Biology subjects

Perna, A.

Publications and source records attributed to Perna, A..

9 recordsLinked to original sources

bioRxiv2026

APOE4 Drives Uniquely Dysfunctional Human Microglial States in Alzheimer's Disease

Variation in APOE, notably the {varepsilon}4 allele, profoundly shapes risk and severity of late-onset Alzheimers disease (AD), yet how it remodels human microglial states remains unresolved. We combine spatially resolved proteomic profiling with single-nuclear multiomic analyses to define microglial organization across APOE3/3 and APOE4/4 genotypes in AD. Quantifying condition-associated variation across the cellular manifold reveals a continuous landscape of microglial states. APOE4/4 shifts cells toward terminal states marked by loss of homeostatic identity, metabolic disruption, and incomplete acquisition of disease-associated programs. We identify an APOE4/4-enriched population in AD that exhibits inflammatory signaling without effective metabolic or phagocytic engagement, localizing to niches of gliosis and senescence, and coupled to chronic stress adaptation programs. Together with evidence that APOE4/4 potentiates the activation threshold of nascent microglia, these findings establish a unified framework for human microglial state change, linking genetic risk to spatial and molecular organization of immune responses in the AD brain. Graphical Abstract.APOE4/4 in Alzheimers disease reshapes microglial fate along continuous trajectories characterized by proteomic, transcriptional, and epigenetic programs consistent with chronic stress adaptation, alongside distinct composite spatial niches comprised of astrocytic gliosis and cellular senescence. O_FIG O_LINKSMALLFIG WIDTH=168 HEIGHT=200 SRC="FIGDIR/small/733295v1_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@b2afa4org.highwire.dtl.DTLVardef@12978f8org.highwire.dtl.DTLVardef@1c4e46dorg.highwire.dtl.DTLVardef@170e44d_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Comparative analysis of T-cell signatures and astroglial reactivity in Parkinson's pathology across animal models with distinct regenerative capacities

Parkinsons disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic (DAergic) neurons in the substantia nigra (SN) and the accumulation of misfolded -synuclein (aSyn). Emerging evidence suggests that the immune system, particularly T-cell-mediated responses, plays a key role in the pathogenesis of PD. However, the heterogeneity of these immune responses across species and preclinical models with varying regenerative capacities remains poorly understood. In this study, we performed a comparative analysis of T-cell infiltration, astroglial reactivity, and DAergic neuronal loss across multiple models and species. These included acute DAergic degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), genetically modified mice with accumulation of aSyn (Thy1-aSyn L61 model), adult zebrafish exposed to MPTP-induced neurotoxicity and human post-mortem midbrain tissue obtained from PD patients. Zebrafish exhibited transient DAergic neurodegeneration followed by neuronal regeneration and a temporary CD4+ T-cell infiltration alongside a regulated astroglial response. In contrast, MPTP-treated mice showed a permanent neuronal loss, increased astrogliosis and CD8+ T-cell infiltration that was negatively correlated with neuronal survival. In contrast, L61 mice exhibited progressive aSyn accumulation with chronic astrogliosis and CD4+ T-cell infiltration not directly linked to neuronal loss. Unlike age-matched controls, the SN from PD brains displayed DAergic degeneration, aSyn aggregation, and elevated CD3+ T-cell infiltration, which correlated with neuronal loss and aSyn burden. These findings emphasise the species- and model-specific immune profiles underlying PD pathology. Our results reveal that CD4+ T-cells contribute to neuronal regeneration following injury in zebrafish. This process is absent in the MPTP and L61 mouse models, which are instead driven by CD8+ or CD4+, respectively. This work underscores the potential of targeted immunomodulation aimed at T cell - glial interactions to slow neurodegeneration and promote repair in PD.

immunology↗

bioRxiv2025

High environmental temperatures put nest excavation by ants on fast forward: they dig the same nests, faster.

