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bioRxiv2025

Ms4a4a deficiency ameliorates plaque pathology in a mouse model of amyloid accumulation

Genome-wide association studies for Alzheimer disease (AD) risk have identified a number of genes enriched in microglia, including MS4A4A. Common variants in MS4A4A influence AD risk, MS4A4A expression, TREM2 signaling, and a specific microglial transcriptional state, though the exact role of MS4A4A in AD remains unclear. Using a mouse model of amyloid beta (A{beta}) accumulation (5xFAD), we examined the impact of Ms4a4a loss on A{beta} pathology. Before A{beta} accumulation, Ms4a4a loss reduces steady-state A{beta} levels and shortens A{beta} half-life in brain interstitial fluid. In aged 5xFAD Ms4a4a-deficient mice, plaques are more compact with reduced overall plaque burden. Microglia lacking Ms4a4a are more pro-inflammatory and produce more MMP-9, which may promote degradation of A{beta} and A{beta} fibrils. Human subjects that carry a variant near MS4A4A (rs1582763) that confers resilience to AD also exhibit significantly elevated levels of MMP-9 in their cerebrospinal fluid. Together, our results suggest that loss of Ms4a4a improves A{beta} pathology by altering A{beta} clearance, offering insights for therapeutic interventions in AD.

neuroscience↗

bioRxiv2025

Hyperactivation of TAK1 causes skeletal muscle pathology reminiscent of inflammatory myopathies

Loss of skeletal muscle mass and strength is a debilitating consequence of various chronic diseases, inflammatory myopathies, and neuromuscular disorders. Inflammation plays a major role in the perpetuation of myopathy in degenerative muscle diseases. TAK1 is a major signaling protein that mediates the activation of multiple signaling pathways in response to inflammatory cytokines and microbial products. Recent studies have demonstrated that TAK1 is essential for the growth and maintenance of skeletal muscle mass in adult mice. However, the effects of overstimulation of TAK1 activity in the regulation of skeletal muscle mass remain unknown. In the present study, using AAV vectors, we investigated the effect of varying levels of TAK1 activation on skeletal muscle in adult mice. Our results demonstrate that while low levels of TAK1 activation improve skeletal muscle mass, sustained hyperactivation of TAK1 causes myopathy in adult mice. Excessive stimulation of TAK1 manifests pathological features, such as myofiber degeneration and regeneration, cellular infiltration, increased expression of proinflammatory molecules, and interstitial fibrosis. Hyperactivation of TAK1 also upregulates proteolytic systems and various catabolic signaling pathways in skeletal muscle of adult mice. Altogether, our study demonstrates that physiological levels of activation of TAK1 lead to myofiber hypertrophy, whereas its hyperactivation results in myofiber damage and other pathological features resembling inflammatory myopathies.

cell biology↗

bioRxiv2025

Subtle Cellular Phenotypes Inform Pathological and Benign Genetic Mutants in the Iduronidase-2 Sulfatase Gene

As with most enzyme-storage disorders, DNA testing at an early age is critical for identifying genetic variants and their impact on disease burden. Still, most variants in genes such as Iduronate-2-sulfatase, IDS, are Variants of Uncertain Significance (VUS). In patients presenting with Hunter Syndrome, clinical testing for IDS enzyme activity has been the mainstay to determine whether a variant is likely damaging. However, these enzyme assays are unable to predict disease severity or neuronal toxicity and may be missing many aspects of IDS pathology. In this study, we have developed an image-based assay using genome-engineered cells with IDS mutations to identify if a specific mutation causes lysosomal and membrane disruptions that characterize the disease. Specifically, we generate twelve mutant cell lines and document both the biochemical changes in IDS activity and the reproducible phenotypic differences therein. Next, we examine two patient-derived cell lines and find the same phenotypic differences in these lines compared to parental controls. The phenotypic changes are measured on a specific scale, which we term the PathScoreLC. To determine whether the observed changes are specific to IDS, we reintroduce a recombinant version of the IDS enzyme (rhIDS) to rescue both the biochemical and phenotypic changes of these cells. Interestingly, even after 120 hours, rescue is present, but not all the cells return to normal, which may also reflect the pathological state. Finally, we examine the gene expression differences and find that recombinant enzyme is not sufficient to induce transcriptional changes in the mutant lines at the time points studied. Overall, these cell-based lysosomal and membrane phenotypes may be key to quickly and accurately profiling clinical variants in the IDS gene.

