Biology subjects

Forner, S.

Publications and source records attributed to Forner, S..

6 recordsLinked to original sources

bioRxiv2022

A Trem2*R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques

Genome-Wide Association Studies revealed the TREM2 R47H variant as one of the strongest genetic risk factors for late-onset Alzheimers Disease (AD). Unfortunately, many current TREM2*R47H mouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. We have developed the Trem2R47H NSS (Normal Splice Site) mouse model where the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele, without evidence of cryptic splicing products, and appropriate inflammatory responses to cuprizone challenge. Utilizing the 5xFAD mouse model, we report age- and disease-dependent changes in response to pathology. At an early disease stage (4 mo), homozygous Trem2R47H NSS; hemizygous 5xFAD (Trem2R47H NSS ; 5xFAD) mice have reduced size and number of microglia plus impaired interaction with plaques, that is associated with increased dystrophic neurites and axonal damage detected through plasma neurofilament light chain (NfL) level and suppressed inflammation. However, homozygosity for Trem2R47H NSS suppressed LTP deficits and presynaptic puncta loss caused by the 5xFAD transgene array. At a more advanced disease stage (12 mo,) Trem2R47H NSS ; 5xFAD mice no longer display impaired plaque-microglia interaction or suppressed inflammatory gene expression, although NfL levels remain elevated, and a unique interferon-related gene expression signature is seen. Furthermore, Trem2R47H NSS ; 5xFAD mice also display robust LTP deficits and exacerbated presynaptic loss. Collectively, we provide a Trem2R47H variant mouse without cryptic splicing, and demonstrate it has disease stage dependent effects when combined with a plaque bearing model, with an initial loss of function that ultimately resolves, giving rise to a unique interferon signature and associated tissue damage.

neuroscience↗

bioRxiv2022

Longitudinal analysis of the gut microbiome in the 5xfAD mouse model of Alzheimer's disease

INTRODUCTIONMicrobial exposures impact Alzheimers disease (AD), and a baseline understanding of AD model microbiomes is vital for improving model efficacy. We describe the evaluation of the microbiome and metabolome in longitudinal samples from the 5xfAD transgenic mouse model. METHODSCecal and fecal samples from 5xfAD and wild-type B6J (WT) animals from 4- 18 months of age were subjected to DNA extraction and shotgun Illumina sequencing. Metabolomics was performed on plasma and feces from a subset of animals. RESULTSSignificant sex, age, and cage-specific differences were observed in the microbiome. Eight bacteria species were elevated in older 5xfAD mice and nine were depleted, including Turicibacter spp. Contradicting published findings covering persons with AD, plasma measurements revealed elevated serotonin in 18 month 5xfAD animals. DISCUSSIONTaken together, these findings strengthen the link between Turicibacter abundance and AD and provide a basis for further microbiome studies of murine models for AD.

microbiology↗

bioRxiv2021

Systematic phenotyping and characterization of the 3xTg-AD mouse model of Alzheimer's Disease

Animal models of disease are valuable resources for investigating pathogenic mechanisms and potential therapeutic interventions. However, for complex disorders such as Alzheimers disease (AD), the generation and availability of innumerous distinct animal models present unique challenges to AD researchers and hinder the success of useful therapies. Here, we conducted an in-depth analysis of the 3xTg-AD mouse model of AD across its lifespan to better inform the field of the various pathologies that appear at specific ages, and comment on drift that has occurred in the development of pathology in this line since its development 20 years ago. This modern characterization of the 3xTg-AD model includes an assessment of impairments in behavior, cognition, and long-term potentiation followed by quantification of amyloid beta (A{beta}) plaque burden and neurofibrillary tau tangles, biochemical levels of A{beta} and tau protein, and neuropathological markers such as gliosis and accumulation of dystrophic neurites. We also present a novel comparison of the 3xTg-AD model with the 5xFAD model using the same deep-phenotyping characterization pipeline. The results from these analyses are freely available via the AD Knowledge Portal (https://admodelexplorer.synapse.org). Our work demonstrates the utility of a characterization pipeline that generates robust and standardized information relevant to investigating and comparing disease etiologies of current and future models of AD. Contribution to the Field StatementAlzheimers Disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory impairments and affects more than 30 million individuals worldwide. Using animal models of AD, researchers have elucidated disease progression and hallmark pathologies that may underpin the memory impairments seen in patients. However, therapeutic targets have failed to translate successfully from animal studies to human clinical trials, prompting a reassessment of the development, use, and interpretation of data acquired using the innumerous AD animal models available to researchers. To address these shortcomings, we have developed a robust and reproducible modern characterization of pathologies within current and future animal models of AD to better assess distinct pathologies that arise at specific brain regions and ages of different models. Using the popular 3xTg-AD mouse, we demonstrate the utility of these deep-phenotyping analyses and highlight the drift that affected development of pathologies in this line over the past two decades. Utilizing this same systematic characterization, we also perform a direct comparison with 5xFAD mice, another popular animal model of AD. The robust and standardized data generated from these systematic deep-phenotyping analyses are available for broad use by the AD research community to assess, compare, and determine appropriate animal models of AD.