Environmental temperature influences the physiology and the behaviour of ectothermic organisms, including ants. However, the complex collective behaviour exhibited by ant colonies means that it is difficult to predict how the effects of temperature translate to colony-level functioning and features, such as the form of their nests. This study aims to determine the effects of environmental temperature on nest excavation rate and on the morphology of excavated nests. To this end, we characterized the nest digging activity of the yellow meadow ant Lasius flavus confined to dig in a nearly two-dimensional experimental setup maintained at a constant temperature ranging from 15 to 30 degrees Celsius. Ants dug faster at higher temperature, with an increase of digging rate that reflected the temperature-induced increase of movement speed of individual ants. Nevertheless, the shape of excavated nests remained statistically unchanged across the full range of temperatures we tested. These results suggest that temperature accelerates all aspects of the excavation process uniformly, rather than selectively influencing specific components such as tunnel branching or elongation. The ability to produce a consistent overall nest structure, irrespective of the temperature conditions encountered at the time of digging, may provide adaptive benefits to the colony.

animal behavior and cognition↗

bioRxiv2024

Single-Cell Peripheral Immunoprofiling of Lewy Body Disease in a Multi-site Cohort

Studies implicated peripheral organs involvement in the development of Lewy body disease (LBD), a spectrum of neurodegenerative diagnoses that include Parkinsons Disease (PD) without or with dementia (PDD) and dementia with Lewy bodies (DLB). This study characterized peripheral immune responses unique to LBD at single-cell resolution. Peripheral mononuclear cell (PBMC) samples were collected from sites across the U.S. The diagnosis groups comprise healthy controls (HC, n=164), LBD (n=132), Alzheimers disease dementia (ADD, n=98), other neurodegenerative disease controls (NDC, n=21), and immune disease controls (IDC, n=14). PBMCs were activated with three stimulants, stained by surface and intracellular signal markers, and analyzed by flow cytometry, generating 1,184 immune features. Our model classified LBD from HC with an AUROC of 0.90{+/-}0.06. The same model distinguished LBD from ADD, NDC, IDC, or other common conditions associated with LBD. Model predictions were driven by pPLC{gamma}2, p38, and pSTAT5 signals from specific cell populations and activations.

neuroscience↗

bioRxiv2023

Disentangling the multiple drivers of ecological adaptation in a microorganism

To survive and reproduce, living organisms need to maintain an efficient balance between energy intake and energy expenditure. Changes in environmental conditions can disrupt previously efficient energy allocation strategies, and organisms are required to change their behaviour, physiology, or morphology to cope with the new environment. However, how multiple phenotypic traits interact with one another and with environmental conditions to shape energy allocation remains poorly understood. To better understand this type of phenotype-environment interactions, we develop a predictive framework, grounded in energetic and biophysical principles that allows us to make predictions on how metabolic rate and movement speed should change in response to environmental temperature and resource supply, differentiating between short-term, acute exposure to novel conditions and longer-term exposure that allows acclimation or adaptation. We tested these predictions by exposing axenic populations of the ciliate Tetrahymena pyriformis to different combinations of temperature and resource availability. We measured population growth, cell size, respiration, and movement. Acute increases in temperature led to higher movement speeds and respiration rates, consistent with expectations from physical scaling relationships such as the Boltzmann-Arrhenius equation and the viscous drag acting on movement. However, by around 3.5 days after the introduction of Tetrahymena into a novel environment, all measured traits shifted toward values closer to those of the original environment. These changes likely reflect phenotypic acclimation responses that restored a more efficient energy allocation under the new conditions. Changes in cell size played a key role in this process, by simultaneously affecting multiple phenotypic traits, including metabolic rate and the energetic costs of movement. In small microbial consumers like Tetrahymena, body size can change rapidly, relative to ecological and seasonal timescales. Changes in body size can therefore be effectively leveraged - alongside physiological and biochemical regulations - to cope with environmental changes. Open researchThe raw data and all the analysis code used for this work are publicly available on github (https://github.com/pernafrost/Tetrahymena), and they are also deposited in Dryad (https://doi.org/10.5061/dryad.2v6wwpzvv). By downloading and running the code, it is possible to reproduce all the figures presented in the manuscript and in the Appendix. Please refer to the linked repositories for additional information, and feel free to contact the authors in case you need additional guidance.

