Biology subjects

Sasner, M.

Publications and source records attributed to Sasner, M..

14 recordsLinked to original sources

bioRxiv2026

Characterization of the knock-in AppSAA mouse model as a powerful tool for Alzheimer's disease preclinical research.

BACKGROUND: Preclinical Alzheimer's disease (AD) research requires models with age-dependent, physiologically relevant amyloid pathology, unlike overexpression in transgenic lines. We characterized the humanized AppSAA knock-in model to define translationally relevant therapeutic windows. METHODS: Homozygous AppSAA and control mice were evaluated from 4 to 19 months using whole-brain 3D plaque imaging, cerebral amyloid angiopathy (CAA) quantification, multiplex neuropathology, brain transcriptomics, and plasma biomarkers. Hippocampal synaptic analysis and context-dependent memory was performed at 12 months. RESULTS: Plaques, CAA, plaque-associated neuroinflammation, and dystrophic neurites accumulated with age. By 12 months, brain transcriptomes aligned with human AMP-AD co-expression modules, and plasma pTau-217, GFAP, and SNAP25 rose with age. AppSAA mice retained associative memory but showed memory interference and CA1 dendritic-spine loss that was exacerbated in proximity to plaques. CONCLUSIONS: AppSAA mice recapitulate age-dependent, human-relevant AD phenotypes with defined therapeutic windows for preclinical research. The model is available without restriction from The Jackson Laboratory.

neuroscience↗

bioRxiv2026

MTHFR*677C>T produces distinct prodromal disease signatures in a mouse model of late-onset Alzheimer's disease

Background: Late-onset Alzheimer's disease (LOAD) comprises more than 95% of all AD cases. Transgenic, overexpression animal models have off target side effects, do not effectively produce the heterogeneity observed clinically in LOAD patients, and are therefore not best suited for preclinical therapeutic development. The Model Organism Development and Evaluation for Late-onset Alzheimer's Disease (MODEL-AD) Consortium was established to develop novel mouse strains to model human-relevant genetic and environmental risk factors for LOAD. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme in the folate/methionine pathway. Variants in the MTHFR gene, notably 677C>T, are associated with ADRD, and we have previously shown the Mthfr677C>T mouse model phenocopies humans carrying the variant and develop cerebrovascular deficits. Methods: To examine the contributions of Mthfr677C>T in the context of late-onset Alzheimer's disease (LOAD), MODEL-AD created a novel mouse strain on the C57BL/6J (B6) background that was homozygous for Mthfr677C>T, in combination with humanized Abeta;, APOEe4, and Trem2*R47H (referred to as LOAD2.Mthfr677C>T). Mice were assessed over multiple ages for disease-relevant phenotypes. Regular behavior measurements and biometric samples were collected longitudinally to 24 months of age. Blood and brain tissue were collected for transcriptomics, proteomics, human disease correlation, and neuropathology. Results: Despite lacking hallmark pathologies such as amyloid deposition and significant neuroinflammation, compared to LOAD2 controls, LOAD2.Mthfr677C>T mice showed transcriptional and proteomic signatures in the brain that relate to the cerebrovasculature, myelination, and synaptic biology, similar to those seen in human LOAD patients. Conclusions: These data further support the use of the LOAD2.Mthfr677C>T mouse model to study aspects of ADRD such as cerebrovascular compromise.

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↗

bioRxiv2025

Synaptic proteins that aggregate and degrade slower with aging accumulate in microglia

Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with aging1,2. We engineered bioorthogonal tools3 which allowed us to tag the nascent neuronal proteome and study its turnover with aging, its propensity to aggregate, and its interaction with microglia. We discovered neuronal proteins degraded on average twice as slowly between 4- and 24-month-old mice with individual protein stability differing between brain regions. Further, we describe the aged neuronal aggregome encompassing 574 proteins, nearly 30% of which showed reduced degradation. The aggregome includes well-known proteins linked to disease as well as a trove of proteins previously not associated with neurodegeneration. Unexpectedly, we found 274 neuronal proteins accumulated in microglia with 65% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins were highly enriched, suggesting a cascade of events emanating from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly by the engulfment of synapses by microglia. These findings reveal the dramatic loss of neuronal proteome maintenance with aging which could be causal for age-related synapse loss and cognitive decline.

