Characterization of a Mouse Model of Alzheimer's Disease Expressing Aβ4-42 and Human Mutant Tau.
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ABSTRACT:
SUBMITTER: Zampar S
PROVIDER: S-EPMC8156793 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPreclinical Alzheimer's disease (AD) research strongly depends on transgenic mouse models that display major symptoms of the disease. Although several AD mouse models have been developed representing relevant pathologies, only a fraction of available mouse models, like the Tg4-42 mouse model, display hippocampal atrophy caused by the death of neurons as the key feature of AD. The Tg4-42 mouse model is therefore very valuable for use in preclinical research. Furthermore, metabolic biomarkers which have the potential to detect biochemical changes, are crucial to gain deeper insights into the pathways, the underlying pathological mechanisms and disease progression.ObjectiveWe thus performed an in-depth characterization of Tg4-42 mice by using an integrated approach to analyze alterations of complex biological networks in this AD in vivo model.MethodsTherefore, untargeted NMR-based metabolomic phenotyping was combined with behavioral tests and immunohistological and biochemical analyses.ResultsOur in vivo experiments demonstrate a loss of body weight increase in homozygous Tg4-42 mice over time as well as severe impaired learning behavior and memory deficits in the Morris water maze behavioral test. Furthermore, we found significantly altered metabolites in two different brain regions and metabolic changes of the glutamate/4-aminobutyrate-glutamine axis. Based on these results, downstream effects were analyzed showing increased Aβ42 levels, increased neuroinflammation as indicated by increased astro- and microgliosis as well as neuronal degeneration and neuronal loss in homozygous Tg4-42 mice.ConclusionOur study provides a comprehensive characterization of the Tg4-42 mouse model which could lead to a deeper understanding of pathological features of AD. Additionally this study reveals changes in metabolic biomarker which set the base for future preclinical studies or drug development.
| S-EPMC8150512 | biostudies-literature
Project description:BackgroundAlzheimer's disease (AD), the most common cause of dementia among neurodegenerative diseases, afflicts millions of elderly people worldwide. In addition to amyloid-beta (A?) peptide and phosphorylated tau, lipid dysregulation is suggested to participate in AD pathogenesis. However, alterations in individual lipid species and their role in AD disease progression remain unclear.MethodsWe performed a lipidomic analysis using brain tissues and plasma obtained from mice expressing mutated human amyloid precursor protein (APP) and tau protein (Tg2576×JNPL3) (APP/tau mice) at 4 (pre-symptomatic phase), 10 (early symptomatic) and 15 months (late symptomatic).ResultsLevels of docosahexaenoyl (22:6) cholesterol ester (ChE) were markedly increased in APP/tau mice compared to controls at all stages examined. Several species of ethanolamine plasmalogens (pPEs) and sphingomyelins (SMs) showed different levels between brains from APP/tau and control mice at various stages of AD. Increased levels of 12-hydroxyeicosatetraenoic acid (12-HETE) during the early symptomatic phase were consistent with previous reports using human AD brain tissue. In addition, 19,20-dihydroxy-docosapentaenoic acid (19,20-diHDoPE) and 17,18-dihydroxy-eicosatetraenoic acid (17,18-diHETE), which are produced from docosahexaenoic acid and eicosapentaenoic acid via 19,20-epoxy-docosapentaenoic acid (19,20-EpDPE) and 17,18-epoxy-eicosatetraenoic acid (17,18-EpETE), respectively, were significantly increased in APP/tau brains during the pre-symptomatic phase, and concomitant increases occurred in plasma. Several arachidonic acid metabolites such as prostaglandin D2 (PGD2) and 15-hydroxyeicosatetraenoic acid (15-HETE), which have potential deteriorating and protective actions, respectively, were decreased in the early symptomatic phase of APP/tau mice. Significant decreases in phosphatidylcholines and PEs with polyunsaturated fatty acids were also detected in the late symptomatic phase, indicating a perturbation of membrane properties.ConclusionOur results provide fundamental information on lipid dysregulation during various stages of human AD.
