scholarly journals Microglial activation in vivo is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of Alzheimer’s disease

2020 ◽  
Vol 16 (S4) ◽  
Author(s):  
Gloria Biechele ◽  
Nicolai Franzmeier ◽  
Michael Ewers ◽  
Tanja Blume ◽  
Florian Eckenweber ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Microglial Activation ◽  
Tau Pathology

scholarly journals Pinpointing Brain TREM2 Levels in Two Mouse Models of Alzheimer’s Disease

2021 ◽  
Author(s):  
Silvio R. Meier ◽  
Dag Sehlin ◽  
Greta Hultqvist ◽  
Stina Syvänen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Mouse Models ◽  
Microglial Activation ◽  
Bispecific Antibody ◽  
Ex Vivo ◽  
Transgenic Animals ◽  
The Brain

Abstract Purpose The triggering receptor expressed on myeloid cells 2 (TREM2) is expressed by brain microglia. Microglial activation, as observed in Alzheimer’s disease (AD) as well as in transgenic mice expressing human amyloid-beta, appears to increase soluble TREM2 (sTREM2) levels in CSF and brain. In this study, we used two different transgenic mouse models of AD pathology and investigated the potential of TREM2 to serve as an in vivo biomarker for microglial activation in AD. Procedures We designed and generated a bispecific antibody based on the TREM2-specific monoclonal antibody mAb1729, fused to a single-chain variable fragment of the transferrin receptor binding antibody 8D3. The 8D3-moiety enabled transcytosis of the whole bispecific antibody across the blood-brain barrier. The bispecific antibody was radiolabeled with I-125 (ex vivo) or I-124 (PET) and administered to transgenic AD and wild-type (WT) control mice. Radioligand retention in the brain of transgenic animals was compared to WT mice by isolation of brain tissue at 24 h or 72 h, or with in vivo PET at 24 h, 48 h, and 72 h. Intrabrain distribution of radiolabeled mAb1729-scFv8D3CL was further studied by autoradiography, while ELISA was used to determine TREM2 brain concentrations. Results Transgenic animals displayed higher total exposure, calculated as the AUC based on SUV determined at 24h, 48h, and 72h post injection, of PET radioligand [124I]mAb1729-scFv8D3CL than WT mice. However, differences were not evident in single time point PET images or SUVs. Ex vivo autoradiography confirmed higher radioligand concentrations in cortex and thalamus in transgenic mice compared to WT, and TREM2 levels in brain homogenates were considerably higher in transgenic mice compared to WT. Conclusion Antibody-based radioligands, engineered to enter the brain, may serve as PET radioligands to follow changes of TREM2 in vivo, but antibody formats with faster systemic clearance to increase the specific signal in relation to that from blood in combination with antibodies showing higher affinity for TREM2 must be developed to further progress this technique for in vivo use.

P2-385: Binding and pharmacokinetic properties of novel 18 F-labeled agents for in vivo imaging of tau pathology in Alzheimer's disease

2010 ◽  
Vol 6 ◽  
pp. S429-S430
Author(s):  
Nobuyuki Okamura ◽  
Shozo Furumoto ◽  
Katsutoshi Furukawa ◽  
Hiroyuki Arai ◽  
Kazuhiko Yanai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Vivo Imaging ◽  
Tau Pathology ◽  
Pharmacokinetic Properties

scholarly journals Conformation-selective tau monoclonal antibodies inhibit tau pathology in primary neurons and a mouse model of Alzheimer’s disease

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Garrett S. Gibbons ◽  
Soo-Jung Kim ◽  
Qihui Wu ◽  
Dawn M. Riddle ◽  
Susan N. Leight ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Monoclonal Antibodies ◽  
Statistical Significance ◽  
Neuritic Plaque ◽  
Plaque Burden ◽  
Primary Neurons ◽  
Tau Pathology ◽  
Model Of Alzheimer’S Disease

Abstract Background The 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. Methods We 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. Results DMR7 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. Conclusions These 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.

scholarly journals Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer’s Disease Not Evident in Mouse Models

Cell Reports ◽  
2018 ◽  
Vol 22 (3) ◽  
pp. 832-847 ◽  
Author(s):  
Brad A. Friedman ◽  
Karpagam Srinivasan ◽  
Gai Ayalon ◽  
William J. Meilandt ◽  
Han Lin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Microglial Activation ◽  
Expression Profiles

P4-307: IN VIVO 18 F-FLORTAUCIPIR CORRELATES STRONGLY WITH POSTMORTEM ALZHEIMER'S DISEASE TAU PATHOLOGY

2006 ◽  
Vol 14 (7S_Part_30) ◽  
pp. P1573-P1573
Author(s):  
Ruben Smith ◽  
Moa Wibom ◽  
Daria Pawlik ◽  
Elisabet Englund ◽  
Oskar Hansson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Pathology

In vivo neuronal gene editing via CRISPR–Cas9 amphiphilic nanocomplexes alleviates deficits in mouse models of Alzheimer’s disease

2019 ◽  
Vol 22 (4) ◽  
pp. 524-528 ◽  
Author(s):  
Hanseul Park ◽  
Jungju Oh ◽  
Gayong Shim ◽  
Byounggook Cho ◽  
Yujung Chang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Gene Editing ◽  
Neuronal Gene

P1-005: AAV-based paradigm for amyloid and Tau pathology as in vivo model for Alzheimer's disease

2008 ◽  
Vol 4 ◽  
pp. T207-T207
Author(s):  
Tomasz Jaworski ◽  
Ilse Dewachter ◽  
Sebastian Kügler ◽  
Fred van Leuven
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Vivo Model ◽  
Tau Pathology

scholarly journals Monitoring protein aggregation and toxicity in Alzheimer’s disease mouse models using in vivo imaging

Methods ◽  
2011 ◽  
Vol 53 (3) ◽  
pp. 201-207 ◽  
Author(s):  
Tara L. Spires-Jones ◽  
Alix de Calignon ◽  
Melanie Meyer-Luehmann ◽  
Brian J. Bacskai ◽  
Bradley T. Hyman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Aggregation ◽  
Mouse Models ◽  
In Vivo Imaging

scholarly journals In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer’s disease

2010 ◽  
Vol 38 (2) ◽  
pp. 343-351 ◽  
Author(s):  
Masamichi Yokokura ◽  
Norio Mori ◽  
Shunsuke Yagi ◽  
Etsuji Yoshikawa ◽  
Mitsuru Kikuchi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Microglial Activation ◽  
Brain Regions ◽  
Amyloid Deposits
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