Combined Plasma and Cerebrospinal Fluid Signature for the Prediction of Midterm Progression From Mild Cognitive Impairment to Alzheimer Disease

“…To assess activation of programmed cell death within the spinal cord, we observed levels of cleaved capase-3 by Western blotting; levels in C9BAC and Ntg mice did not differ significantly (Fig S2F). Recent studies have demonstrated cortical hyperexcitability in patients with C9ORF72 -ALS using transcranial magnetic stimulation [36]. Therefore, we next asked whether neurons from neonatal (P4-P5) C9BAC mice showed altered electrophysiological characteristics, targeting the two main excitatory projection neurons in layer 5 (L5) of motor cortex for analysis, pyramidal tract (PT)-type, which include corticospinal neurons, and intratelencephalically projecting (IT)-type neurons, which include corticocortical neurons [37]…”

Section: Resultsmentioning

confidence: 99%

Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice

Peters

Cabrera

Tran

et al. 2015

Neuron

224

237

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Summary A non-coding hexanucleotide repeat expansion in the C9ORF72 gene is the most common mutation associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Patients harboring this expansion develop several unique histopathological hallmarks, including intranuclear foci composed of either sense or antisense RNA transcripts from the expanded repeats and dipeptide repeat proteins generated by non-canonical translation of the expanded RNA transcripts. To further investigate the pathological role of C9ORF72 in these diseases, we generated a line of mice carrying a bacterial artificial chromosome containing exons 1 to 6 of the human C9ORF72 gene with approximately 500 repeats of the GGGGCC motif. The mice showed no overt behavioral phenotype but recapitulated distinctive histopathological features that are the hallmark of C9ORF72 ALS/FTD, including sense and antisense intranuclear RNA foci and poly(glycine-proline) dipeptides repeat proteins. Finally, using a synthetic microRNA that targets human C9ORF72 in cultures of primary cortical neurons from the C9BAC mice, we have attenuated expression of the C9BAC transgene and the poly(GP) dipeptides. The C9ORF72 BAC transgenic mice will be a valuable tool in the study of ALS/FTD pathobiology and therapy.

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“…Several reports have now demonstrated that KORD silences neurons in vivo and that this silencing affects behaviors in a manner consistent with neuronal silencing (52) (54, 55). Additionally, as KORD is activated by salvinorin B, it can be used in combination with the clozapine-N-oxide (CNO)-based DREADDs (53, 56) for the multiplexed chemogenetic modulation of signaling and behavior (52, 57). Thus, based on high-resolution structures of KOR, a new DREADD-based chemogenetic tool has been developed that should be broadly useful for interrogating neural circuits and signaling.…”

Section: New Insights Into the Structure And Function Of Opioid Recepmentioning

confidence: 99%

New Technologies for Elucidating Opioid Receptor Function

Bruchas

Roth

2016

Trends in Pharmacological Sciences

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Recent advances in technology, including high resolution crystal structures of opioid receptors, novel chemical tools, and new genetic approaches have provided an unparalleled pallette of tools for deconstructing opioid receptor actions in vitro and in vivo. Here we provide a brief description of our understanding of opioid receptor function from both molecular and atomic perspectives, as well as their role in neural circuits in vivo. We then show how insights into the molecular details of opioid actions can facilitate the creation of functionally-selective (biased) and photoswitchable opioid ligands. Finally, we describe how newly engineered opioid receptor-based chemo- and optogenetic tools, and new mouse lines are expanding and transforming our understanding of opioid function and, perhaps, paving the way for new therapeutics.

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Combined Plasma and Cerebrospinal Fluid Signature for the Prediction of Midterm Progression From Mild Cognitive Impairment to Alzheimer Disease

Cited by 74 publications

References 70 publications

Models for predicting risk of dementia: a systematic review

Models for predicting risk of dementia: a systematic review

Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice

New Technologies for Elucidating Opioid Receptor Function

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