| S-EPMC3668217 | biostudies-literature
Project description:BackgroundAugmenting the brain clearance of toxic oligomers with small molecule modulators constitutes a promising therapeutic concept against tau deposition. However, there has been no test of this concept in animal models of Alzheimer's disease (AD) with initiation at a late disease stage. Thus, we aimed to investigate the effects of interventional late-stage Anle138b treatment, which previously indicated great potential to inhibit oligomer accumulation by binding of pathological aggregates, on the metabolic decline in transgenic mice with established tauopathy in a longitudinal 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) study.MethodsTwelve transgenic mice expressing all six human tau isoforms (hTau) and ten controls were imaged by FDG-PET at baseline (14.5?months), followed by randomization into Anle138b treatment and vehicle groups for 3?months. FDG-PET was repeated after treatment for 3?months, and brains were analyzed by tau immunohistochemistry. Longitudinal changes of glucose metabolism were compared between study groups, and the end point tau load was correlated with individual FDG-PET findings.ResultsTau pathology was significantly ameliorated by late-stage Anle138b treatment when compared to vehicle (frontal cortex -?53%, p <?0.001; hippocampus -?59%, p <?0.005). FDG-PET revealed a reversal of metabolic decline during Anle138b treatment, whereas the vehicle group showed ongoing deterioration. End point glucose metabolism in the brain of hTau mice had a strong correlation with tau deposition measured by immunohistochemistry (R =?0.92, p <?0.001).ConclusionLate-stage oligomer modulation effectively ameliorated tau pathology in hTau mice and rescued metabolic function. Molecular imaging by FDG-PET can serve for monitoring effects of Anle138b treatment.
| S-EPMC6670231 | biostudies-literature
Project description:The relationship between amyloid-? (A?) species and tau pathology in Alzheimer's disease (AD) is not fully understood. Here, we provide direct evidence that A?42/40 ratio, not total A? level, plays a critical role in inducing neurofibrillary tangles (NTFs) in human neurons. Using 3D-differentiated clonal human neural progenitor cells (hNPCs) expressing varying levels of amyloid ? precursor protein (APP) and presenilin 1 (PS1) with AD mutations, we show that pathogenic tau accumulation and aggregation are tightly correlated with A?42/40 ratio. Roles of A?42/40 ratio on tau pathology are also confirmed with APP transmembrane domain (TMD) mutant hNPCs, which display differential A?42/40 ratios without mutant PS1. Moreover, naïve hNPCs co-cultured with APP TMD I45F (high A?42/40) cells, not with I47F cells (low A?42/40), develop robust tau pathology in a 3D non-cell autonomous cell culture system. These results emphasize the importance of reducing the A?42/40 ratio in AD therapy.
| S-EPMC7070004 | biostudies-literature
Project description:BackgroundTau pathology is a hallmark of Alzheimer's disease (AD) and other tauopathies. During disease progression, abnormally phosphorylated forms of tau aggregate and accumulate into neurofibrillary tangles, leading to synapse loss, neuroinflammation, and neurodegeneration. Thus, targeting of tau pathology is expected to be a promising strategy for AD treatment.MethodsThe effect of rutin on tau aggregation was detected by thioflavin T fluorescence and transmission electron microscope imaging. The effect of rutin on tau oligomer-induced cytotoxicity was assessed by MTT assay. The effect of rutin on tau oligomer-mediated the production of IL-1β and TNF-α in vitro was measured by ELISA. The uptake of extracellular tau by microglia was determined by immunocytochemistry. Six-month-old male Tau-P301S mice were treated with rutin or vehicle by oral administration daily for 30 days. The cognitive performance was determined using the Morris water maze test, Y-maze test, and novel object recognition test. The levels of pathological tau, gliosis, NF-kB activation, proinflammatory cytokines such as IL-1β and TNF-α, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunolabeling, immunoblotting, or ELISA.ResultsWe showed that rutin, a natural flavonoid glycoside, inhibited tau aggregation and tau oligomer-induced cytotoxicity, lowered the production of proinflammatory cytokines, protected neuronal morphology from toxic tau oligomers, and promoted microglial uptake of extracellular tau oligomers in vitro. When applied to Tau-P301S mouse model of tauopathy, rutin reduced pathological tau levels, regulated tau hyperphosphorylation by increasing PP2A level, suppressed gliosis and neuroinflammation by downregulating NF-kB pathway, prevented microglial synapse engulfment, and rescued synapse loss in mouse brains, resulting in a significant improvement of cognition.ConclusionIn combination with the previously reported therapeutic effects of rutin on Aβ pathology, rutin is a promising drug candidate for AD treatment based its combinatorial targeting of tau and Aβ.
