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bioRxiv2021

Immunological and cardio-vascular pathologies associated with SARS-CoV-2 infection in golden syrian hamster

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection in golden Syrian hamster (GSH) causes lung pathology and resembles human coronavirus disease (Covid-19). However, extra-pulmonary pathologies of SARS-CoV-2 infection that result in long Covid remains undefined in GSH. Here, using in silico modelling we show that hamster angiotensin-converting enzyme-2 (ACE-2) and neuropilin-1 (NRP-1) interaction with SARS-CoV-2 is similar to human. Intranasal SARS-CoV-2 infection in GSH resulted in early onset of lung pathologies marked by aggressive inflammatory response. Remarkably, late phase of SARS-CoV2 infection in GSH showed cardiovascular complications (CVC) characterized by ventricular hypertrophy, ventricular wall thickening, interstitial coronary fibrosis and altered lipidomics with elevated cholesterol, low-density lipoprotein and long chain fatty acid triglycerides. Moreover, serum metabolomics profile of infected GSH correlated with Covid19 patients. Together, we propose GSH as a suitable animal model to study immediate and long Covid19 pathologies that could be extended to therapeutics against Covid19 related CVC.

microbiology↗

bioRxiv2021

Antisense therapy in a new rat model of Alexander disease reverses GFAP pathology, white matter deficits, and motor impairment.

Alexander disease (AxD) is a devastating leukodystrophy caused by gain of function mutations in GFAP, and the only available treatments are supportive. Recent advances in antisense oligonucleotide (ASO) therapy have demonstrated that transcript targeting can be a successful strategy for human neurodegenerative diseases amenable to this approach. We have previously used mouse models of AxD to show that Gfap-targeted ASO suppresses protein accumulation and reverses pathology; however, the mice have a mild phenotype with no apparent leukodystrophy or overt clinical features and are therefore limited for assessing functional outcomes. In this report we introduce a new rat model of AxD that exhibits hallmark pathology with GFAP aggregation in the form of Rosenthal fibers, widespread astrogliosis, and white matter deficits. These animals develop normally during the first postnatal weeks but fail to thrive after weaning and develop severe motor deficits as they mature, with approximately 15 % dying of unknown cause between 6 to 12 weeks of age. In this model, a single treatment with Gfap-targeted ASO provides long lasting suppression, reverses GFAP pathology, and depending on age of treatment, prevents or mitigates white matter deficits and motor impairment. This is the first report of an animal model of AxD with myelin pathology and motor impairment, recapitulating prominent features of the human disease. We use this model to show that ASO therapy has the potential to not only prevent but also reverse many aspects of disease.

neuroscience↗

bioRxiv2021

New App knock-in mice that accumulate wild-type human Aβ as rapidly as AppNL-G-F mice exhibit intensive cored plaque pathology and neuroinflammation.

We previously developed single App knock-in mouse models of Alzheimers disease (AD), harboring the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL-G-F and AppNL-F mice). These models showed amyloid {beta} peptide (A{beta}) pathology, neuroinflammation and cognitive impairment in an age-dependent manner. The former line exhibits extensive pathology as early as 6 months but is unsuitable for investigating A{beta} metabolism and clearance because the Arctic mutation renders A{beta} resistant to proteolytic degradation and prone to aggregation. In particular, it is inapplicable to preclinical immunotherapy studies due to its discrete affinity for anti-A{beta} antibodies. The weakness of the latter model is that it may take as long as 18 months for the pathology to become prominent. We have thus generated a new model that exhibits early deposition of wild-type human A{beta} by crossbreeding the AppNL-F line with the Psen1P117L/WT line. We show that the effects of the pathogenic mutations in the App and Psen1 genes are additive or synergistic. This new mouse model showed more cored plaque pathology and neuroinflammation than AppNL-G-F mice and will help accelerate the development of disease-modifying therapies to treat preclinical AD.

