Biology subjects

Territo, P. R.

Publications and source records attributed to Territo, P. R..

12 recordsLinked to original sources

bioRxiv2026

Neuro-Metabolic and Vascular Dysregulation are Functional Biomarkers of Acquired Brain Injury

Emerging clinical and neuropathological evidence suggests a direct link between traumatic brain injury (TBI) and neurodegenerative diseases (ND), but the mechanisms by which TBI contributes to ND onset and progression remain unclear. To bridge this gap, the NINDS TBI-ADRD consortium developed a diagnostic framework to guide the design and evaluation of TBI-ADRD experiments using translational neuroimaging (DCE-MRI, 18F-FDG-PET) and advanced image-processing pipelines. Neuro-metabolic and vascular dysregulation (MVD) and metabolic functional connectomics (MFC) were evaluated in 8-month C57BL/6J mice at 30- and 60-days post-injury (DPI). Both MVD and MFC revealed significant changes at 30- and 60-DPI that were sex- and injury side-dependent. Female mice showed greater regional MVD alterations, while MFC identified sex-dependent changes at 30-DPI that diminished by 60-DPI. These findings suggest that a single mid-life closed-head injury induces sexually dimorphic MVD and brain network remodeling, supporting the potential of MVD as a sensitive biomarker for improved clinical monitoring post-TBI.

neuroscience↗

bioRxiv2026

Anti-amyloid immunotherapy drives APOE4 specific increases in glial reactivity, perivascular immune activation, and ARIA-like events

Anti-amyloid antibodies represent the first disease modifying therapeutics for Alzheimers disease (AD). Adoption of these novel treatments has been slowed by the occurrence of amyloid related imaging abnormalities (ARIA) - treatment-associated edema (ARIA-E) or microhemorrhages (ARIA-H) that disproportionately affect carriers of the E4 allele of apolipoprotein E (APOE). With E4 carriers comprising nearly 70% of the AD population, there is a critical need to understand the unique vulnerability of E4 carriers to these events. To address this gap, we utilized the EFAD mouse model - which expresses human APOE isoforms on the 5xFAD background of amyloidosis - to directly compare the effects of anti-amyloid therapy across APOE genotypes. 9-month-old E2, E3, and E4FAD mice received weekly injections of chimeric Aducanumab (chAdu) or IgG control for 12 weeks, to assess APOE isoform-specific effects on amyloid dynamics, ARIA-H-like microhemorrhages, and underlying cellular and transcriptomic responses. E4FAD mice demonstrated plaque reductions with accompanying increases in microhemorrhages (measured on both MRI and histology), and increases in microglial and astrocyte reactivity - especially in the perivascular compartment. Additionally, vascular branching analysis and parallel single cell and spatial transcriptomics revealed a loss of vascular plasticity and increased inflammatory and immune signaling in the neurovascular units of E4FAD mice. Together, these findings suggest the cerebrovasculature of E4s is uniquely susceptible to antibody mediated vascular damage and provide immunological targets for the assessment or mitigation of ARIA risk in this highest need population

neuroscience↗

bioRxiv2026

Molecular mechanisms underlying amyloid lowering by aducanumab: differential and comparative effects of sex and IgG reveal the post-treatment disease brain

INTRODUCTIONImproving the predictive validity of preclinical studies for Alzheimers disease (AD) requires rigorous evaluation of therapeutic efficacy, safety, and sex-specific responses in translationally relevant models. As amyloid-targeting monoclonal antibodies continue to advance clinically, there is an urgent need to define the molecular milieu that persists after amyloid is reduced and disease progression continues. Leveraging the NIA-funded MODEL-AD Preclinical Testing Core, we investigated the biochemical, functional, and multi-omic signatures associated with chronic administration of murine chimeric aducanumab (chAdu) in 5XFAD mice, including the contribution of IgG-mediated effects. METHODSMale and female 5XFAD mice were treated weekly with chAdu beginning at 8 months of age and compared to age-and sex-matched murine IgG2a{kappa} isotype (IgG) and saline controls. Plasma and brain pharmacokinetics, amyloid-beta (A{beta}), behavioral assessments, and treatment-emergent anti-drug antibodies (ADAs) were quantified. Post-treatment transcriptomic and proteomic analyses were performed to assess molecular pathways associated with chAdu and IgG exposure following 17-week treatment. RESULTSchAdu produced sex-dependent changes in A{beta}, including increased plasma A{beta}42:40 and reductions in brain A{beta} which were associated with mild behavioral impairments in the absence of improvements in cognitive function. IgG control treatment produced similar reductions, indicating biologically active IgG-mediated processes independent of A{beta}-targeted specificity. Treatment-emergent ADAs occurred in 10% of chAdu-treated mice and were associated with reduced drug exposure and efficacy. Multi-omics analyses confirmed sex-dependent and IgG-mediated effects at both the transcriptomic and proteome level revealing disease-associated genes and proteins not altered despite reductions in amyloid with treatment. DISCUSSIONThese findings demonstrate sex-dependent PK and pharmacodynamic responses to chAdu, identify biologically meaningful IgG-driven effects, and reveal molecular signatures that persist after amyloid reduction. This work provides biological insights into pathways that may remain insufficiently addressed following amyloid lowering; revealing novel targets for future drug discovery to prevent and treat disease.