cell biology↗

bioRxiv2025

Decisional reference point pathology: a mechanism and marker for major depressive disorder in humans

The decisional reference point, the central mechanism of behavioral economics, conditions our evaluations of reinforcers. It determines whether a given event is experienced as positive or negative. Here we show, for the first time, a significant and pathological elevation of the reference point in patients with depression that correlates with disease severity. We also show that the mechanism for reference point setting is profoundly impaired in patients with depression. These findings link the previously demonstrated treatment of depression by deep brain stimulation to modulation of the reference point in the anterior cingulate cortex and identify pathology in the dynamics of reference point setting as a novel mechanism in the disorder. Finally, these results lay the foundation for a three-minute virtual diagnostic test for depression.

neuroscience↗

bioRxiv2025

Pathologic and phylogenetic characterization of Usutu virus infections in free-ranging wild birds in Switzerland (2015-2020)

Usutu Virus (USUV) is an emerging flavivirus causing fatal disease in free-ranging and captive birds but also infecting mammals and representing a significant zoonotic agent in Europe, making monitoring and investigations of this viral agent crucial both for conservation and public health. We carried out a retrospective investigation focusing on free-ranging wild birds confirmed to be USUV infected examined at the Institute for Fish and Wildlife Health (FIWI), Switzerland. The pathology and virology findings together with the phylogeographic and environmental data were examined for underlying factors to the dynamics of the USUV infection in Switzerland, between 2015 and 2020, with particular focus to the major peak of 2018. USUV infection was confirmed by reverse transcription-PCR in 67 birds, with common blackbirds (Turdus merula, 73%; 49/67) being overrepresented, showing signs of diseases including poor body condition (84%; 56/67) and splenomegaly (75%; 50/67). Histology (n=34) revealed changes in the heart (58%; 19/33), the central nervous system (67%; 22/33) and the liver (62%; 21/34). Of interest, the splenic changes (86%, 25/29) showed different, but likely correlated phenotypes, characterized by the presence of discrete and/or diffuse histiocytic infiltrates in the congested and lymphoid depleted spleen parenchyma, possibly reflecting different stages of the disease. Phylogenetic analysis unambiguously revealed that the recent USUV infections were predominantly caused by strains of the Europe 3 lineage. USUV Africa 3 strains were detected exclusively from southern Switzerland in one location (two blackbirds). Our investigation revealed intralesional Usutu viral RNA consistent with infection in previously undescribed hosts (Corvus frugilegus, Cygnus olor) and provided new insights into the pathogenesis and the ecology of the disease. The environmental data suggested the occurrence of unique weather conditions, possibly boosting the mosquito population and favoring an unprecedented increase of cases in 2018. Finally, the increase in genetic diversity of the circulating strains might have contributed to the recorded high mortality in 2018. Author SummaryAt the end of the 20th century, Usutu virus (USUV) was associated for the first time with mass mortality in wild black birds in Italy. Shortly after, reports on avian fatalities associated with USUV all over Europe appeared. In 2018 an unprecedented high occurrence of Usutu virus disease (UVD) caused high mortalities in wild birds in Switzerland and other European countries. Here we examined deceased wild birds with UVD with an emphasis on pathological examination and identification of USUV strains. The spleen is one of the main organs affected and we propose a timeline of lesion progression correlating with early, intermediate and late changes. Whereas we mainly identified strains of the European 3 lineage, we also found a hotspot of African 3 lineage strains. This indicates multiple entries of USUV into Switzerland. Although the disease is especially fatal in Strigiformes and Passeriformes, we expanded the spectrum of bird species (mute swans, rooks) naturally infected with the USUV. Usutu virus is an arthropod-borne virus and transmission occurs mainly via blood feeding vectors such as mosquitoes. We discuss the influence of weather conditions on mosquito population and the potential role of invasive mosquito species, such as the Asian tiger mosquito and other Aedes spp., as additional vectors for disease.

microbiology↗

bioRxiv2025

Human- and Rodent-derived Extracellular Vesicles Mediate the Spread of Pathology in MSA-like Models