neuroscience↗

bioRxiv2021

Early Detection of Tau Pathology

While a definitive Alzheimers disease (AD) diagnosis remains a post-mortem exercise, the ATN Research Framework proposed by the National Institute on Aging and the Alzheimers Association utilizes a score representing the presence of amyloid deposits (A), tau deposits (T) and neuronal degeneration markers (N), with A+T+ necessary for a positive diagnosis. Current detection of tau pathology lags amyloid detection by years and by the time both markers are detected the disease is fairly advanced. We describe the development of a new generation of molecular imaging probes for in vivo detection of cells undergoing abnormal phosphorylation representing the initial stages of pTau pathology, potentially enabling a very early stage diagnosis of AD. We describe a novel nanoparticle formulation that binds such abnormally phosphorylating cells in a mouse model of tau pathology, enabling in vivo visualization of the hyperphosphorylative state by magnetic resonance imaging. Our results demonstrate the potential of this novel platform to identify a correlative marker signifying the development of future tau pathology, and has implications for early-stage diagnosis of Alzheimers disease.

neuroscience↗

bioRxiv2021

Evolutionary Inference Predicts Novel ACE2 Protein Interactions Relevant to COVID-19 Pathologies

Angiotensin-converting enzyme 2 (ACE2) is the cell receptor that the coronavirus SARS-CoV-2 binds to and uses to enter and infect human cells. COVID-19, the pandemic disease caused by the coronavirus, involves diverse pathologies beyond those of a respiratory disease, including micro-thrombosis (micro-clotting), cytokine storms, and inflammatory responses affecting many organ systems. Longer-term chronic illness can persist for many months, often well after the pathogen is no longer detected. A better understanding of the proteins that ACE2 interacts with can reveal information relevant to these disease manifestations and possible avenues for treatment. We have undertaken an approach to predict candidate ACE2 interacting proteins which uses evolutionary inference to identify a set of mammalian proteins that "coevolve" with ACE2. The approach, called evolutionary rate correlation (ERC), detects proteins that show highly correlated evolutionary rates during mammalian evolution. Such proteins are candidates for biological interactions with the ACE2 receptor. The approach has uncovered a number of key ACE2 protein interactions of potential relevance to COVID-19 pathologies. Some proteins have previously been reported to be associated with severe COVID-19, but are not currently known to interact directly with ACE2, while additional predicted novel ACE2 interactors are of potential relevance to the disease. Using reciprocal rankings of protein ERCs, we have identified strongly interconnected ACE2 associated protein networks relevant to COVID-19 pathologies. ACE2 has clear connections to coagulation pathway proteins, such as Coagulation Factor V and fibrinogen components FGG, FGB, and FGA, the latter possibly mediated through ACE2 connections to Clusterin (which clears misfolded extracellular proteins) and GPR141 (whose functions are relatively unknown). ACE2 also connects to proteins involved in cytokine signaling and immune response (e.g. IFNAR2, XCR1, and TLR8), and to Androgen Receptor (AR). The ERC prescreening approach has also elucidated possible functions for previously uncharacterized proteins and possible new functions for well-characterized ones. Suggestions are made for the validation of ERC predicted ACE2 protein interactions. We propose that ACE2 has novel protein interactions that are disrupted during SARS-CoV-2 infection, contributing to the spectrum of COVID-19 pathologies.

bioinformatics↗

bioRxiv2021

Allele-specific gene editing rescues pathology in a human model of Charcot-Marie-Tooth disease type 2E

Many neuromuscular disorders are caused by dominant missense mutations that lead to dominant-negative or gain-of-function pathology. This category of disease is challenging to address via drug treatment or gene augmentation therapy because these strategies may not eliminate the effects of the mutant protein or RNA. Thus, effective treatments are severely lacking for these dominant diseases, which often cause severe disability or death. The targeted inactivation of dominant disease alleles by gene editing is a promising approach with the potential to completely remove the cause of pathology with a single treatment. Here, we demonstrate that allele-specific CRISPR gene editing in a human model of axonal Charcot-Marie-Tooth (CMT) disease rescues pathology caused by a dominant missense mutation in the neurofilament light chain gene (NEFL, CMT type 2E). We utilized a rapid and efficient method for generating spinal motor neurons from human induced pluripotent stem cells (iPSCs) derived from a patient with CMT2E. Diseased motor neurons recapitulated known pathologic phenotypes at early time points of differentiation, including aberrant accumulation of neurofilament light chain protein in neuronal cell bodies. We selectively inactivated the disease NEFL allele in patient iPSCs using Cas9 enzymes to introduce a frameshift at the pathogenic N98S mutation. Motor neurons carrying this allele-specific frameshift demonstrated an amelioration of the disease phenotype comparable to that seen in an isogenic control with precise correction of the mutation. Our results validate allele-specific gene editing as a therapeutic approach for CMT2E and as a promising strategy to silence dominant mutations in any gene for which heterozygous loss-of-function is well tolerated. This highlights the potential for gene editing as a therapy for currently untreatable dominant neurologic diseases.