ecology↗

bioRxiv2023

Substrate evaporation drives collective construction in termites

Termites build complex nests which are an impressive example of self-organization. We know that the coordinated actions involved in the construction of these nests by multiple individuals are primarily mediated by signals and cues embedded in the structure of the nest itself. However, to date there is still no scientific consensus about the nature of the stimuli that guide termite construction, and how they are sensed by termites. In order to address these questions, we studied the early building behavior of Coptotermes gestroi termites in artificial arenas, decorated with topographic cues to stimulate construction. Pellet collections were evenly distributed across the experimental setup, compatible with a collection mechanism that is not affected by local topography, but only by the distribution of termite occupancy (termites pick pellets at the positions where they are). Conversely, pellet depositions were concentrated at locations of high surface curvature and at the boundaries between different types of substrate. The single feature shared by all pellet deposition regions was that they correspond to local maxima in the evaporation flux. We can show analytically and we confirm experimentally that evaporation flux is directly proportional to the local curvature of nest surfaces. Taken together, our results indicate that surface curvature is sufficient to organize termite building activity, and that termites likely sense curvature indirectly through substrate evaporation. Our findings reconcile the apparently discordant results of previous studies.

biophysics↗

bioRxiv2022

Adipocyte differentiation of 3T3-L1 cells under TAF, TDF and INSTIs selective challenge: an in vitro model.

Integrase strand transfer inhibitors (INSTI) are a recently available class of antiretroviral therapy (ART) medications with a good tolerability profile and a high genetic barrier to HIV drug resistance. However, several studies report more significant weight gain among persons receiving INSTI-based ART regimens for initial therapy compared to protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NNRTI)-based regimens. In our experimental setting, we used the in vitro model of adipogenesis of 3T3-L1 cells to investigate the effects of the NRTIs tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), alone or in combination with four integrase strand transfer inhibitors: raltegravir (RAL), elvitegravir (ELV), dolutegravir (DTG) and bictegravir (BIC) on adipose differentiation. In addition, protein expression levels of PPAR{gamma} and C/EBP, and the intracellular lipid accumulation by Red Oil staining, were used to monitor adipocyte differentiation. Compared to control, RAL, ELV, DTG, and BIC were all able to increase adipogenesis, being in this, RAL and ELV more efficient. On the other hand, TAF and TDF inhibited adipogenesis. Moreover, when used in combination with the other INSTI molecules, TAF and TDF were able to reduce the adipogenic effects of all four drugs. This ability was more evident when TAF was used in combination with DTG and BIC. All these data suggest that TAF and TDF have an inhibitory effect on adipogenesis in vitro and that they could also effectively counteract the increased adipogenesis caused by the treatment with INSTIs. Finally, to evaluate if the 3T3-L1 cell could express fibroblast-like features following INSTIs treatment, we evaluated the immunohistochemical expression of ER-TR7, a well-known fibroblastic marker. This last assay showed that treatment with INSTIs increased the expression of ER-TR7 compared to control and to cells treated with TAF o TDF. In conclusion, our experimental data support the evidence that in vitro challenge of 3T3-L1 cells with INSTIs is able to increase adipocytic differentiation and to drive a number of these cells toward the expression of fibroblastic features, with a different degree according to the various drugs used, while TAF and TDF have an antagonistic role on this phenomenon.

pharmacology and toxicology↗

bioRxiv2021

Translational control of polyamine metabolism by CNBP is required for Drosophila locomotor function