Multiple system atrophy (MSA) is characterized by the presence of protein-rich inclusions mainly within oligodendrocytes, comprised primarily by the neuronal protein Synuclein and the oligodendroglial-specific phosphoprotein TPPP/p25. Mature oligodendrocytes do not normally express detectable Synuclein levels, suggesting that its oligodendroglial accumulation may arise from intercellular transfer, potentially via extracellular vesicles (EVs); however the precise role of oligodendroglial-derived EVs in MSA progression remains relatively understudied. Herein, we characterized the cargo/features and pathogenic potential of EVs released by oligodendrocytes treated with human Synuclein fibrils amplified from MSA or Parkinsons disease patient brains (or human recombinant Synuclein fibrils) and EVs isolated from murine and human MSA (or respective control) brains. Our findings reveal that both oligodendroglial cell- and brain-derived EVs harbor pathological Synuclein and TPPP/p25 conformations, similar to those accumulating in human MSA brains. These EVs are readily taken up by both neurons and oligodendrocytes, driving Synuclein propagation in vitro. Importantly, inoculation of these MSA-like EVs in animal models induce robust pSer129-Synuclein accumulation along the nigrostriatal axis, colocalizing with markers of mature oligodendrocytes and dopaminergic neurons. These findings underscore the pivotal role of oligodendroglial-derived EVs in pathology progression and neuronal-oligodendroglial communication, positioning them as promising targets for therapeutic strategies aimed at combating alpha-Synucleinopathies.

neuroscience↗

bioRxiv2025

Bisdemethoxycurcumin mitigates Alzheimer disease pathology through autophagy-mediated reduction of senescence and amyloid beta

AD pathology is accompanied by increased senescence and reduced levels of autophagy in the brain. We investigated whether pharmacologically inducing autophagy could alter the senescent phenotype and help ameliorate AD pathology. We discovered that Bisdemethoxycurcumin (BDMC), a natural compound found in Curcuma longa, stimulates autophagy in primary astrocytes. We found that autophagy and senescence exhibit an inverse relationship in aging astrocytes, with increased expression of senescent proteins and downregulation of autophagic proteins. However, treatment of aged astrocytes with BDMC reversed the senescent phenotype by ameliorating the impaired autophagy. Interestingly, the senescent phenotype persisted when autophagy was downregulated by knockdown of AMPK. Additionally, BDMC-induced autophagy aided in the removal of amyloid beta that was administered externally to the astrocytes. Further, to validate these results in a mouse model of AD, we confirmed that BDMC can significantly penetrate the blood-brain barrier (BBB) in mice. Therefore, we administered 50 and 100 mg/kg b.w. of BDMC to transgenic 3xTg-AD mice for two months. In their hippocampus, the Control 3xTg-AD animals showed more senescent cells and lower autophagy levels. In contrast, autophagic proteins were significantly upregulated while senescence indicators, such as senescence-associated secretory phenotype (SASP) proteins, were sharply downregulated in the brain of treated animals. Additionally, we discovered that the treated mices hippocampus had a significantly lower amyloid beta load. These molecular changes in the brain were ultimately reflected in the improved working memory and neuromuscular coordination behavior of mice treated with BDMC. This study warrants further evaluation of BDMC for the management of AD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/654834v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@1176bbforg.highwire.dtl.DTLVardef@a2e2cdorg.highwire.dtl.DTLVardef@1d824f5org.highwire.dtl.DTLVardef@1628a30_HPS_FORMAT_FIGEXP M_FIG This illustration was created by using biorender.com C_FIG

pharmacology and toxicology↗

bioRxiv2025

Pathological meprin α expression associated with degradation of dermokine drives a psoriasis-like skin phenotype in a genetic mouse model

Keratinocyte proliferation and differentiation is regulated via proteolytic networks. Dysregulation of proteases within these networks can cause hyperproliferative and inflammatory skin disorders. In healthy skin the metalloprotease meprin is localized in the stratum basale. In contrast, in wound healing tissue and psoriatic lesions increased meprin levels are found in the upper epidermal layers. We developed a transgenic mouse model for inducible expression of pathological meprin levels (K5M) to investigate its epidermal degradome and identify molecular links to keratinocyte proliferation and skin inflammation. K5M mice developed a severe skin phenotype characterized by hyperkeratosis, acanthosis and parakeratosis accompanied by increased transepidermal water loss and a strong inflammatory response within six days after induction of meprin overexpression. Histological and molecular analyses showed that increasing meprin expression correlates with meprin activity and keratinocyte hyperproliferation. Proteomics analyses revealed massive changes in proteins associated with keratinocyte differentiation and epidermal barrier integrity already three days after induction. N-terminomics data indicated a dominant chymotryptic activity with elevated proteolytic turnover of proteins associated with the cytoskeleton, cellular stress responses and cell adhesion. By filtering for cleavage sites that match with the specificity of meprin , we identified highly elevated dermokine-derived peptides. Subsequent mass spectrometric analyses validated dermokine as a novel substrate of meprin and identified the cleavage site, which is highly conserved in mammals. Based on the striking similarities with the phenotype reported for dermokine {beta}{gamma}-/- mice, we propose meprin as a central regulator of keratinocyte proliferation and leukocyte recruitment by proteolytic inactivation of dermokine. Hence, pathological meprin activity could be a driver of hyperproliferative, inflammatory skin disorders like psoriasis vulgaris.

