suppression of dystrophic neurites and regulation of microglial genes in AppNL-F mice, whereas Trem2 R47H knock-in mice do not. C_LIO_LIRNA-seq reveals transcriptional profiles of Trem2 R47H knock-in mice C_LIO_LIqPCR confirms that Gpnmb and Pmel are or tended to be downregulated in Trem2 R47H knock-in mice. C_LIO_LIFindings demonstrate that TREM2 R47H is hypomorphic rather than loss of function. C_LI

BackgroundDysregulated peptidyl deiminase 2 (PAD2) and aberrant protein citrullination (PC), a posttranslational modification (PTM), are involved in various inflammatory and neurodegenerative diseases. We previously showed in transgenic mice and postmortem human tissues that PC and PAD2 are altered in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by motor neurons loss, paralysis, and death. Herein, we investigated the role of PAD2 in ALS by PAD2 knockout in a SOD1-ALS mouse model. MethodsTo investigate the role of PAD2-induced citrullination in ALS pathogenesis, we generated PAD2 knockout (PAD2KO) in SOD1G93A ALS mouse model and investigated the consequent modulation on the neuropathology and clinical symptoms, using molecular biology techniques such as qPCR, Western blotting, confocal microscopy, and electron microscopy. Additionally, we identified C3 as being citrullinated in human ALS using ionFinder. ResultsOur results show that PAD2KO blocked the increased PC and reduced myelin basic protein (MBP) aggregates in the ALS model. PAD2KO also improved motor neuron survival and the integrity of myelin, axons, and neuromuscular junctions, and reduced microgliosis in the white matter and C3 protein levels in astrocytes. Clinically, data from monitoring the body weight changes suggests that PAD2KO modulates the course of the disease in the ALS mouse model, accelerating the onset while slowing the progression after the onset, and modestly extending the survival of male mice. ConclusionThese results show that PAD2 is responsible for the increased PC in ALS and PC contributes to neuroinflammation and degeneration of motor neurons and myelinated axons. The modest modulation of the disease phenotype suggests that the role of PC in ALS is complex, involving altered PC in numerous proteins and in multiple cell types. Future studies are needed to investigate how PC modulates individual protein functions in various cell types to understand the contribution of PC to ALS pathogenesis.

Oligodendroglioma is a primary central nervous system tumor classified by the presence of isocitrate dehydrogenase (IDH) mutations and codeletion of 1p/19q. Here we describe the generation of an IDH-mutant 1p/19q-codeleted oligodendroglioma mouse model using in utero electroporation. We identified IDH1R132H, PIK3CAE545K, CicKO, Fubp1KO and Cdkn2aKO as the optimal combination (termed OligoCdkn2a) to drive fully penetrant tumors that histologically resemble human grade II/III IDH-mutant, 1p/19q-codeleted oligodendroglioma. Replacing Cdkn2a with Trp53 loss in this mouse model shifted tumor histology towards high grade astrocytoma. OligoCdkn2a tumors displayed metabolic and transcriptional changes associated with IDH and CIC mutations, and single cell sequencing identified a bias towards oligodendrocyte differentiation compared to an IDH wild-type glioblastoma mouse model. OligoCdkn2a tumors represent the first mouse model system to recapitulate the genetic, histological and transcriptional features of human IDH-mutant 1p/19q-codeleted oligodendrogliomas, offering a platform to further dissect tumor biology and test new therapeutic strategies.