neuroscience↗

bioRxiv2021

Single-cell and nucleus RNA-seq in a mouse model of AD reveal activation of distinct glial subpopulations in the presence of plaques and tangles

Multiple mouse models have been generated that strive to recapitulate human Alzheimers disease (AD) pathological features to investigate disease mechanisms and potential treatments. The 3xTg-AD mouse presents the two major hallmarks of AD, which are plaques and tangles that increase during aging. While behavioral changes and the accumulation of plaques and tangles have been well described in the 3xTg-AD mice, the subpopulations of neurons and glial cells present throughout disease progression have not been characterized. Here, we used single-cell RNA-seq to investigate changes in subpopulations of microglia, and single-nucleus RNA-seq to explore subpopulations of neurons, astrocytes, and oligodendrocytes in the hippocampus and cortex of aging 3xTg-AD as well as 5xFAD mice for comparison. We recovered a common path of age-associated astrocyte activation between the 3xTg-AD and the 5xFAD models and found that 3xTg-AD-derived astrocytes seem to be less activated. We identified multiple subtypes of microglia, including a subpopulation with a distinct transcription factor expression profile that showed an early increase in Csf1 expression before the switch to disease associated microglia (DAM). We used bulk RNA-seq in the hippocampus of 3xTg-AD mice across their lifespan to identify distinct modules of genes whose expression increases with aging and worsening pathology. Finally, scATAC-seq revealed multiple subpopulations of cells with accessible chromatin in regions around genes associated with glial activation. Overall, differences between the main glial groups point to a slower activation process in the 3xTg-AD model when compared to the 5xFAD. Our study contributes to the identification of progressive transcriptional changes of glial cells in a mouse model that has plaques and tangles, thus providing information to aid in targeted AD therapeutics that could translate into positive clinical outcomes.

genomics↗

bioRxiv2021

Transcriptomic similarities and differences between mouse models and human Alzheimer's Disease

Alzheimers disease (AD) is a multifactorial pathology, with most cases having a sporadic origin. Recently, knock-in (KI) models have been developed with the promise of resembling better sporadic human AD, such as the novel hA{beta}-KI mouse. Here, we compared hippocampal publicly available transcriptomic profiles of transgenic (5xFAD and APP/PS1) and KI (hA{beta}-KI) mouse models with early- (EOAD) and late- (LOAD) onset AD patients. Experimental validation of consistently dysregulated genes revealed four altered in mice (SLC11A1, S100A6, CD14, CD33, C1QB) and three in humans (S100A6, SLC11A1, KCNK). Additionally, the three mouse models presented more Gene Ontology biological processes terms and enriched signaling pathways in common with LOAD than with EOAD individuals. Finally, we identified 17 transcription factors potentially acting as master regulators of AD. Our cross-species analyses revealed that the three mouse models presented a remarkable similarity to LOAD, with the hA{beta}-KI being the more specific one.

neuroscience↗

bioRxiv2021

Systematic Phenotyping and Characterization of the 5xFAD mouse model of Alzheimer's Disease

Mouse models of human diseases are invaluable tools for studying pathogenic mechanisms and testing interventions and therapeutics. For disorders such as Alzheimers disease in which numerous models are being generated, a challenging first step is to identify the most appropriate model and age to effectively evaluate new therapeutic approaches. Here we conducted a detailed phenotypic characterization of the 5xFAD model on a congenic C57BL/6J strain background, across its lifespan - including a seldomly analyzed 18-month old time point to provide temporally correlated phenotyping of this model and a template for characterization of new models of LOAD as they are generated. This comprehensive analysis included quantification of plaque burden, A{beta} biochemical levels, and neuropathology, neurophysiological measurements and behavioral and cognitive assessments, and evaluation of microglia, astrocytes, and neurons. Analysis of transcriptional changes was conducted using bulk-tissue generated RNA-seq data from microdissected cortices and hippocampi as a function of aging, which can be explored at the UCI Mouse Explorer and AD Knowledge Portal. This deep-phenotyping pipeline identified novel aspects of age-related pathology in the 5xFAD model.

neuroscience↗