genetics↗

bioRxiv2021

Sustained TREM2 stabilization accelerates microglia heterogeneity and Abeta pathology in a mouse model of Alzheimer s disease

TREM2 is a transmembrane protein expressed exclusively in microglia in the brain that regulates inflammatory responses to pathological conditions. Proteolytic cleavage of membrane TREM2 affects microglial function and is associated with Alzheimers disease, but the consequence of reduced TREM2 proteolytic cleavage has not been determined. We generated a transgenic mouse model of reduced TREM2 shedding (Trem2-IPD) through amino acid substitution of ADAM-protease recognition site. We found that Trem2-IPD mice displayed increased TREM2 cell surface receptor load, survival and function in myeloid cells. Using single cell transcriptomic profiling of mouse cortex we show that sustained TREM2 stabilization induces a shift of fate in microglial maturation and accelerates microglial responses to A{beta} pathology in a mouse model of Alzheimers disease. Our data indicate that reduction of TREM2 proteolytic cleavage aggravates neuroinflammation during the course of AD pathology suggesting that TREM2 shedding is a critical regulator of microglial activity in pathological states.

neuroscience↗

bioRxiv2021

Mutant huntingtin crosses the neuromuscular junction and causes transmission-selective pathological alterations in huntingtin expressing myotubes

A potential explanation for the spatiotemporal accumulation of pathological lesions in the brain of patients with neurodegenerative protein misfolding diseases (PMDs) is cell-to-cell transmission of aggregation-prone, misfolded proteins. Little is known about central to peripheral transmission and its contribution to pathology. We show that transmission of Huntingtons disease- (HD-) associated mutant HTT exon 1 (mHTTEx1) occurs across the neuromuscular junctions in human iPSC cultures and in vivo in wild-type mice. We found that transmission is an active and dynamic process, that happens prior to aggregate formation and is regulated by synaptic activity. Furthermore, we find that transmitted mHTTEx1 causes HD-relevant pathology at a molecular and functional level in human muscle cells, even in the presence of ubiquitous expression mHTTEx1. With this work we uncover a casual-link between mHTTEx1 synaptic transmission and pathology, highlighting the therapeutic potential in blocking toxic protein transmission in PMDs.

neuroscience↗

bioRxiv2021

Low dose pig anti-influenza virus monoclonal antibodies reduce lung pathology but do not prevent virus shedding

We have established the pig, a large natural host animal for influenza, with many physiological similarities to humans, as a robust model for testing the therapeutic potential of monoclonal antibodies (mAbs). In this study we demonstrated that prophylactic intravenous administration of 15mg/kg of porcine mAb pb18, against the K160-163 site of the haemagglutinin, significantly reduced lung pathology and nasal virus shedding and eliminated virus from the lung of pigs following H1N1pdm09 challenge. When given at 1mg/kg, pb18 significantly reduced lung pathology and lung and BAL virus loads, but not nasal shedding. Similarly, when pb18 was given in combination with pb27, which recognised the K130 site, at 1mg/kg each, lung virus load and pathology were reduced, although without an apparent additive or synergistic effect. No evidence for mAb driven virus evolution was detected. These data indicate that intravenous administration of high doses was required to reduce nasal virus shedding, although this was inconsistent and seldom complete. In contrast the effect on lung pathology and lung virus load is consistent and is also seen at one log lower doses, strongly indicating that a lower dose might be sufficient to reduce severity of disease, but for prevention of transmission other measures would be needed.

immunology↗

bioRxiv2021

Amyloid-beta and tau pathologies are both necessary to induce novel stage-specific microglia subtypes during Alzheimer's disease progression.