BackgroundThe Netrin-1 dependence receptor pathway plays critical roles in neural development, but its expression landscape and prognostic significance in glioblastoma (GBM) remain poorly characterized. MethodsSingle-cell RNA-seq data from 148,019 cells across 34 tumors (Neftel et al., 2019) were analyzed to map Netrin-1 pathway gene expression across GBM cellular states. Differential gene expression and pathway enrichment analyses were performed on NEO1-defined subpopulations. Bulk RNA-seq survival analysis was conducted across three independent GBM cohorts TCGA (n=106), CGGA mRNAseq_325 (n=137), and CGGA mRNAseq_693 (n=237), totaling 480 patients. Primary analysis used continuous Cox regression (per-SD hazard ratios); meta-analysis employed fixed-effects inverse-variance weighting. ResultsIn GBM single-cell data, Netrin-1 pathway genes showed state-specific enrichment --NEO1, DCC, NTN1, and RGMB were predominantly expressed in oligodendrocyte-precursor (OPC) and neural-progenitor (NPC) states. Cells positive for NEO1 were enriched for neural differentiation programs (nervous system development, p=9.6x10-; Axon Guidance, p=2.8x10-), whereas NEO1-negative cells were dominated by ribosomal/translational and immune activation programs. In the 3-cohort survival meta-analysis, NTN1 (Netrin-1 ligand) emerged as the sole gene reaching meta-analytic significance as a risk factor (Meta HR=1.163 per SD, 95% CI 1.056-1.281, p=0.0021, I{superscript 2}=0%, 3/3 cohorts concordant), while DCC and RGMB showed directionally consistent protective trends (DCC: Meta HR=0.938, 95% CI 0.858-1.025, p=0.156; RGMB: Meta HR=0.979, 95% CI 0.881-1.087, p=0.686; both 3/3 cohorts concordant). NEO1 itself did not independently predict survival (Meta HR=1.008, 95% CI 0.885-1.147, p=0.910). After Bonferroni correction for 10 genes tested (threshold p<0.005), only NTN1 met strict significance. In exploratory sex-stratified analysis of a single cohort (CGGA 693, n=237), NEO1 and NTN1 exhibited female-specific risk enhancement (NEO1: HR=1.417, p=0.014; NTN1: HR=1.249, p=0.019), with minimal effects in males. UNC5B showed context-dependent risk in MGMT-unmethylated tumors (HR=1.331, p=0.037). These sex-dimorphic findings require independent validation. ConclusionsThe Netrin-1 pathway exhibits divergent prognostic trends in GBM, with NTN1 as a risk factor and DCC trending toward protection--consistent with the dependence receptor model. These findings, which should be interpreted as hypothesis-generating, nominate NTN1 as a candidate therapeutic target and highlight the potential importance of sex-stratified evaluation in future Netrin-1-directed trials. Independent replication in larger cohorts is warranted.

Sleep abnormalities and dysfunction of gamma band (30-80 Hz) activity generated by parvalbumin (PV) interneurons are early characteristics of Alzheimers disease (AD) which correlate with the severity of amyloid-{beta} deposition (A{beta}) and cognitive impairment. However, the timing of these alterations in vivo with respect to disease progression is unclear. Here, in longitudinal recordings from APP/PS1/PV-cre (AD mice) from 3-6 months, we found reduced sleep slow-wave power (0.5-4 Hz) in hippocampus and medial prefrontal cortex in AD mice as young as 3 months old, compared to non-AD (PV-cre) mice, well before overt pathology. This finding was primarily due to reductions in the NREM delta range (1.5-4 Hz), a hallmark of restorative functions of sleep. In contrast, beta (15-30 Hz) power linked to insomnia was significantly higher across all sleep-wake states. Loss of deep NREM sleep was not compensated by an increase in NREM sleep time, instead NREM sleep during the dark (active) phase was slightly but significantly lower in AD mice. 40-Hz auditory steady-state responses and associated evoked calcium responses of hippocampal PV neurons recorded using fiber photometry were also impaired by 3 months old. However, Y-maze performance in 3- and 6-month-old AD mice was not significantly different from non-AD mice. These results reveal reduced deep sleep and PV-associated 40-Hz activity as very early changes amenable to early intervention occurring prior to cognitive deficits. Furthermore, they establish APP/PS1 mice as a good model to causally test the relationship between sleep, PV neuronal activity and amyloid-mediated pathology.