molecular biology↗

bioRxiv2025

Opposing effects of H2A.Z on memory, transcription and pathology in male and female Alzheimer's disease mice and patients

Alzheimers disease (AD) is a devastating neurodegenerative disease that disproportionately impacts women, but underlying mechanisms for sex-divergent outcomes are unknown. Here, we show that the histone variant H2A.Z is a novel sex-specific regulator of AD in human patients and AD model mice. Specifically, H2A.Z binding in chromatin declines in female and increases in male AD patients, indicating opposite patterns of AD-related H2A.Z dysregulation each sex. These sex differences were recapitulated in the 5xFAD model of AD, in which females accumulated H2A.Z at early disease stages and lost H2A.Z as the disease progressed, suggesting that H2A.Z occupancy shifts with advancing disease. Males showed no change in H2A.Z binding in early disease, but exhibited increased binding as disease progressed, albeit to a lesser extent than females. Consistent with sex-specific H2A.Z dysregulation, H2A.Z depletion produced sex-specific changes in gene expression, whereby H2A.Z was more repressive in female than in male mice and in 5xFAD than in WT males, suggesting that H2A.Zs role in transcription varies with sex and disease. Moreover, H2A.Z depletion improved memory and AD pathology in females, while impairing memory and worsening pathology in male mice. Together, these data suggest that H2A.Z is protective in males and detrimental in females with AD, with key implications for sex-specific therapeutic targeting of chromatin factors.

neuroscience↗

bioRxiv2025

Prenatal alcohol exposure promotes nerve injury-induced pathological pain following morphine treatment via NLRP3-mediated peripheral and central proinflammatory immune actions.

Adverse in-utero conditions may exert a lifelong impact on neuroimmune function. Our prior work showed that prenatal alcohol exposure (PAE) increases pathological pain sensitivity (allodynia) following peripheral sciatic nerve injury. While the immune mechanism(s) of PAE-induced immune dysfunction are poorly understood, prior studies implicated the involvement of Toll-like receptor 4 (TLR4) and the nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasomes. Interestingly, emerging data suggest a surprising overlap of spinal glial proinflammatory activation via the TLR4-NLRP3-interleukin (IL)-1{beta} axis due to opioid treatment in nerve-injured non-PAE rodents. Considering this preclinical evidence, we explored whether PAE poses a risk factor in creating proinflammatory immune bias consequent to opioid (morphine) exposure. We hypothesized that under nerve injury conditions, PAE may interact with morphine, promoting peripheral and CNS proinflammatory factors in a NLRP3-dependent manner. Using a minor nerve injury model in adult mice, we demonstrate that PAE prolongs the chronicity of ongoing allodynia in both sexes, with a more pronounced effect observed in male mice. Our study shows that PAE amplifies proinflammatory responses at the injury site and the spinal cord, driving morphine-prolonged allodynia through NLRP3 inflammasome activation. Furthermore, high mobility group box 1 (HMGB1), a well-established pain-promoting TLR4 agonist, is elevated in allodynic PAE mice. NLRP3 inhibitor, MCC950, effectively reverses morphine-induced allodynia and reduces Caspase-1 activity, IL-1{beta}, and related proinflammatory factors. Although few sex-specific effects were observed, our data convincingly support that PAE and morphine interactions ultimately converge on NLRP3-driven mechanisms in both sexes. Together, this study suggests that PAE modulates later-life neuroimmune function and provides critical insights into immune regulators underlying PAE-induced biological vulnerability to pathological pain processing and adverse effects of opioids.

