Pharmacogenetic neuronal stimulation increases human tau pathology and trans-synaptic spread of tau to distal brain regions in mice

Schultz, Mark; Gentzel, Renee; Usenovic, Marija; Gretzula, Cheryl A.; Ware, Christopher; Parmentier-Batteur, Sophie; Schachter, Joel B.; Zariwala, Hatim A.

doi:10.1016/j.nbd.2018.07.003

Cited by 39 publications

(45 citation statements)

References 83 publications

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“…The spreading was associated with signs of neurodegeneration in recipient brain regions. Similar results were obtained when AAV‐Tau/DREADD were injected into Mapt −/− mice and treated with CNO (Schultz et al, ), confirming the findings from transgenic mice with localized P301L Tau expression on a Mapt −/− background that endogenous Tau protein is not required for spreading of transgenic Tau (Wegmann et al, ).…”

Section: Aavs To Investigate Ad Mechanismssupporting

confidence: 72%

“…When injected into the ventral hippocampus of naïve, 11-week-old mice, twice daily administration of CNO over 8 weeks resulted in significantly more pronounced Tau pathology in the injected brain areas and spreading of Tau protein to interconnected brain areas when compared to vehicle-treated animals (Schultz et al, 2018). The spreading was associated with signs of neurodegeneration in recipient brain regions.…”

Section: Spreading Of Tau Pathology In Admentioning

confidence: 93%

“…Local injection of AAV‐eGFP‐2A‐huTauP301L into the EC of naïve C57Bl/6 mice resulted in spreading of Tau protein to DG recipient neurons (Wegmann et al, ); Tau protein is released from neurons in an activity dependent manner, as shown by microdialysis paired with electrical stimulation in brains for freely moving mice (Yamada et al, ). In a recent study, Schultz and colleagues followed up on this work and used AAV‐mediated gene expression to study the effects of neuronal activity on spreading of non‐mutant human Tau protein in primary neurons and mice (Schultz et al, ). In this study, full‐length Tau (2N4R) was expressed together with an excitatory designer receptors exclusively activated by a designer drug (DREADD) using rAAV2 and rAAV8 respectively.…”

Section: Aavs To Investigate Ad Mechanismsmentioning

confidence: 99%

“…Treatment with clozapine N‐oxide of cells expressing Tau protein/DREADD resulted in dose‐dependent increase of both neuronal activity (as determined by Ca 2+ imaging) and Tau protein release. When injected into the ventral hippocampus of naïve, 11‐week‐old mice, twice daily administration of CNO over 8 weeks resulted in significantly more pronounced Tau pathology in the injected brain areas and spreading of Tau protein to interconnected brain areas when compared to vehicle‐treated animals (Schultz et al, ). The spreading was associated with signs of neurodegeneration in recipient brain regions.…”

Section: Aavs To Investigate Ad Mechanismsmentioning

confidence: 99%

“…In a recent study, Schultz and colleagues followed up on this work and used AAV-mediated gene expression to study the effects of neuronal activity on spreading of non-mutant humanTau protein in primary neurons and mice (Schultz et al, 2018). In this study, full-length Tau (2N4R) was expressed together with an excitatory designer receptors exclusively activated by a designer drug (DREADD) using rAAV2 and rAAV8…”

Section: Spreading Of Tau Pathology In Admentioning

confidence: 99%

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Adeno‐associated virus‐based Alzheimer's disease mouse models and potential new therapeutic avenues

Ittner

Klugmann

2019

British J Pharmacology

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Alzheimer's disease (AD) is a highly prevalent neurodegenerative condition that presents with cognitive decline. The current understanding of underlying disease mechanisms remains incomplete. Genetically modified mouse models have been instrumental in deciphering pathomechanisms in AD. While these models were typically generated by classical transgenesis and genome editing, the use of adeno‐associated viruses (AAVs) to model and investigate AD in mice, as well as to develop novel gene‐therapy approaches, is emerging. Here, we reviewed literature that used AAVs to study and model AD and discuss potential gene therapy strategies. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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Section: Aavs To Investigate Ad Mechanismssupporting

confidence: 72%

Section: Spreading Of Tau Pathology In Admentioning

confidence: 93%

Section: Aavs To Investigate Ad Mechanismsmentioning

confidence: 99%

Section: Aavs To Investigate Ad Mechanismsmentioning

confidence: 99%

Section: Spreading Of Tau Pathology In Admentioning

confidence: 99%

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Adeno‐associated virus‐based Alzheimer's disease mouse models and potential new therapeutic avenues

Ittner

Klugmann

2019

British J Pharmacology

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AnNoBrainer, An Automated Annotation of Mouse Brain Images using Deep Learning

Peter,

Hrobar,

Navratil

et al. 2024

Neuroinform

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Annotation of multiple regions of interest across the whole mouse brain is an indispensable process for quantitative evaluation of a multitude of study endpoints in neuroscience digital pathology. Prior experience and domain expert knowledge are the key aspects for image annotation quality and consistency. At present, image annotation is often achieved manually by certified pathologists or trained technicians, limiting the total throughput of studies performed at neuroscience digital pathology labs. It may also mean that simpler and quicker methods of examining tissue samples are used by non-pathologists, especially in the early stages of research and preclinical studies. To address these limitations and to meet the growing demand for image analysis in a pharmaceutical setting, we developed AnNoBrainer, an open-source software tool that leverages deep learning, image registration, and standard cortical brain templates to automatically annotate individual brain regions on 2D pathology slides. Application of AnNoBrainer to a published set of pathology slides from transgenic mice models of synucleinopathy revealed comparable accuracy, increased reproducibility, and a significant reduction (~ 50%) in time spent on brain annotation, quality control and labelling compared to trained scientists in pathology. Taken together, AnNoBrainer offers a rapid, accurate, and reproducible automated annotation of mouse brain images that largely meets the experts’ histopathological assessment standards (> 85% of cases) and enables high-throughput image analysis workflows in digital pathology labs.

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Role of dopamine neuron activity in Parkinson's disease pathophysiology

Rademacher,

Nakamura

2024

Experimental Neurology

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Pharmacogenetic neuronal stimulation increases human tau pathology and trans-synaptic spread of tau to distal brain regions in mice

Cited by 39 publications

References 83 publications

Adeno‐associated virus‐based Alzheimer's disease mouse models and potential new therapeutic avenues

Adeno‐associated virus‐based Alzheimer's disease mouse models and potential new therapeutic avenues

AnNoBrainer, An Automated Annotation of Mouse Brain Images using Deep Learning

Role of dopamine neuron activity in Parkinson's disease pathophysiology

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