| S-EPMC8196535 | biostudies-literature
Project description:BackgroundDelirium and dementia share symptoms of cognitive dysfunctions, and mechanisms of neuroinflammation appear involved in both conditions. Triggering receptor expressed on myeloid cells 2 (TREM2) is linked to dementia and neurodegenerative disease. It encodes expression of an innate immune receptor in the brain expressed by microglia. The level of the soluble fragment of TREM2 (sTREM2) is reported to increase in the cerebrospinal fluid (CSF) already in prodromal and asymptomatic Alzheimer's disease.MethodsWe analyzed the level of CSF sTREM2 in relation to delirium and dementia. The study included patients with or without pre-existing dementia who underwent acute hip fracture surgery (n?=?120), and some of the patients developed delirium (n?=?65). A medical delirium cohort (n?=?26) was also examined. ELISA was used to determine the level of sTREM2 in CSF.ResultsDelirium was associated with a higher level of CSF sTREM2 only among those without pre-existing dementia (p?=?0.046, n?=?15, n?=?44), particularly among patients developing delirium after CSF sampling (p?=?0.02, n?=?7, n?=?44). Between patients with dementia, there was no group difference, but the CSF sTREM2 level increased with waiting time for surgery (rS?=?0.39, p?=?0.002, n?=?60) and correlated well with the CSF Alzheimer's disease biomarkers, A?42, and t-tau/p-tau (rS?=?0.40, p?=?0.002, rS?=?0.46, p?<?0.001/ rS?=?0.49, p?<?0.001, n?=?60). Among patients with dementia, the level of A?38 and A?40 also correlated positively with sTREM2 in CSF (A?38MSDrS?=?0.44, p?=?0.001; A?40MSDrS?=?0.48, p?<?0.001; A?42MSDrS?=?0.43, p?<?0.001, n?=?60).ConclusionThe findings reinforce the involvement of neuroinflammation in delirium, yet with separate responses in patients with or without pre-existing dementia. Our findings support the concept of primed microglia in neurodegenerative disease and central immune activation after a peripheral trauma in such patients. A CSF biomarker panel of neuroinflammation might be valuable to prevent delirium by identifying patients at risk.
| S-EPMC6215363 | biostudies-literature
Project description:Drosophila melanogaster expressing amyloid-?42 (A?42) transgenes have been used as models to study Alzheimer's disease. Various A?42 transgenes with different structures induce different phenotypes, which make it difficult to compare data among studies which use different transgenic lines. In this study, we compared the phenotypes of four frequently used A?42 transgenic lines, UAS-A?422X , UAS-A?42BL33770 , UAS-A?4211C39 , and UAS-A?42H29.3 . Among the four transgenic lines, only UAS-A?422X has two copies of the upstream activation sequence-amyloid-?42 (UAS-A?42) transgene, while remaining three have one copy. UAS-A?42BL33770 has the 3' untranslated region of Drosophila ?-tubulin, while the others have that of SV40. UAS-A?4211C39 and UAS-A?42H29.3 have the rat pre-proenkephalin signal peptide, while UAS-A?422X and UAS-A?42BL33770 have that of the fly argos protein. When the transgenes were expressed ectopically in the developing eyes of the flies, UAS-A?422X transgene resulted in a strongly reduced and rough eye phenotype, while UAS-A?42BL33770 only showed a strong rough eye phenotype; UAS-A?42H29.3 and UAS-A?4211C39 had mild rough eyes. The levels of cell death and reactive oxygen species (ROS) in the eye imaginal discs were consistently the highest in UAS-A?422X , followed by UAS-A?42BL33770 , UAS-A?4211C39 , and UAS-A?42H29.3 . Surprisingly, the reduction in survival during the development of these lines did not correlate with cell death or ROS levels. The flies which expressed UAS-A?4211C39 or UAS-A?42H29.3 experienced greatly reduced survival rates, although low levels of ROS or cell death were detected. Collectively, our results demonstrated that different Drosophila AD models show different phenotypic severity, and suggested that different transgenes may have different modes of cytotoxicity. Abbreviations: A?42: amyloid-?42; AD: Alzheimer's disease; UAS: upstream activation sequence.