neuroscience↗

bioRxiv2025

DAPL1 deficiency impairs autophagy in retinal pigment epithelium to drive age-dependent retinal pathologies

Age-related retinopathy, primarily comprising age-related macular degeneration (AMD), is a major cause of irreversible blindness in the elderly population worldwide. Although its precise mechanisms remain incompletely understood, autophagy deficiency in retinal pigment epithelium (RPE) cells has been associated with AMD in patients; however, the regulatory pathways involved are not fully elucidated. In this study, we report that deficiency in the Dapl1 gene inhibits RPE cell autophagy and leads to age-dependent retinal pathologies in mice. Specifically, 18-month-old Dapl1-/- mice manifest age-related retinal dysfunction and structural abnormities, including increased retinal stress, photoreceptor/RPE cell damage, lipid aggregates and microglial activation. Furthermore, we demonstrate that autophagy is impaired in the RPE cells of Dapl1-/- mice, while overexpression of DAPL1 in RPE cells enhances autophagy activity. Mechanistically, we elucidate that DAPL1 suppresses the expression of E2F1 and c-MYC, which consequently downregulates mTOR and upregulates ATG16 and Beclin1 expression via DAPK1 in RPE cells, thereby promoting autophagy. Taken together, our findings demonstrate that DAPL1 acts as a novel regulator of autophagy in RPE cells, and its deficiency increases susceptibility to age-dependent retinal pathologies in mice.

molecular biology↗

bioRxiv2025

Multiplex Proteomics of Lewy Body Dementia Reveals Cerebrospinal Fluid Biomarkers of Disease Pathology and Progression

Lewy body dementia (LBD), which encompasses Parkinsons disease dementia (PDD) and Dementia with Lewy bodies (DLB), lacks established biofluid markers of its complex clinical and neuropathological heterogeneity. Multiplex proteomic tools, such as the recently developed NUcleic acid Linked ImmunoSandwich Assay (NULISATM), can assess a diverse array of neurodegenerative targets and address these biomarker gaps. We used this platform to analyze 852 baseline and longitudinal cerebrospinal fluid (CSF) samples from control, PD, and DLB subjects from the Parkinsons Disease Biomarker Program (PDBP). We then examined LBD protein signatures across different clinical diagnoses, patterns of cognitive progression, and underlying neuropathologies. Of the 124 markers analyzed, 54 were significantly altered in PD with cognitive impairment and/or DLB compared to controls, many serving as informative clinical classifiers in machine learning models. We also identified 15 proteins with significant baseline and/or longitudinal changes linked to cognitive progression. To identify neuropathological signatures, we stratified 209 cases by the presence of underlying synuclein and amyloid-beta (A{beta}) pathology using CSF alpha-synuclein seed amplification assay (Syn-SAA) results and NULISA pTau-217 levels, respectively. Select synaptic markers were decreased relative to synucleinopathy but increased relative to A{beta} accumulation, complicating their interpretation in cases with co-pathology. These neuropathological analyses were replicated in an independent cohort of 917 cases from the Alzheimers Disease Neuroimaging Initiative (ADNI). Overall, these results highlight the utility of multiplex proteomic analysis in the identification of candidate CSF biomarkers of disease heterogeneity in LBD. One Sentence SummaryThis multiplex proteomic analysis using the recently released NULISA platform revealed unique targets of Lewy body dementia progression and neuropathology.

systems biology↗

bioRxiv2025

NERVE GROWTH FACTOR IS SUFFICIENT TO CAUSE MULTIPLE OSTEOARTHRITIS-RELEVANT PATHOLOGICAL FEATURES IN NAIVE MURINE KNEE JOINTS