It is unknown whether specific microglia are selectively induced by amyloid-{beta} (A{beta}), tau pathologies, or both in combination. To address this, we use single-cell RNA-sequencing to profile mice bearing both A{beta} and tau pathologies during Alzheimers disease (AD) progression. We identify novel microglia subtypes induced in a disease stage-specific manner. We show that during early-stage disease, interferon signaling induces a subtype of microglia termed EADAM. During late-stage disease, a second microglia subtype termed LADAM is detected. While EADAM and LADAM-like microglia are observed in other neurodegenerative models, the magnitude and composition of subtype markers are distinct from microglia observed with AD-like pathology. The pattern of EADAM- and LADAM-associated gene expression is observed in microglia from human AD, during the early and late stages of disease, respectively. Furthermore, we observe that several siglec genes are selectively expressed in either EADAM or LADAM. Siglecg is expressed in white-matter-associated LADAM, and expression of the human orthologue of Siglecg is progressively elevated in AD-stage-dependent manner but not shown in non-AD tauopathy. Our findings imply that both A{beta} and tau pathologies are required for disease stage-specific induction of EADAM and LADAM.

neuroscience↗

bioRxiv2022

A visual atlas of genes tissue-specific pathological roles

Dysregulation of a genes function, either due to mutations or impairments in regulatory networks, often triggers pathological states in the affected tissue. Comprehensive mapping of these apparent gene-pathology relationships is an ever daunting task, primarily due to genetic pleiotropy and lack of suitable computational approaches. With the advent of high throughput genomics platforms and community scale initiatives such as the Human Cell Landscape (HCL) project [1], researchers have been able to create gene expression portraits of healthy tissues resolved at the level of single cells. However, a similar wealth of knowledge is currently not at our finger-tip when it comes to diseases. This is because the genetic manifestation of a disease is often quite heterogeneous and is confounded by several clinical and demographic covariates. To circumvent this, we mined ~18 million PubMed abstracts published till May 2019 and selected ~6.1 million of them that describe the pathological role of genes in different diseases. Further, we employed a word embedding technique from the domain of Natural Language Processing (NLP) to learn vector representation of entities such as genes, diseases, tissues, etc., in a way such that their relationship is preserved in a vector space. Notably, Pathomap, by the virtue of its underpinning theory, also learns transitive relationships. Pathomap provided a vector representation of words indicating a possible association between DNMT3A/BCOR with CYLD cutaneous syndrome (CCS). The first manuscript reporting this finding was not part of our training data. Key pointsO_LIWe mined ~18 million PubMed abstracts to extract latent knowledge pertaining to tissue specific pathological roles of genes. C_LIO_LIWe found well-defined gene modules implicated in disease pathogenesis in anatomically proximal tissues. C_LIO_LIWe demonstrated an ahead of time discovery of the association between DNMT3A/BCOR with CYLD cutaneous syndrome (CCS), as a knowledge synthesis use-case. C_LI

bioinformatics↗

bioRxiv2022

Pathological relevance of post-translationally modified alpha-synuclein (pSer87, pSer129, nTyr39) in idiopathic Parkinson's disease and Multiple System Atrophy.

Aggregated alpha-synuclein (-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinsons disease (IPD) and multiple system atrophy (MSA), respectively. Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of -synuclein exist, including phosphorylated and nitrated forms. It is unclear which -synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant -synuclein PTMs in post-mortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three -synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology-affected regions of 15 PD, 5 MSA, 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 -synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures followed by nY39 -synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 -synuclein in MSA. Quantification of the LB scores revealed that pS129 -synuclein was the dominant and earliest -synuclein PTM followed by nY39 -synuclein, while lower amounts of pSer87 -synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments.

neuroscience↗

bioRxiv2022

HIV and FIV glycoproteins increase cellular tau pathology via cGMP-dependent kinase II activation