4-Methylumbelliferone (4-MU) inhibits hyaluronic acid (HA) synthesis and is currently approved in Europe for biliary spasm. 4-MU administration reduces perineuronal nets (PNNs), and enzymatic degradation of PNNs in mouse models of Alzheimers disease (AD) attenuates memory impairment. Although 4-MU has therapeutic efficacy in rodent models of fibrosis and cancer, it has not been examined in an Alzheimers model. Here, we evaluated the impact of long-term 4-MU treatment in the APP/PS1 amyloid mouse model. From three months of age, mice were on either a vehicle or 4-MU-supplemented diet for 70 days or 52 weeks. Short and long-term 4-MU treatment decreased the soluble parenchymal A{beta}1-42/A{beta}1-40 ratio. Reductions in insoluble amyloid plaque were observed following 52 weeks of treatment. Extended 4-MU administration also reduced PNN intensity and ameliorated spatial memory deficits in APP/PS1 mice. These findings provide support for targeting brain extracellular matrix (ECM) as a therapeutic strategy for AD.

Background: Frontotemporal dementia (FTD) lacks widely accessible disease-specific biomarkers. Optical coherence tomography (OCT) and OCT angiography (OCTA) may provide non-invasive measures of retinal changes associated with neurodegeneration. We conducted a systematic review and meta-analysis evaluating retinal biomarkers in FTD compared with Alzheimer disease (AD) and controls. Methods: A systematic search of PubMed and Embase was conducted through April 25, 2026 according to PRISMA guidelines. Studies evaluating OCT/OCTA biomarkers in FTD with comparator groups were included. Inverse weighted random-effects models, publication bias assessments, and meta-regressions were performed. Results: Ten studies involving 139 individuals with FTD, 87 with AD, 29 with mild cognitive impairment, 14 with TDP-43 proteinopathy, 5 with tauopathy, and 255 controls were included in the systematic review; five studies were eligible for meta-analysis. Compared with AD, individuals with FTD demonstrated significantly thinner retinal nerve fiber layer (RNFL) thickness (SMD = -0.61, 95% CI -0.98, -0.24). Compared with controls, individuals with FTD exhibited significantly thinner ganglion cell layer-inner plexiform layer (GCL-IPL) thickness (SMD = -0.55, 95% CI -1.02, -0.08), whereas pooled analyses across multiple retinal biomarkers were non-significant (SMD = -0.19, 95% CI -0.52, 0.14). RNFL thickness correlated negatively with female % in FTD and positively with age in both AD and controls. Conclusions: Individuals with FTD exhibit lower RNFL thickness than AD and lower GCL-IPL thickness than controls, suggesting retinal alterations may reflect neurodegeneration. However, larger longitudinal studies with standardized OCT/OCTA protocols are needed to determine the diagnostic and prognostic utility of retinal biomarkers in FTD

Cells that store lipids for other cells or organs can contain "giant" or large lipid droplets (LLDs) greater than 2 {micro}m in diameter. In this study, human postmortem choroid plexus was evaluated for lipid droplets. Staining with hematoxylin and eosin (H&E), the lipophilic dye Oil red O, and anti-adipophilin antibodies established the presence of LLDs exceeding 10 {micro}m in diameter in choroid plexus epithelial cells (CPECs). Manual annotation of H&E stains from 105 cases revealed a significant association between age and the percentage of CPECs containing LLDs (reaching up to 69%) and involving LLDs in our largest annotated category (>5 {micro}m in diameter). The LLD association with age was replicated and extended to a total of 245 cases using a trained convolutional neural network, which further showed significant associations with body mass index at time of death (increasing with BMI), sex (higher in females >65 years old), and a near-significant association with Alzheimers Disease (lower in AD). Like HepG2 and derived hepatocytes, excess fatty acids in culture media readily induced LLDs and steatosis in human embryonic stem cell-derived CPECs. Akin to hepatocytes for the human body, we propose that CPECs store lipids for the human brain and become steatotic in the setting of excess adiposity.