neuroscience↗

bioRxiv2023

In vivo validation of late-onset Alzheimer's disease genetic risk factors

Structured AbstractO_ST_ABSIntroductionC_ST_ABSGenome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimers disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action. MethodsCandidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE4 and Trem2*R47H. Potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts. ResultsWe created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes. DiscussionThese results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics.

neuroscience↗

bioRxiv2022

Perivascular SPP1 Mediates Microglial Engulfment of Synapses in Alzheimers Disease Models

Microglia are phagocytes of the brain parenchyma, where they interact with neurons to engulf synapses in a context-dependent manner. Genetic studies in Alzheimers disease (AD) highlight dysfunctional phagocytic signaling in myeloid cells as disease-associated pathway. In AD models, there is a region-specific reactivation of microglia-synapse phagocytosis involving complement; however, what drives microglia-synapse engulfment remains unknown. Here, we show that SPP1 (Osteopontin), a glycoprotein associated with inflammation, is regionally upregulated and modulates microglial synaptic engulfment in AD mouse models. Ultrastructural examination revealed SPP1 expression predominantly by perivascular macrophages, a subtype of border-associated macrophages, in the hippocampus of mice and patient tissues. Cell-cell interaction networks of single-cell transcriptomics data suggested that perivascular SPP1 drives microglial functional states in the hippocampal microenvironment of AD mice. Absence of Spp1 expression resulted in failure of microglia to mediate synaptic phagocytosis. This study suggests a critical role for perivascular SPP1 in neuroimmune crosstalk in AD-relevant context.

neuroscience↗

bioRxiv2022

APOEϵ4 and exercise interact to influence systemic and cerebral risk factors for dementia

INTRODUCTIONAPOE{varepsilon}4 is the strongest genetic risk factor for Alzheimers disease and related dementias (ADRDs) affecting many different pathways that lead to cognitive decline. Exercise is one of the most widely proposed prevention, and intervention strategies to mitigate risk and symptomology of ADRDs. Importantly, exercise and APOE{varepsilon}4 affect similar processes on the body and brain. While both APOE{varepsilon}4, and exercise have been studied extensively, their interactive effects are not well understood. METHODSTo address this, male and female APOE{varepsilon}3/{varepsilon}3, APOE{varepsilon}3/{varepsilon}4 and APOE{varepsilon}4/{varepsilon}4 mice ran voluntarily from wean (1mo) to midlife (12mo). Longitudinal and cross-sectional phenotyping was performed on the periphery and the brain, on markers of risk for dementia such as weight, body composition, circulating cholesterol composition, activities of daily living, energy expenditure, and cortical and hippocampal transcriptional profiling. RESULTSData revealed chronic running decreased age-dependent weight gain, lean and fat mass, and serum LDL concentration dependent on APOE genotype. Additionally, murine activities of daily living and energy expenditure were significantly influenced by an interaction between APOE genotype and running in both sexes. Transcriptional profiling of the cortex and hippocampus predicted that APOE genotype and running interact to affect numerous biological processes including vascular integrity, synaptic/neuronal health, cell motility, and mitochondrial metabolism, in a sex-specific manner. DISCUSSIONThese data provide compelling evidence that APOE genotype should be considered for population-based strategies that incorporate exercise to prevent ADRDs.

genetics↗

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↗

bioRxiv2021

Fibrillar Aβ causes profound microglial metabolic perturbations in a novel APP knock-in mouse model

Microglial dysfunction is believed to play a pathogenic role in Alzheimers disease (AD). Here, we characterize the amyloid-{beta} related pathology and microglial responses in an engineered APP knock-in mouse model of familial AD. This model recapitulates key pathological features of AD such as a progressive accumulation of parenchymal amyloid plaques and vascular amyloid deposits, altered glial responses and neurodegeneration. Leveraging multi-omics approaches, we found lipid accumulation and an exacerbated disease-associated transcriptomic response in methoxy-X04-positive, phagocytic microglia. Together, these findings highlight the potential of this novel, open-access mouse model to investigate AD pathogenesis and demonstrate that fibrillar A{beta} triggers lipid dysregulation and immuno-metabolic perturbations in phagocytic microglia. HighlightsO_LINovel open-access APP KI mouse model shows salient AD pathological features C_LIO_LIDeep phenotyping of sorted microglia reveals profound lipidomic perturbations in line with Alois Alzheimers original descriptions of glial adipose inclusions C_LIO_LIImmunometabolic perturbations are exacerbated in microglia accumulating fibrillar A{beta} C_LI

neuroscience↗

bioRxiv2020

APOEε3/ε4 and APOEε4/ε4 genotypes drive unique gene signatures in the cortex of young mice