As the development of combination antiretroviral therapy (cART) against human immunodeficiency virus (HIV) drastically improves the lifespan of individuals with HIV, many are now entering the prime age when Alzheimers disease (AD)-like symptoms begin to manifest. Hyperphosphorylated tau, a known AD pathological characteristic, has been prematurely increased in the brains of HIV-infected patients as early as in their 30s and is increased with age. This thus suggests that HIV infection may lead to accelerated AD phenotypes. However, whether HIV infection causes AD to develop more quickly in the brain is not yet fully determined. Interestingly, we have previously revealed that viral glycoproteins, HIV gp120 and feline immunodeficiency virus (FIV) gp95, induce neuronal hyperexcitation via cGMP-dependent kinase II (cGKII) activation in cultured hippocampal neurons. Here, we use cultured mouse cortical neurons to demonstrate that HIV gp120 and FIV gp95 are sufficient to increase cellular tau pathology, including intracellular tau hyperphosphorylation and tau release to the extracellular space. We further reveal that viral glycoprotein-induced cellular tau pathology requires cGKII activation. Together, HIV infection likely accelerates AD-related tau pathology via cGKII activation.

neuroscience↗

bioRxiv2022

Adversarial attacks and adversarial robustness in computational pathology

Artificial Intelligence (AI) can support diagnostic workflows in oncology by aiding diagnosis and providing biomarkers. AI applications are therefore expected to evolve from academic prototypes to commercial products in the coming years. However, AI applications are vulnerable to adversarial attacks, such as malicious interference with test data aiming to cause misclassifications. Therefore, it is essential for the use of AI-based diagnostic devices to secure them against such attacks before widespread use. Unfortunately, no resistant systems exist in computational pathology so far. To address this problem, we investigate the susceptibility of convolutional neural networks (CNNs) to multiple types of white- and black-box attacks. We demonstrate that both attacks can easily confuse CNNs in clinically relevant pathology tasks and impair classification performance. Classical adversarially robust training and dual batch normalization (DBN) are possible mitigation strategies but require precise knowledge of the type of attack used in the inference. We demonstrate that vision transformers (ViTs) perform equally well compared to CNNs at baseline and are orders of magnitude more robust to different types of white-box and black-box attacks. At a mechanistic level, we show that this is associated with a more robust latent representation of clinically relevant categories in ViTs compared to CNNs. Our results are in line with previous theoretical studies. We show that ViTs are robust learners in computational pathology. This implies that large-scale rollout of AI models in computational pathology should rely on ViTs rather than CNN-based classifiers to provide inherent protection against adversaries.

bioinformatics↗

bioRxiv2022

Two therapeutic CRISPR/Cas9 gene editing approaches revert FTD/ALS cellular pathology caused by a C9orf72 repeat expansion mutation in patient derived cells

CRISPR gene editing holds promise to cure or arrest genetic disease, if we can find and implement curative edits reliably, safely and effectively. Expansion of a hexanucleotide repeat in C9orf72 is the leading known genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated three approaches to editing the mutant C9orf72 gene for their ability to correct pathology in neurons derived from patient iPSCs: excision of the repeat region, excision of the mutant allele, and excision of regulatory region exon 1A. All three approaches normalized RNA abnormalities and TDP-43 pathology, but only repeat excision and mutant allele excision completely eliminated pathologic dipeptide repeats. Our work sheds light on the complex regulation of the C9orf72 gene and suggests that because of sense and anti-sense transcription, silencing a single regulatory region may not reverse all pathology. Our work also provides a roadmap for evaluating CRISPR gene correction using patient iPSCs.

neuroscience↗

bioRxiv2022

An integrative web-based software tool for multi-dimensional pathology whole-slide image analytics

In the era of precision medicine, human tumor atlas oriented studies have been significantly facilitated by high-resolution, multi-modal tissue based microscopic pathology image analytics. To better support such tissue-based investigations, we develop Digital Pathology Laboratory (DPLab), a publicly available web-based platform, to assist biomedical research groups, non-technical end users, and clinicians for pathology Whole-Slide Image (WSI) visualization, annotation, analysis, and sharing via web browsers. A major advance of this work is the easy-to-follow methods to reconstruct three-dimension (3D) tissue image volumes by registering two-dimension (2D) whole-slide pathology images of serial tissue sections stained by hematoxylin and eosin (H&E), and immunohistochemistry (IHC). The integration of these serial slides stained by different methods provides cellular phenotype and pathophysiologic states in the context of a 3D tissue micro-environment. DPLab is hosted on a publicly accessible server and connected to a backend computational cluster for intensive image analysis computations, with results visualized, downloaded, and shared via a web interface. Equipped with an analysis toolbox of numerous image processing algorithms, DPLab supports continued integration of community-contributed algorithms and presents an effective solution to improve the accessibility and dissemination of image analysis algorithms by research communities. It represents the first step in making next generation tissue investigation tools widely available to the research community, enabling and facilitating discovery of clinically relevant disease mechanisms in a digital 3D tissue space.