BackgroundHuntington disease (HD) is a neurological disorder caused by an aberrant CAG expansion in the HTT gene, producing a mutant protein (mHTT). Although HD is classically characterized by adult-onset cortical and striatal degeneration, accumulating evidence suggests that altered cortical development may also contribute to disease pathogenesis. ObjectiveWe sought to investigate the impact of mHTT on neocortical patterning, which is a largely unexplored aspect of HD. MethodsUsing the HdhQ140 HD knock-in mouse model, we performed immunofluorescence and in situ hybridization to analyze the patterning of the cortex from embryonic day 10 to postnatal day 7. ResultsDuring embryogenesis, HTT expression exhibited a high medial-to-low lateral gradient in the neocortex, like that observed for key transcription factors involved in cortical patterning. Notably, HTT expression was absent from the cortical hem, a critical patterning center. In HD, the protein gradient remained unchanged whereas the expression in medial pallium seemed increased. During the early development of the cerebral hemispheres, the expression of morphogens and signaling pathways, including Shh, Fgf8, and Wnt/BMP genes, were disrupted in organizing centers, leading to altered expression of major neocortical transcription factors. At postnatal stages, the motor and somatosensory cortical areas were misplaced. These developmental alterations were associated with postnatal sensorimotor deficits relevant to HD. ConclusionsOur findings demonstrate that HD-related neurodevelopmental alterations arise as early as embryonic day 10 in mice. This supports previous work suggesting that defects in brain development contribute to HD pathogenesis prior to clinical onset.

Phagocytic and immune-like cells have been observed in the satellite envelope of neuronal somata in peripheral sensory ganglia of many species for several decades. These cells likely play an important role in normal function of sensory neurons and they may also play an important role in neuronal dysfunction and neurodegeneration seen with neuropathy. Recent findings have described a satellite macrophage population transcriptomically similar to microglia in peripheral ganglia of some mammalian species. The function of these cells, and the mechanisms by which they may influence neurons in neuropathy are unclear. We sought to understand the phenotype and localization of these cells in the human dorsal root ganglion (hDRG) using large-scale single nucleus and spatial transcriptomic datasets from individuals with and without a history of peripheral diabetic neuropathy. We observed a large population of macrophages that express classical microglia makers such as TMEM119 and P2RY12 in the hDRG, as previously described. Our findings confirm that these microglia-like cells (MLCs) localize to the satellite envelope around neuronal somata, yet are transcriptomically distinct from all glial cell types characterized in the hDRG. These MLCs exhibit changes in abundance and localization with diabetic painful neuropathy (DPN) in both the hDRG and sural nerves suggesting that they are not exclusively localized to the DRG. We conclude that microglia-like cells are likely the resident tissue macrophage (RTM) of the hDRG, and perhaps the peripheral nervous system (PNS) given their localization to the sural nerve and other ganglia, where they are predicted to regulate homeostatic neuronal functions and response to injury. HighlightsO_LIMLCs are likely the RTM of hDRGs C_LIO_LIMLCs localize to the satellite envelope and recede with Nageotte nodule formation C_LIO_LIMLC activation state and signaling shift with diabetic neuropathy C_LIO_LIMLCs are also present in other ganglia and sural nerve C_LI