neuroscience↗

bioRxiv2026

Multidomain Analysis of Clinical Cognitive Assessments and Imaging Data in Alzheimer's Disease Accurately Predicts Disease Stage and Grade Independent of Amyloid and Tau

BackgroundIndividual clinical cognitive assessments (CCA) for Alzheimers disease (AD) provide broad disease stratification but are limited in sensitivity and specificity, requiring integration of multiple CCA for optimal disease staging. Recent work from our lab suggests that neuro-metabolic and vascular dysregulation (MVD) occurs early in AD, prior to clinical symptoms, and may provide higher sensitivity and specificity than CCA alone. In this study, we combined three widely accepted CCA with MVD readouts and developed a multimodal ensemble machine learning approach across the AD spectrum to predict disease stage and grade. MethodsAD subjects (N=372) across the disease spectrum with imaging (PET:18F-FDG, MRI:T1w, T2 FLAIR, ASL) and CCAs (ADAS-Cog, CDR, MoCA) data were analyzed from ADNI. Imaging data were registered to MNI152+, z-scored relative to cognitively normal controls, and processed for MVD. A clinical-set-enrichment analysis (CSEA) was developed to link regional brain changes with CCA scores, map changes to functional categories, project them into a 3D Cartesian space, and model trajectories, thus revealing at-risk and resilient regions. In addition, an ensemble machine-learning approach was utilized for disease stage classification, and a disease grading scheme across the AD spectrum was developed to further stratify within disease stages. FindingsRegional data followed an MVD pattern across AD stages stratified by CSEA scores. Females showed greater stage separation along the CCA axis within each region, indicating faster disease progression. Moreover, progression in at-risk brain regions (e.g., mid- and inf-temporal gyri, amygdala) was associated with longer disease path lengths, whereas progression in resilient brain regions (supramarginal gyrus) was not. Moreover, our classification and grading approach can predict AD stage and grade independent of amyloid-beta and tau with high precision and accuracy. InterpretationA framework was developed to evaluate MVD and CCA variations across the AD spectrum, thereby distinguishing at-risk and resilient brain regions. Distinct disease trajectories were identified, and a new data-driven grading scheme was proposed to highlight the potential for precision medicine and therapeutic evaluation. FundingNIH T32AG071444

neuroscience↗

bioRxiv2025

WSB.APP/PS1 mice develop age-dependent cerebral amyloid angiopathy, cerebrovascular deficits, and white matter damage, which are modified by humanized APOE alleles.