BackgroundRestrictions on mouse models have significantly impacted research towards understanding the most common genotype contributing to dementia in the human population - APOE{varepsilon}3/{varepsilon}4. To address this, as part of MODEL-AD, we created new versions of humanized APOE{varepsilon}4 and APOE{varepsilon}3 mice on a C57BL/6J background that allow for unrestricted distribution and breeding. MethodsTo determine similarities and differences between APOE{varepsilon}3/{varepsilon}4 and APOE{varepsilon}4/{varepsilon}4 risk genotypes, we analyzed peripheral lipid concentrations as well as performed unbiased transcriptional profiling of the cortex at two and four months of age, comparing APOE{varepsilon}3/{varepsilon}4 and APOE{varepsilon}4/{varepsilon}4 to the reference APOE{varepsilon}3/{varepsilon}3. To further compare APOE genotypes, cohorts of APOE{varepsilon}3/{varepsilon}3, APOE{varepsilon}3/{varepsilon}4, and APOE{varepsilon}4/{varepsilon}4 mice were exercised by voluntary running from 1 month to 4 months of age. ResultsCholesterol composition was significantly influenced by APOE genotype as early as 2 months, while triglycerides were affected by APOE genotype at 4 months. Importantly, RNA-sequencing of the cortex followed by linear modeling or weighted gene co-expression network analysis (WGCNA) revealed that the APOE{varepsilon}3/{varepsilon}4 genotype showed unique transcriptomic signatures to that of APOE{varepsilon}4/{varepsilon}4. Functional enrichment of the APOE{varepsilon}3/{varepsilon}4, but not APOE{varepsilon}3/{varepsilon}4 genotype, revealed sulfur and heparin binding as significant terms at 2 months, and extracellular matrix and blood coagulation at 4 months. Further, cell specific contributions of significant genes identified endothelial cells as overrepresented in the APOE{varepsilon}3/{varepsilon}4 but not APOE{varepsilon}4/{varepsilon}4 genotype. WGCNA analysis confirmed findings from linear modeling but also predicted that running at a young age affects myelination and gliogenesis across APOE genotypes. ConclusionsIn summary, APOE{varepsilon}3/{varepsilon}4 genotype-specific effects were observed in cortical transcriptional profiles, suggesting therapies aimed at modifying APOE biology to treat dementias may need to be targeted to specific APOE genotypes.

genomics↗

bioRxiv2020

The Alzheimer's disease protective P522R variant of PLCG2, consistently enhances stimulus-dependent PLCγ2 activation, depleting substrate and altering cell function.

Recent genome-wide association studies of Alzheimers disease (AD) have identified variants implicating immune pathways in disease development. A rare coding variant of PLCG2, which encodes PLC{gamma}2, shows a significant protective effect for AD (rs72824905, P522R, P=5.38x10-10, Odds Ratio = 0.68). Molecular dynamic modelling of the PLC{gamma}2-R522 variant, situated within the auto-inhibitory domain of PLC{gamma}2, suggests a structural change to the protein. Through CRISPR-engineering we have generated novel PLCG2-R522 harbouring human induced pluripotent cell lines (hiPSC) and a mouse knockin model, neither of which exhibits alterations in endogenous PLCG2 expression. Mouse microglia and macrophages and hiPSC-derived microglia-like cells with the R522 mutation, all demonstrate a consistent non-redundant hyperfunctionality in the context of normal expression of other PLC isoforms. This signalling alteration manifests as enhanced cellular Ca2+ store release ([~]20-40% increase) in response to physiologically-relevant stimuli (e.g. Fc receptor ligation and A{beta} oligomers). This hyperfunctionality resulted in increased PIP2 depletion in the cells with the PLC{gamma}2-R522 variant after exposure to stimuli and reduced basal detection of PIP2 levels in vivo. These PLC{gamma}2-R522 associated abnormalities resulted in impairments to phagocytosis (fungal and bacterial particles) and enhanced endocytosis (A{beta} oligomers and dextran). PLC{gamma}2 sits downstream of disease relevant pathways, such as TREM2 and CSF1R and alterations in its activity, direct impacts cell function, which in the context of the inherent drugability of enzymes such as PLC{gamma}2, raise the prospect of manipulation of PLC{gamma}2 as a therapeutic target in Alzheimers Disease.