Disruption of glutamate homeostasis is believed to contribute to the early progression of Alzheimers disease (AD) and associated neurodegeneration. Soluble amyloid-{beta} oligomers impair excitatory amino acid transporters (EAATs), reducing glutamate clearance, while also enhancing glutamate release from neurons and astrocytes. Together, these effects produce persistent glutamatergic dysregulation that disrupts synaptic and network function. Here, we asked whether the effects of EAAT attenuation can be mitigated through ion-channel modulation. TBOA, a selective EAAT inhibitor, was used to model early-stage glutamatergic dysregulation. TBOA reduced the local field potential amplitude of hippocampal sharp-wave ripples (SWRs) in mouse hippocampal slices, suggesting that glutamate accumulation disrupts network synchrony. Calcium imaging further showed that TBOA diminished SWR-associated population calcium transients while promoting spontaneous calcium transients in individual neurons, indicating a shift from coordinated population activity toward disorganized cellular activity. KCNQ-channel openers ML213 and ICA-27243 partially restored the TBOA-induced decline in SWR amplitude. In contrast, similar restorative effects were not observed following modulation of other ion channels, including blockade of AMPA and NMDA receptors or HCN/Ih channels, or activation of large-conductance Ca2+-activated K+ (BK) channels and G-protein-activated inwardly rectifying potassium (GIRK) channels. Together, these findings suggest that KCNQ-channel openers may occupy a unique position in mitigating glutamate-related hyperexcitability during early AD-associated network dysfunction.

Presenilin 2 (PS2) mutations cause familial Alzheimers disease, yet their effects beyond amyloid processing remain poorly understood. Here, we investigated how PS2 deletion and the N141I mutation affect neuronal lipid homeostasis and mitochondrial dynamics in mouse primary neurons. Both PS2 deletion and N141I mutation reduced neuronal lipid content. However, exogenous lipid supplementation rescued this deficit only in N141I-expressing neurons, indicating a partial loss-of-function effect. N141I neurons also displayed reduced OPA1, a mitochondrial fusion regulator, restored by lipid supplementation. RNA-sequencing identified Gbf1, a Golgi-specific guanine nucleotide exchange factor, as selectively downregulated in N141I but not knockout tissue, which was confirmed at the protein level in mouse brain and primary neurons. Gbf1 knockdown in mouse embryonic fibroblasts (MEFs) recapitulated the N141I lipid profile. Together, these findings reveal a PS2-GBF1-lipid-mitochondria axis disrupted specifically by the N141I mutation, suggesting an amyloid-independent pathway contributing to neurodegeneration and identifying potential therapeutic targets for familial Alzheimers disease.

Diabetes mellitus (DM) is a major risk factor contributing to the development of Alzheimers disease-related dementias (ADRD). While one of the early symptoms of both Alzheimers disease (AD) and DM-related ADRD is a reduction in cerebral blood flow, the underlying biological mechanisms driving this decline remain to be fully elucidated. Genome-wide association studies have linked AD/ADRD to single-nucleotide polymorphisms in the gene encoding soluble epoxide hydrolase (sEH), an enzyme we previously reported to be upregulated in the brains of an AD rat model. Our previous work also demonstrated that chronic inhibition of sEH with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) preserves hippocampal-dependent spatial learning and memory and improves cerebral hemodynamics in both AD and DM-ADRD models. In the present study, we found that chronic TPPU treatment (1 mg/kg/day for 9 weeks) reduced brain sEH expression, improved cortical-based long-term non-spatial recognition memory involving both cortical and hippocampal networks, and reduced anxiety in DM-ADRD rats. TPPU improved brain perfusion and normalized impaired whisker-evoked functional hyperemia, an effect linked to upregulation of Kir2.1 expression in cerebral capillaries. Furthermore, TPPU restored tight junction proteins (ZO-1 and OCLN), mitigated capillary rarefaction, and suppressed astrocyte and microglial activation. At the cellular level, TPPU attenuated hippocampal neurodegeneration, restored the expression of synaptic proteins (PSD95 and SY38), and reduced levels of key pro-inflammatory chemokines, including MCP-1, RANTES, and MIP-1, in DM-ADRD. In conclusion, TPPU preserves cognitive function in DM-ADRD by mitigating cerebrovascular dysfunction, neuroinflammation, and gliosis while protecting synaptic integrity and neuronal survival, representing a promising therapeutic strategy for DM-ADRD.