INTRODUCTIONGrowing evidence suggests cerebrovascular deficits, including cerebral amyloid angiopathy (CAA), play a key role in Alzheimers disease (AD) pathogenesis. However, these facets of AD are not well understood, due in part to the lack of mouse models that develop robust vascular deficits and CAA. Here, we characterize human-relevant cerebrovascular phenotypes in WSB.APP/PS1 mice with and without humanized APOE alleles. METHODSAD-relevant cerebrovascular phenotypes in WSB, WSB.APP/PS1, WSB.APOE2/2APP/PS1, WSB.APOE3/3APP/PS1, and/or WSB.APOE4/4APP/PS1 mice were characterized using immunohistochemistry, transcriptomics, positron emission tomography/computed tomography, and ex-vivo analyses. RESULTSWSB.APP/PS1 mice exhibited age-related plaque deposition and CAA, significant transcriptomic overlap with human AD, myelin deficits, cerebrovascular/metabolic uncoupling, and altered cerebrovascular morphology. Aged WSB vasculature retained vasoreactivity, but exhibited increased stiffness. Compared to APOE2, APOE4 expression in WSB.APP/PS1 mice increased CAA and plaque-associated microglial area. DISCUSSIONThese data illustrate the utility of the WSB genetic context to model CAA and uncover vascular contributions to AD. HighlightsO_LIWSB.APP/PS1 mice developed CAA with age. C_LIO_LITranscriptomic profiling revealed significant molecular overlap between human AD and WSB.APP/PS1 brains. C_LIO_LITranscriptomics and immunofluorescence suggested age-related myelin deficits in WSB.APP/PS1 brains. C_LIO_LIWSB.APP/PS1 brains exhibited neurovascular uncoupling, changes in vascular volume and surface area, and increased permeability changes. C_LIO_LIWSB.APP/PS1 cerebrovasculature was resilient to loss of responsivity with age but exhibited increased vascular stiffness. C_LIO_LIHumanized APOE {varepsilon}4 alleles significantly increased CAA and parenchymal plaque-associated microglial area in WSB.APP/PS1 mice. C_LI Research in ContextO_LISystematic review: The authors characterized WSB.APP/PS1 as a unique human-relevant model of Alzheimers Disease and explored several facets of cerebrovascular deficits. C_LIO_LIInterpretation: WSB and/or WSB.APP/PS1 mice exhibited human-relevant vascular phenotypes, including CAA, neurovascular uncoupling, increased vascular tree volume, vascular stiffness, and resilience to age-related loss of responsivity. Furthermore, the transcriptomic profile of WSB.APP/PS1 brains significantly overlaps with signatures observed in human AD. WSB.APP/PS1 brains exhibited myelin deficits with age. Furthermore, humanized APOE {varepsilon}2, {varepsilon}3, and {varepsilon}4 alleles significantly modified WSB.APP/PS1 susceptibility to CAA, plaque deposition, and plaque-associated microglial area. C_LIO_LIFuture Directions: The WSB genetic context will be leveraged to identify specific molecular mechanisms associated with cerebrovascular deficits in AD. C_LI

neuroscience↗

bioRxiv2023

Characterizing Molecular and Synaptic Signatures in Mouse Models of Late-Onset Alzheimer's Disease Independent of Amyloid and Tau Pathology

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSMODEL-AD is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to more accurately mimic LOAD than commonly used transgenic models. METHODSWe created the LOAD2 model by combining APOE4, Trem2*R47H, and humanized amyloid-beta. Mice aged up to 24 months were subjected to either a control diet or a high-fat/high-sugar diet (LOAD2+HFD) from two months of age. We assessed disease-relevant outcomes, including in vivo imaging, biomarkers, multi-omics, neuropathology, and behavior. RESULTSBy 18 months, LOAD2+HFD mice exhibited cortical neuron loss, elevated insoluble brain A{beta}42, increased plasma NfL, and altered gene/protein expression related to lipid metabolism and synaptic function. In vivo imaging showed age-dependent reductions in brain region volume and neurovascular uncoupling. LOAD2+HFD mice also displayed deficits in acquiring touchscreen-based cognitive tasks. DISCUSSIONCollectively the comprehensive characterization of LOAD2+HFD mice reveal this model as important for preclinical studies that target features of LOAD independent of amyloid and tau.

neuroscience↗

bioRxiv2023

Assessment of Neurovascular Uncoupling: APOE Status is a Key Driver of Early Metabolic and Vascular Dysfunction

STRUCTURED ABSTRACTO_ST_ABSBACKGROUNDC_ST_ABSAlzheimers disease (AD) is the most common cause of dementia worldwide, with apolipoprotein {varepsilon}4 (APOE{varepsilon}4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. METHODSPET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. RESULTSAll hAPOE strains showed AD phenotype progression by 8 mo, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOE{varepsilon}4/{varepsilon}4 exhibited significant Type-1 uncoupling ({downarrow} glucose uptake, {uparrow} perfusion) at 8 and 12 mo, while APOE{varepsilon}3/{varepsilon}4 demonstrated Type-2 uncoupling ({uparrow} glucose uptake, {downarrow} perfusion), while immunopathology confirmed cell specific contributions. DISCUSSIONThis work highlights APOE{varepsilon}4 status in AD progression manifest as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker.

neuroscience↗

bioRxiv2023

Levetiracetam Modulates Brain Metabolic Networks and Transcriptomic Signatures in the 5XFAD Mouse Model of Alzheimer's disease.