| S-EPMC6138326 | biostudies-other
Project description:BackgroundThe spread of tau pathology in Alzheimer's disease (AD) is mediated by cell-to-cell transmission of pathological tau seeds released from neurons that, upon internalization by recipient neurons, template the misfolding of naïve cellular tau, thereby propagating fibrillization. We hypothesize that anti-tau monoclonal antibodies (mAbs) that selectively bind to pathological tau seeds will inhibit propagation of tau aggregates and reduce the spread of tau pathology in vivo.MethodsWe inoculated mice with human AD brain-derived extracts containing tau paired helical filaments (AD-tau) and identified two novel mAbs, DMR7 and SKT82, that selectively bind to a misfolded pathological conformation of tau relative to recombinant tau monomer. To evaluate the effects of these mAbs on the spread of pathological tau in vivo, 5xFAD mice harboring significant brain Aβ plaque burden were unilaterally injected with AD-tau in the hippocampus, to initiate the formation of neuritic plaque (NP) tau pathology, and were treated weekly with intraperitoneal (i.p.) injections of DMR7, SKT82, or IgG isotype control mAbs.ResultsDMR7 and SKT82 bind epitopes comprised of the proline-rich domain and c-terminal region of tau and binding is reduced upon disruption of the pathological conformation of AD-tau by chemical and thermal denaturation. We found that both DMR7 and SKT82 immunoprecipitate pathological tau and significantly reduce the seeding of cellular tau aggregates induced by AD-tau in primary neurons by 60.5 + 13.8% and 82.2 + 8.3%, respectively, compared to IgG control. To investigate the mechanism of mAb inhibition, we generated pH-sensitive fluorophore-labeled recombinant tau fibrils seeded by AD-tau to track internalization of tau seeds and demonstrate that the conformation-selective tau mAbs inhibit the internalization of tau seeds. DMR7 and SKT82 treatment reduced hyperphosphorylated NP tau as measured with AT8 immunohistochemistry (IHC) staining, but did not achieve statistical significance in the contralateral cortex and SKT82 significantly reduced tau pathology in the ipsilateral hippocampus by 24.2%; p = 0.044.ConclusionsThese findings demonstrate that conformation-selective tau mAbs, DMR7 and SKT82, inhibit tau pathology in primary neurons by preventing the uptake of tau seeds and reduce tau pathology in vivo, providing potential novel therapeutic candidates for the treatment of AD.
| S-EPMC7643305 | biostudies-literature
Project description:A central question in Alzheimer's Disease (AD) is whether the neuritic plaque is necessary and sufficient for the development of tau pathology. Hyperphosphorylation of tau is found within dystrophic neurites surrounding ?-amyloid deposits in AD mouse models but the pathological conversion of tau is absent. Likewise, expression of a human tau repeat domain in mice is insufficient to drive the pathological conversion of tau. Here we developed an A?-amyloidosis mouse model that expresses the human tau repeat domain and show that in these mice, the neuritic plaque facilitates the pathological conversion of wild-type tau. We show that this tau fragment seeds the neuritic plaque-dependent pathological conversion of wild-type tau that spreads from the cortex and hippocampus to the brain stem. These results establish that in addition to the neuritic plaque, a second determinant is required to drive the conversion of wild-type tau.
| S-EPMC4932197 | biostudies-literature
Project description:Stem cell (SC) lines that capture the genetics of disease susceptibility provide new research tools. To assess the utility of mouse central nervous system (CNS) SC-containing neurosphere cultures for studying heritable neurodegenerative disease, we compared neurosphere cultures from transgenic mice that express human tau with the P301L familial frontotemporal dementia (FTD) mutation, rTg(tau(P301L))4510, with those expressing comparable levels of wild type human tau, rTg(tau(wt))21221. rTg(tau(P301L))4510 mice express the human tau(P301L) variant in their forebrains and display cellular, histological, biochemical and behavioral abnormalities similar to those in human FTD, including age-dependent differences in tau phosphorylation that distinguish them from rTg(tau(wt))21221 mice. We compared FTD-hallmark tau phosphorylation in neurospheres from rTg(tau(P301L))4510 mice and from rTg(tau(wt))21221 mice. The tau genotype-specific phosphorylation patterns in neurospheres mimicked those seen in mice, validating use of neurosphere cultures as models for studying tau phosphorylation. Genotype-specific tau phosphorylation was observed in 35 independent cell lines from individual fetuses; tau in rTg(tau(P301L))4510 cultures was hypophosphorylated in comparison with rTg(tau(wt))21221 as was seen in young adult mice. In addition, there were fewer human tau-expressing cells in rTg(tau(P301L))4510 than in rTg(tau(wt))21221 cultures. Following differentiation, neuronal filopodia-spine density was slightly greater in rTg(tau(P301L))4510 than rTg(tau(wt))21221 and control cultures. Together with the recapitulation of genotype-specific phosphorylation patterns, the observation that neurosphere lines maintained their cell line-specific-differences and retained SC characteristics over several passages supports the utility of SC cultures as surrogates for analysis of cellular disease mechanisms.
| S-EPMC3377636 | biostudies-literature