Biology subjects

Vassallu, F.

Publications and source records attributed to Vassallu, F..

3 recordsLinked to original sources

bioRxiv2026

Region-specific features of early glial activation and Aquaporin-4 dysregulation in conditional mouse models of TDP-43 proteinopathies

Aggregation and cytoplasmic mislocalization of TDP-43 are key features of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuroinflammatory processes mediated by glial cells play crucial roles in the pathophysiology of these and other diseases, defined as TDP-43 proteinopathies. Here, we characterized region-specific glial activation in two conditional mouse models: hTDP-43-WT (overexpressing nuclear wild-type human TDP-43) and hTDP-43-{Delta}NLS (expressing cytoplasmic TDP-43 with altered nuclear localization signal) following one month of transgene expression. Immunofluorescence analysis revealed distinct patterns of microglial activation across brain regions. hTDP-43-WT mice exhibited significant microgliosis in motor (MC) and somatosensory (SSC) cortices and hippocampal dentate gyrus (DG) with pronounced morphological alterations (i.e. increased soma size). Sholl analysis demonstrated reduced branching length and complexity in MC, SSC and hippocampal subfields. hTDP-43-{Delta}NLS mice displayed more pronounced microglial activation in hippocampal regions (CA1, DG) compared to cortical areas, with significant increases in microglial density. Additionally, we observed region-specific cortical astrocytosis in both models, suggesting coordinated glial reactivity. hTDP-43-{Delta}NLS mice showed decreased polarization of astrocytic water channel Aquaporin-4 (AQP4) around vascular structures in SSC and hippocampal CA1/DG. The changes in AQP4 localization, which is critical for glymphatic function, supports the hypothesis that this waste clearance system for the brain is altered in TDP-43 proteinopathies. These findings demonstrate that these different animal models of ALS/FTD induce distinct neuroinflammatory signatures, potentially contributing to the region-specific vulnerability observed in these diseases. Our data provide insights into early glial-mediated pathogenic mechanisms that could guide targeted therapeutic strategies for TDP-43 proteinopathies.

neuroscience↗

bioRxiv2025

TDP-43 expression in the cytoplasm leads to early synaptic and mitochondrial abnormalities in an inducible mouse model of ALS/FTD

TDP-43 proteinopathy is the primary pathology associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), indicating that these neurodegenerative diseases have common underlying mechanisms. We have previously shown that transgenic (Tg) mice conditionally overexpressing a cytoplasmic form of human TDP-43 protein (TDP-43-{Delta}NLS) in forebrain neurons replicate key features of FTD/ALS, including altered cognitive, motor and social behaviors. These behavioral phenotypes and changes in plasticity-related gene expression can be detected as early as 1 month after Tg induction, before overt neurodegeneration occurs. To assess early ultrastructural features in this model, we performed Transmission Electron Microscopy (TEM) analysis in the cortex (Ctx) and hippocampus (Hp) of Tg animals and their non-Tg controls. TEM evaluation of Ctx and Hp revealed that synaptic density was significantly decreased and synapse length was increased in both regions of Tg animals. Synaptic cleft thickness was increased and post-synaptic density thickness was decreased only in the Ctx of Tg mice, revealing differential regional effects in synaptic morphology. We analysed mitochondrial density and we found an increase in the Ctx and a decrease in the Hp of Tg animals, with preserved individual mitochondrial area. Lastly, transcriptomic and proteomic analysis from both transgenic TDP-43-{Delta}NLS mice and human proteinopathy showed widespread decreased expression of synaptic structure and function genes. The alterations in synaptic density and architecture reported here, combined with the mRNA/protein expression data, suggest that TDP-43-{Delta}NLS mice may exhibit abnormal synaptic transmission and that ultrastructural changes play a role in the early behavioral deficits observed in this model. HighlightsO_LICytoplasmic TDP-43 expression in vivo causes early synaptic and mitochondrial abnormalities. C_LIO_LIReduced synaptic density observed in cortical and hippocampal regions of TDP-43-{Delta}NLS mice. C_LIO_LISynaptic ultrastructure altered, including increased cleft width and reduced PSD thickness. C_LIO_LIRegion-specific mitochondrial density changes: increased in cortex, decreased in hippocampus. C_LIO_LIFindings link TDP-43 mislocalization to early structural and functional brain deficits. C_LI

neuroscience↗

bioRxiv2025

Synaptic changes contribute to persistent extra-motor behaviour deficits in the rNLS8 TDP-43 mouse model of amyotrophic lateral sclerosis

Extra-motor symptoms are increasingly recognised in amyotrophic lateral sclerosis (ALS), encompassing cognitive, social, and behavioural deficits that can substantially impact quality of life. TAR DNA binding protein 43 (TDP-43) pathology is the central disease marker of almost all cases of ALS and approximately half of all frontotemporal dementia (FTD). However, the mechanisms linking TDP-43 pathology with extra-motor symptoms in TDP-43-associated neurodegenerative diseases remain unresolved. In this study, we used the rNLS8 mouse model, which expresses human TDP-43 with an ablated nuclear localisation sequence (hTDP-43∆NLS) in a doxycycline-regulatable manner causing progressive motor decline reminiscent of ALS, to delineate the molecular changes associated with disease-relevant phenotypes. We found that in addition to previously reported dramatic motor decline, rNLS8 mice also develop extra-motor phenotypes consistent with FTD, including disinhibition-like and anxiety-like behaviours, and social interaction impairments. These changes began in the earliest disease stages and remained readily detectable even when rNLS8 mice became severely motor impaired. Notably, extra-motor deficits persisted in rNLS8 mice that had recovered motor function upon hTDP-43∆NLS transgene suppression, regardless of whether recovery was initiated at timepoints prior to or after overt neurodegeneration begins. Transcriptomic analysis of rNLS8 mouse cortex tissues revealed early alterations in expression of 321 genes, most notably involving neuroinflammatory-related pathway activation, and all but 2 of these genes returned to control levels upon suppression of hTDP-43∆NLS expression. Further, 814 genes showed differential exon usage, indicating changes in alternative splicing, in rNLS8 mouse cortex. Of these, differential exon usage of 10 neuronal genes persisted after hTDP-43∆NLS transgene suppression, including synapse component genes Nrxn1, Unc13a, and Gls. Similarly, proteomics analysis of the cortex of rNLS8 mice revealed depletion of synaptic proteins, particularly those involved in glutamatergic signalling pathways, which also persisted following hTDP-43∆NLS transgene suppression. Similar glutamatergic pathway changes were detected in human ALS and FTD post-mortem cortex tissues. Our findings indicate that extra-motor phenotypes emerge early in disease in rNLS8 mice and remain evident despite progressive motor impairments. Further, extra-motor phenotypes persist even upon motor recovery, correlating with specific synaptic gene expression and splicing changes. Overall, this study suggests the potential utility of an expanded suite of behavioural paradigms in preclinical testing using rNLS8 mice, with enhanced relevance to the diversity of TDP-43 proteinopathies including FTD. Our findings further suggest that targeting glutamatergic synaptic components may be an avenue to correct extra-motor deficits associated with TDP-43 pathology.

neuroscience↗