INTRODUCTIONSubcritical epileptiform activity is associated with impaired cognitive function and is commonly seen in patients with Alzheimers disease (AD). The anti-convulsant, levetiracetam (LEV), is currently being evaluated in clinical trials for its ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of the current study was to apply pharmacokinetics (PK), network analysis of medical imaging, gene transcriptomics, and PK/PD modeling to a cohort of amyloidogenic mice to establish how LEV restores or drives alterations in the brain networks of mice in a dose-dependent basis using the rigorous preclinical pipeline of the MODEL-AD Preclinical Testing Core. METHODSChronic LEV was administered to 5XFAD mice of both sexes for 3 months based on allometrically scaled clinical dose levels from PK models. Data collection and analysis consisted of a multi-modal approach utilizing 18F-FDG PET/MRI imaging and analysis, transcriptomic analyses, and PK/PD modeling. RESULTSPharmacokinetics of LEV showed a sex and dose dependence in Cmax, CL/F, and AUC0-{infty}, with simulations used to estimate dose regimens. Chronic dosing at 10, 30, and 56 mg/kg, showed 18F-FDG specific regional differences in brain uptake, and in whole brain covariance measures such as clustering coefficient, degree, network density, and connection strength (i.e. positive and negative). In addition, transcriptomic analysis via nanoString showed dose-dependent changes in gene expression in pathways consistent 18F-FDG uptake and network changes, and PK/PD modeling showed a concentration dependence for key genes, but not for network covariance modeling. DISCUSSIONThis study represents the first report detailing the relationships of metabolic covariance and transcriptomic network changes resulting from LEV administration in 5XFAD mice. Overall, our results highlight non-linear kinetics based on dose and sex, where gene expression analysis demonstrated LEV dose- and concentration-dependent changes, along with cerebral metabolism, and/or cerebral homeostatic mechanisms relevant to human AD, which aligned closely with network covariance analysis of 18F-FDG images. Collectively, this study show cases the value of a multimodal connectomic, transcriptomic, and pharmacokinetic approach to further investigate dose dependent relationships in preclinical studies, with translational value towards informing clinical study design.

neuroscience↗

bioRxiv2023

Brain Metabolic Network Covariance and Aging in a Mouse Model of Alzheimer's Disease

INTRODUCTIONAlzheimers disease (AD), the leading cause of dementia worldwide, represents a human and financial impact for which few effective drugs exist to treat the disease. Advances in molecular imaging have enabled assessment of cerebral glycolytic metabolism, and network modeling of brain region have linked to alterations in metabolic activity to AD stage. METHODSWe performed 18F-FDG Positron Emission Tomography (PET) imaging in 4-, 6-, and 12-month-old 5XFAD and littermate controls (WT) of both sexes and analyzed region data via brain metabolic covariance analysis. RESULTS5XFAD model mice showed age related changes glucose uptake relative to WT mice. Analysis of community structure of covariance networks was different across age and sex, with a disruption of metabolic coupling in the 5XFAD model. DISCUSSIONThe current study replicates clinical AD findings and indicates that metabolic network covariance modeling provides a translational tool to assess disease progression in AD models. RESEARCH IN CONTEXTO_ST_ABSSYSTEMATIC REVIEWC_ST_ABSThe authors extensively reviewed literature (e.g., PubMed), meeting abstracts, and presentations on approaches to evaluate brain network analysis in animal models. Based on the available data, there were clear gaps in our understanding of how metabolic networks change with disease progression at the preclinical phase, thus limiting the utility of these measures for clinical comparison in Alzheimers disease (AD). INTERPRETATIONOur findings indicate that employing metabolic covariance modeling in mouse models of AD and littermate controls of both sexes with age provides a mechanism to evaluate brain changes in network function which align closely with previous clinical stages of AD. Moreover, utilizing open-source clinical tools from the Brain Connectivity Toolbox (BCT), we demonstrated that brain networks reorganize with AD progression at multiple levels, and these changes are consistent with previous reports in human AD studies. FUTURE DIRECTIONSThe open-source framework developed in the current work provides valuable tools for brain metabolic covariance modeling. Such tools can be used in both preclinical and clinical settings and they enable more direct translation of preclinical imaging studies to those in the clinic. When matched with an appropriate animal model, genetics, and/or treatments, this study will enable assessment of in vivo target engagement, translational pharmacodynamics, and insight into potential treatments of AD.