Microsatellite expansions of CCTG repeats in the CNBP gene leads to accumulation of toxic RNA and have been associated to DM2. However, it is still unclear whether the dystrophic phenotype is also linked to CNBP decrease, a conserved CCHC-type zinc finger RNA binding protein that regulates translation and is required for mammalian development. Here we show that depletion of Drosophila CNBP in muscles causes age-dependent locomotor defects that are correlated with impaired polyamine metabolism. We demonstrate that the levels of ornithine decarboxylase (ODC) and polyamines are significantly reduced upon dCNBP depletion. Of note, we show a reduction of the CNBP-polyamine axis in muscle from DM2 patients. Mechanistically, we provide evidence that dCNBP controls polyamine metabolism through binding dOdc mRNA and regulating its translation. Remarkably, the locomotor defect of dCNBP-deficient flies is rescued by either polyamine supplementation or dOdc1 overexpression. We suggest that this dCNBP function is evolutionarily conserved in vertebrates with relevant implications for CNBP-related pathophysiological conditions. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/441910v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@a8c31corg.highwire.dtl.DTLVardef@1a18260org.highwire.dtl.DTLVardef@76a3d4org.highwire.dtl.DTLVardef@fdd041_HPS_FORMAT_FIGEXP M_FIG C_FIG CNBP controls muscle function by regulating the polyamine metabolism O_LILack of dCNBP impairs locomotor function through ODC-polyamine downregulation C_LIO_LIdCNBP binds dOdc mRNA and regulates its translation C_LIO_LIPolyamine supplementation or dOdc1 reconstitution rescues locomotor defects C_LIO_LICNBP-ODC-polyamine levels are reduced in muscle of DM2 patients C_LI

genetics↗

bioRxiv2021

Revealing Notch-dependencies in synaptic targets associated with Alzheimer's disease

Alzheimers disease (AD) is a progressive neurodegenerative disorder and the major cause of dementia. There is evidence that synaptic dysfunction and perturbation of Excitatory/Inhibitory (E/I) balance arise at the early stages of AD, altering the normal neural network activity, and leading to cognitive decline. Recent studies have identified Notch signaling as a contributor of neurodegenerative advancement including AD pathophysiology. As part of the efforts to understand molecular mechanisms and players involved in cognitive decline, we employed transgenic mouse models with Notch1 and RBPJK loss of function (LOF) in pyramidal neurons of the CA fields. Using bulk RNAseq. We have investigated the differential expression of Notch-dependent genes either upon environmental enrichment (EE) or upon Kainate injury (KA). We found a substantial genetic diversity in absence of both Notch1 receptor or Rbpjk transcriptional activator. Among differentially expressed genes, we observed a significant upregulation of Gabra2a in both knockout models, suggesting a role for Notch signaling in the modulation of E/I balance. Upon neuroexcitotoxic stimulation, loss of Rbpjk results in decreased expression of synaptic proteins with neuroprotective effects. We confirmed Nptx2, Npy, Pdch8, TncC as direct Notch1/Rbpjk targets and Bdnf and Scg2 as indirect targets. Finally, we translate these findings into human entorhinal cortex containing the hippocampal region from Alzheimers Disease patients performing targeted transcripts analysis. We observe an increased trend for Rbpjk and the ligand DNER but not Notch1 expression. On the other hand, neuron-specific targets, Nptx2, Npy, BDNF and Gabra2a are upregulated during the mild-moderate stage, and decline in the severe phase of the disease. These findings identify Notch as a promising signaling cascade to fine-tune in order to ameliorate synaptic transmission and memory deficits that occur during early phase of the Alzheimers Disease. HighlightsO_LILoss of canonical and/or non-canonical Notch1 signaling in pyramidal neurons of the hippocampal CA field mainly affects the post-synaptic compartment. C_LIO_LIIn both RBPJKcKO and Notch1cKO mouse models there is upregulation of GABAergic receptor subunit alpha2 (Gabra2a). C_LIO_LIThe plasticity genes: Npy, Nptx2,Pcdh8 and TncC with neuroprotective functions and known association with Alzheimers Disease are direct Notch/Rbpjk targets. C_LIO_LIDuring the mild-moderate stage of AD dementia, Notch canonical signaling promotes the expression of neuroprotective proteins, in the attempt of mitigating the effect of the excitatory-inhibitory imbalance. This activity is not observed during severe stages of the disease. C_LI

neuroscience↗