BACKGROUNDNerve growth factor (NGF), a key mediator of pain and inflammation, is increased in joints with osteoarthritis (OA). Neutralizing NGF with monoclonal antibodies has shown analgesic effects in painful knee OA, but clinical development was stopped due to side effects in the joints. Knowledge about the biological effects of long-term exposure of joint tissues to NGF is limited. Therefore, we aimed to explore the effects of repeated intra-articular (IA) injections of NGF into the knee joints of healthy mice on pain and sensitization, as well as joint innervation and structure. METHODSWe conducted five experiments in male C57BL/6 mice. In Experiment 1, NGF (50ng or 500ng) or vehicle was injected IA into the knee of naive wildtype (WT) mice, twice a week for 4 weeks. We assessed knee swelling, knee hyperalgesia and histopathology. In Experiment 2, mice were injected with 500ng NGF or vehicle, twice a week for 4 weeks and microCT of the knee was performed. In Experiment 3, NaV1.8-tdTomato reporter mice were injected with 500ng NGF or vehicle, twice a week for 4 weeks, and joint innervation was assessed. In Experiment 4, WT mice received 500ng NGF or vehicle twice a week for 4 weeks and were used for single cell RNA sequencing (scRNAseq) of the synovium. In Experiment 5, L3-L5 DRGs of mice that received 3 IA injections of 500ng NGF or vehicle twice a week were used for bulk RNA sequencing. RESULTSRepeated bi-weekly IA injections of NGF caused knee hyperalgesia in naive mice. NGF caused dose-dependent knee swelling, synovial pathology, increased bone mineral density and trabecular bone thickness in the medial subchondral bone, growth of pre-osteophytes in the medial compartment, but no cartilage degeneration. NGF injection caused sprouting of NaV1.8+ neurons in the medial but not the lateral synovium. ScRNAseq of the synovium revealed upregulated genes related to neuronal sprouting, synovial fibrosis and ossification, confirming histopathological findings. Bulk RNA seq of DRG showed upregulated pathways related to axonal growth. CONCLUSIONSIn healthy mouse knees, NGF induced mechanical sensitization, synovitis, neoinnervation in the medial synovium, subchondral bone changes and pre-osteophyte growth in the medial compartment, thus capturing many pathological changes observed in OA, except cartilage damage.

neuroscience↗

bioRxiv2025

TDP-43 pathology induces CD8+ T cell activation through cryptic epitope recognition

Aggregation and nuclear depletion of the RNA binding protein TDP-43 are the crucial pathological features of amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM), two degenerative diseases of the CNS and muscle. The loss of TDP-43 nuclear function results in the aberrant inclusion of cryptic exons in mRNA transcripts, leading to the expression of de novo proteins. Clonally expanded and highly differentiated CD8+ T cells have been observed in individuals with TDP-43 proteinopathies and therapeutics modulating the T cell response have recently been found to extend survival. However, the target antigens mediating T cell activation have remained elusive. Here, we investigate whether the de novo proteins induced by aberrant cryptic splicing due to TDP-43 nuclear loss can act as neo-antigens. We detect the HDGFL2 cryptic peptide and multiple other TDP-43 cryptic exons in IBM skeletal muscle, where their presence correlates with enrichment of T cells and class I antigen presentation pathways. Furthermore, we identify epitopes deriving from HDGFL2 and IGLON5 cryptic peptides which are recognized by clonally expanded and functionally differentiated populations of CD8+ T cells in ALS and IBM Patients. Finally, we demonstrate that T cells engineered to express the identified TCRs can bind and activate in response to the cryptic peptide derived epitopes (cryptic epitopes) and are able to kill TDP-43 deficient astrocytes. This work identifies for the first time specific T cell antigens in ALS and IBM, directly linking adaptive immune response to TDP-43 pathology.

immunology↗

bioRxiv2025

Amyloid pathology reduces dynamic range and disrupts neural coding in a mouse model of Alzheimer's Disease

Alzheimers disease (AD) disrupts neural circuits vital for memory and cognition. Using two-photon calcium imaging in behaving 5xFAD mice, we examined how amyloid pathology alters hippocampal CA1 activity and spatial coding. We found elevated baseline activity but reduced locomotion-driven firing, leading to a diminished neuronal dynamic range. To our knowledge, this is the first direct experimental evidence for reduced dynamic range in an AD model. These abnormalities were strongest near amyloid plaques and became more widespread with age. We also observed altered network synchrony, degraded spatial coding and increased neuronal response variability. Furthermore, place fields emerged more slowly in both familiar and novel environments, indicating impaired recall and learning. By showing a link between local plaque pathology and impaired flexible modulation of CA1 activity and progressive deficits in spatial memory coding, our study offers new insights into the circuit basis of cognitive decline in AD.

neuroscience↗

bioRxiv2025

Registration-based 3D Light Sheet Fluorescence Microscopy and 2D histology image fusion tool for pathological specimen