bioinformatics↗

bioRxiv2022

SorCS1 inhibits amyloid-β binding to neurexin and rescues amyloid-β-induced synaptic pathology

Amyloid-{beta} oligomers (A{beta}Os), toxic peptide aggregates found in Alzheimers disease (AD), cause synapse pathology. A{beta}Os interact with Neurexins (NRXs), key synaptic organizers, and this interaction dampens normal trafficking and function of NRXs. Axonal trafficking of NRX is in part regulated by its interaction with SorCS1, a protein sorting receptor, but the impact of SorCS1 regulation of NRXs in A{beta} pathology was previously unstudied. Here, we show competitive interaction of SorCS1 and A{beta}Os with {beta}-NRXs and rescue effects of SorCS1 on A{beta}O-induced synaptic pathology. Like A{beta}Os, SorCS1 binds to NRX1{beta} through the histidine-rich-domain (HRD) of NRX1{beta}, and SorCS1 and A{beta}Os compete for NRX1{beta} binding. In cultured hippocampal neurons, SorCS1 colocalizes with NRX1{beta} on the axon surface, and axonal expression of SorCS1 rescues A{beta}O-induced impairment of NRX-mediated presynaptic organization and presynaptic vesicle recycling as well as A{beta}O-induced structural defects in excitatory synapses. Thus, we reveal a role of SorCS1 in the rescue of A{beta}O-induced NRX dysfunction and synaptic pathology, providing the basis for a novel potential therapeutic strategy for AD.

neuroscience↗

bioRxiv2022

Molecular and anatomical roadmap of stroke pathology in immunodeficient mice

BackgroundStroke remains a leading cause of disability and death worldwide. It has become apparent that inflammation and immune mediators have a pre-dominant role in initial tissue damage and long-term recovery following the injury. Still, different immunosuppressed mouse models are necessary in stroke research e.g., to evaluate therapies using human cell grafts. Despite mounting evidence delineating the importance of inflammation in the stroke pathology, it is poorly described to what extent partial immune deficiency influences the overall stroke outcome. MethodsHere, we assessed the stroke pathology of popular genetic immunodeficient mouse models, i.e., NOD scid gamma (NSG) and recombination activating gene 2 (Rag2-/-) mice as well as pharmacologically immunosuppressed mice and compared them to immune competent, wildtype (WT) C57BL/6J mice up to three weeks after injury. We performed histology, gene expression profiling, serum analysis and functional behavioural tests to identify the impact of immunosuppression on the stroke progression. ResultsWe detected distinct changes in microglia infiltration, scar-forming and vascular repair in immune-suppressed mice three weeks after injury. Gene expression analysis of stroked tissue revealed the strongest deviation from immune competent mice was observed in NSG mice, for instance, affecting immunological and angiogenic pathways. Pharmacological immunosuppression resulted in the least variation in gene expression compared with the WT. Major differences have been further identified in the systemic inflammatory response following stroke acutely and three weeks following injury. These anatomical, genetic, and systemic changes did not affect functional deficits and recovery in a time course of three weeks. To determine whether the timing of immunosuppression after stroke is critical, we compared mice with acute and delayed pharmacological immunosuppression after stroke. Mice with a delayed immunosuppression (7d) after stroke showed increased inflammatory and scarring responses compared to animals acutely treated with tacrolimus, thus more closely resembling WT pathology. Transplantation of human cells in the brains of immunosuppressed mouse models led to prolonged cell survival in all immunosuppressed mouse models, which was most consistent in NSG and Rag2-/- mice. ConclusionsIn sum, we detected distinct anatomical and molecular changes in the stroke pathology between the individual immunosuppressed mouse models that should be carefully considered when selecting an appropriate mouse model for stroke research.

neuroscience↗