neuroscience↗

bioRxiv2023

Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer's disease

The 5xFAD mouse model is a popular model of familial Alzheimers Disease (AD) that is characterized by early beta-amyloid (A{beta}) deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic perturbations over its lifespan. Male and female 5xFAD and WT littermates underwent in vivo 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at 4, 6, and 12 months of age to assess regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent "vessel painting" which labels all cerebral vessels and were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals and vessel diameter. With increasing age, vessels on the cortical surface in both 5xFAD and WT mice showed increased vessel length, vessel and junction densities. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but collateral diameters were significantly increased only in 5xFAD mice. MCA total vessel length and junction density were decreased in 5xFAD mice compared to WT at 4 months. Analysis of 18F-FDG cortical uptake revealed significant differences between WT and 5xFAD mice spanning 4-12 months. Broadly, 5xFAD males had significantly increased 18F-FDG uptake at 12 months compared to WT mice. In most cortical regions, female 5xFAD mice had reduced 18F-FDG uptake compared to WT across their lifespan. While the 5xFAD mouse exhibits AD-like cognitive deficits as early as 4 months of age that are associated with increasing A{beta} deposition, we only found significant differences in cortical vascular features in males, not in females. Interestingly, 5xFAD male and female mice exhibited opposite effects in 18F-FDG uptake. The MCA supplies blood to large portions of the somatosensory cortex and portions of the motor and visual cortex and increased vessel lengths alongside decreased collaterals coincided with higher metabolic rates in 5xFAD mice. Thus, a potential mismatch between metabolic demand and vascular delivery of nutrients in the face of increasing A{beta} deposition could contribute to the progressive cognitive deficits seen in the 5xFAD mouse model.

neuroscience↗

bioRxiv2022

Plcg2M28L interacts with high fat-high sugar diet to accelerate Alzheimers disease-relevant phenotypes in mice

Obesity is recognized as a significant risk factor for Alzheimers disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority of studies to date have focused on the use of early-onset AD models. Here we evaluate the impact of genetic risk factors on late-onset AD (LOAD) in mice fed a high fat/high sugar diet. We focused on three mouse models created through the IU/JAX/Pitt MODEL-AD Center, LOAD1, LOAD1.Plcg2M28L and LOAD1.Mthfr677C>T. At 2 months of age, animals were placed on a high fat/high sugar diet (HFD) that induces obesity, or a control diet (CD) that does not, until 12 months of age. Throughout the study, blood was collected to assess cholesterol and glucose. Positron emission tomography/computed tomography (PET/CT) was completed prior to sacrifice to image for glucose utilization and brain perfusion. At the completion of the study, blood and brains were collected for analysis. As expected, animals fed the HFD, regardless of genotype or sex, showed a significant increase in body weight compared to those fed the CD. Glucose and cholesterol increased as a function of HFD as well. Interestingly, LOAD1.Plcg2M28L demonstrated an increase in microglia density as well as alterations in regional brain glucose and perfusion when on a HFD. These changes were not observed in LOAD1 or LOAD1.Mthfr677C>T animals when fed a HFD. Furthermore, LOAD1.Plcg2M28L but not LOAD1.Mthfr677C>T or LOAD1 animals showed transcriptomics correlations to human AD modules. Our results show HFD affects brain health in a genotype-specific manner. Further insight into this process may have significant implications in the development of lifestyle interventions for treatment of AD.

neuroscience↗

bioRxiv2021

The 677C>T variant in methylenetetrahydrofolate reductase causes morphological and functional cerebrovascular deficits in mice

Vascular contributions to cognitive impairment and dementia (VCID) particularly Alzheimers disease and related dementias (ADRDs) are increasing; however, mechanisms driving cerebrovascular decline are poorly understood. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate and methionine cycles. Variants in MTHFR, notably 677C>T, are associated with dementias, but no mouse model existed to identify mechanisms by which MTHFR677C>T increases risk. Therefore, MODEL-AD created a novel knock-in (KI) strain carrying the Mthfr677C>T allele on the C57BL/6J background (Mthfr677C>T) to characterize morphology and function perturbed by the variant. Consistent with human clinical data, Mthfr677C>T mice have reduced enzyme activity in the liver and elevated plasma homocysteine levels. MTHFR enzyme activity as well as critical metabolites in the folate and methionine cycles are reduced in the Mthfr677C>T brain. Mice showed reduced tissue perfusion in numerous brain regions by PET/CT as well as significantly reduced vascular density and increased GFAP-expressing astrocytes in frontal cortex. Electron microscopy revealed cerebrovascular damage including endothelial and pericyte apoptosis, reduced luminal size, and increased astrocyte and microglial presence in the microenvironment. Collectively, these data suggest critical perturbations to cerebrovascular function in Mthfr677C>T mice supporting its use as a model for preclinical studies of VCID.

genetics↗