BackgroundHistological analysis traditionally relies on thin tissue sections, providing inherently two-dimensional (2D) information. However, this approach captures only a fraction of the entire sample and lacks the spatial context nec-essary for comprehensive tissue assessment. Recent advancements in multimodal imaging have introduced the fusion of histological data with three-dimensional (3D) imaging techniques, such as Light Sheet Fluorescence Microscopy (LSFM), to enhance tissue analysis by integrating complementary spatial information. A key challenge in this fusion process is the accurate alignment of corresponding structures across modalities, which is complicated by differences in resolution, sectioning-induced deformations, and varying imaging orientations. Existing solu-tions often require manual selection of image pairs or technical expertise, limiting accessibility to non-specialist users. MethodsTo address these limitations, we introduce LitSHi (Light Sheet meets Histology), a novel registration tool that enables the automated and precise align-ment of LSFM and histological images. LitSHi allows multimodal image fusion to be performed fully automatically, which significantly reduces the need for manual intervention. ResultsWe evaluated LitSHi on testicular tumor specimens, demonstrating its ability to achieve enhanced structural correspondence between LSFM and histological images. The automated registration process significantly improved efficiency and alignment accuracy compared to traditional manual or semi-automated approaches. ConclusionLitSHi could improve digital pathology by optimizing multimodal tissue analysis and supporting future developments in computational pathology and AI-driven diagnostics.

bioengineering↗

bioRxiv2025

A compendium of adipocyte morphologies across different breast pathologies

Adipocytes are abundant in the breast tissue microenvironment. In breast cancer, they can change morphologically according to their proximity to tumour cells, with the closest becoming cancer-associated adipocytes (CAAs). It remains unclear whether breast cancer risk factors, including menopausal status, body mass index (BMI), and mammographic density (MD), influence CAAs morphology in breast carcinogenesis. This study aimed to quantify morphological differences in adipocytes across breast cancer pathologies and associated risk factors. Whole slide images of hematoxylin and eosin stained cancer (n = 149) and normal (n = 182) breast tissue samples were analysed. Parameters representative of adipocyte morphology: perimeter, area, concavity, and aspect ratio, were measured using ImageJ. Adipocytes were considered close ([≤] 2 mm) or distant (>2 mm) to cancer cells in cancer samples or breast epithelial cells in normal samples. Close adipocytes in cancer samples were designated CAAs. CAAs decreased in size compared to distant adipocytes (p [≤] 0.0001). A similar trend was observed between close and distant adipocytes in normal (p [≤] 0.0001). CAAs size increased post menopause (p [≤] 0.0001). CAAs size positively correlated with BMI (p [≤] 0.0001). In cancer cases, distant adipocyte size increased and concavity decreased with increasing MD (p [≤] 0.01). Smaller CAAs were associated with poorer survival (p [≤] 0.05). Morphological differences were identified in adipocytes dependent on location within the breast, tissue, pathology and risk factors. Understanding what drives these morphological differences could provide mechanistic insight into whether risk factor-induced alterations in adipocytes influence their role in breast carcinogenesis.

cancer biology↗

bioRxiv2025

White Matter Tract Vulnerability to Amyloid Pathology on the Alzheimer's Disease Continuum

Alzheimers disease (AD) is marked by progressive cognitive decline and memory loss, due to the abnormal accumulation of amyloid-beta (A{beta}) plaques, which facilitate the spread of tau pathology, and a gradually spreading pattern of neuronal loss. Understanding how amyloid positivity affects the brains neural pathways is critical for understanding how the brain changes with AD pathology. Tractometry offers a powerful approach for the in vivo, 3D quantitative assessment of white matter tracts, enabling the localization of microstructural abnormalities in diseased populations and those at risk. In this study, we applied BUAN (Bundle Analytics) tractometry to multi-cohort diffusion MRI data from a total of 1,908 participants: 606 participants in ADNI3 (Alzheimers Disease Neuroimaging Initiative Phase 3) and 1,302 participants from the HABS-HD (Health and Aging Brain Study-Health Disparities). Using BUAN and along-tract statistical analysis, we assessed the localized effects of amyloid positivity on white-matter pathways, which may be further influenced by downstream tau accumulation. Amyloid positivity was quantified via amyloid-sensitive positron emission tomography (PET). BUAN enables tract-specific quantification of white matter microstructure and supports statistical testing along the full length of fiber bundles to detect subtle, spatially localized associations. We present 3D visualizations of tractwise amyloid associations, highlighting distinct patterns of white matter degeneration in AD.

neuroscience↗