neuroscience↗

bioRxiv2019

Staging Alzheimer’s disease in the brain and retina of B6.APP/PS1 mice by transcriptional profiling

Alzheimers disease (AD) is a common form of dementia characterized by amyloid plaque deposition, TAU pathology, neuroinflammation and neurodegeneration. Mouse models recapitulate some key features of AD. For instance, the B6.APP/PS1 model (carrying human transgenes for mutant forms of APP and PSEN1) shows plaque deposition and associated neuroinflammatory responses involving both astrocytes and microglia beginning around 6 months of age. However, in our colony, TAU pathology, significant neurodegeneration and cognitive decline are not apparent in this model even at older ages. Therefore, this model is ideal for studying neuroinflammatory responses to amyloid deposition. Here, RNA sequencing of brain and retinal tissue, generalized linear modeling (GLM), functional annotation followed by validation by immunofluorescence (IF) was performed in B6.APP/PS1 mice to determine the earliest molecular changes prior to and around the onset of plaque deposition (2-6 months of age). Multiple pathways were shown to be activated in response to amyloid deposition including the JAK/STAT and NALFD pathways. Putative, cell-specific targets of STAT3, a central component of the JAK/STAT pathway, were identified that we propose provide more precise options for assessing the potential for targeting activation of the JAK/STAT pathway as a treatment for human AD. In the retina, GLM predicted activation of vascular-related pathways. However, many of the gene expression changes comparing B6 with B6.APP/PS1 retina samples occurred prior to plaque onset (2 months of age). This suggests retinal changes in B6.APP/PS1 mice may be an artefact of overexpression of mutant forms of APP and PSEN1 providing limited translatability to human AD. Therefore, caution should be taken when using this mouse model to assess the potential of using the eye as a window to the brain for AD.

neuroscience↗

bioRxiv2019

A novel systems biology approach to evaluate mouse models of late-onset Alzheimer’s disease

BackgroundLate-onset Alzheimers disease (LOAD) is the most common form of dementia worldwide. To date, animal models of Alzheimers have focused on rare familial mutations, due to a lack of frank neuropathology from models based on common disease genes. Recent multi-cohort studies of postmortem human brain transcriptomes have identified a set of 30 gene co-expression modules associated with LOAD, providing a molecular catalog of relevant endophenotypes.\n\nResultsThis resource enables precise gene-based alignment between new animal models and human molecular signatures of disease. Here, we describe a new resource to efficiently screen mouse models for LOAD relevance. A new NanoString nCounter(R) Mouse AD panel was designed to correlate key human disease processes and pathways with mRNA from mouse brains. Analysis of three mouse models based on LOAD genetics, carrying APOE4 and TREM2*R47H alleles, demonstrated overlaps with distinct human AD modules that, in turn, are functionally enriched in key disease-associated pathways. Comprehensive comparison with full transcriptome data from same-sample RNA-Seq shows strong correlation between gene expression changes independent of experimental platform.\n\nConclusionsTaken together, we show that the nCounter Mouse AD panel offers a rapid, cost-effective and highly reproducible approach to assess disease relevance of potential LOAD mouse models.

neuroscience↗

bioRxiv2017

Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis

Transgenesis has been a mainstay of mouse genetics for over 30 years, providing numerous models of human disease and critical genetic tools in widespread use today. Generated through the random integration of DNA fragments into the host genome, transgenesis can lead to insertional mutagenesis if a coding gene or essential element is disrupted, and there is evidence that larger scale structural variation can accompany the integration. The insertion sites of only a tiny fraction of the thousands of transgenic lines in existence have been discovered and reported due in part to limitations in the discovery tools. Targeted Locus Amplification (TLA) provides a robust and efficient means to identify both the insertion site and content of transgenes through deep sequencing of genomic loci linked to specific known transgene cassettes. Here, we report the first large-scale analysis of transgene insertion sites from 40 highly used transgenic mouse lines. We show that the transgenes disrupt the coding sequence of endogenous genes in half of the lines, frequently involving large deletions and/or structural variations at the insertion site. Furthermore, we identify a number of unexpected sequences in some of the transgenes, including undocumented cassettes and contaminating DNA fragments. We demonstrate that these transgene insertions can have phenotypic consequences, which could confound certain experiments, emphasizing the need for careful attention to control strategies. Together, these data show that transgenic alleles display a high rate of potentially confounding genetic events, and highlight the need for careful characterization of each line to assure interpretable and reproducible experiments.

genetics↗