scholarly journals Neuroprotection of cholinergic neurons with tau aggregation inhibitor and rivastigmine in L1 mice with Alzheimer’s‐like tauopathy

2020 ◽  
Vol 16 (S3) ◽  
Author(s):  
Marta Steczkowska ◽  
Maciej Zadrozny ◽  
Malgorzata Wydrych ◽  
Anna Gasiorowska ◽  
Wiktor Niewiadomski ◽  
...  
Keyword(s):  
Cholinergic Neurons ◽  
Aggregation Inhibitor ◽  
Tau Aggregation

scholarly journals The Rational Discovery of a Tau Aggregation Inhibitor

Biochemistry ◽  
2018 ◽  
Vol 57 (42) ◽  
pp. 6099-6107 ◽  
Author(s):  
David W. Baggett ◽  
Abhinav Nath
Keyword(s):  
Aggregation Inhibitor ◽  
Tau Aggregation

[P1-126]: USE OF THE TAU AGGREGATION INHIBITOR LMTM TO EVALUATE OLIGOMER DETECTION CAPACITY OF WESTERN BLOT AND MASS SPECTROMETRY

2017 ◽  
Vol 13 (7S_Part_5) ◽  
pp. P290-P290
Author(s):  
Arnaud François ◽  
Valérie Pasteau ◽  
Rodolphe Billiras ◽  
Karine Albinet ◽  
Gaëlle Rollin-Jego ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Western Blot ◽  
Aggregation Inhibitor ◽  
Tau Aggregation

scholarly journals Mechanisms of Anticholinesterase Interference with Tau Aggregation Inhibitor Activity in a Tau-Transgenic Mouse Model

2020 ◽  
Vol 17 (3) ◽  
pp. 285-296 ◽  
Author(s):  
Gernot Riedel ◽  
Jochen Klein ◽  
Grazyna Niewiadomska ◽  
Constantin Kondak ◽  
Karima Schwab ◽  
...  
Keyword(s):  
Mouse Model ◽  
Glutamate Release ◽  
Symptomatic Treatment ◽  
Transgenic Mouse Model ◽  
Wild Type ◽  
Mitochondrial Complex ◽  
Tau Pathology ◽  
Complex Iv ◽  
Aggregation Inhibitor ◽  
Tau Aggregation

Background: Symptomatic treatments of Alzheimer’s Disease (AD) with cholinesterase inhibitors and/or memantine are relatively ineffective and there is a need for new treatments targeting the underlying pathology of AD. In most of the failed disease-modifying trials, patients have been allowed to continue taking symptomatic treatments at stable doses, under the assumption that they do not impair efficacy. In recently completed Phase 3 trials testing the tau aggregation inhibitor leuco-methylthioninium bis (hydromethanesulfonate) (LMTM), we found significant differences in treatment response according to whether patients were taking LMTM either as monotherapy or as an add-on to symptomatic treatments. Methods: We have examined the effect of either LMTM alone or chronic rivastigmine prior to LMTM treatment of tau transgenic mice expressing the short tau fragment that constitutes the tangle filaments of AD. We have measured acetylcholine levels, synaptosomal glutamate release, synaptic proteins, mitochondrial complex IV activity, tau pathology and Choline Acetyltransferase (ChAT) immunoreactivity. Results: LMTM given alone increased hippocampal Acetylcholine (ACh) levels, glutamate release from synaptosomal preparations, synaptophysin levels in multiple brain regions and mitochondrial complex IV activity, reduced tau pathology, partially restored ChAT immunoreactivity in the basal forebrain and reversed deficits in spatial learning. Chronic pretreatment with rivastigmine was found to reduce or eliminate almost all these effects, apart from a reduction in tau aggregation pathology. LMTM effects on hippocampal ACh and synaptophysin levels were also reduced in wild-type mice. Conclusion: The interference with the pharmacological activity of LMTM by a cholinesterase inhibitor can be reproduced in a tau transgenic mouse model and, to a lesser extent, in wild-type mice. Long-term pretreatment with a symptomatic drug alters a broad range of brain responses to LMTM across different transmitter systems and cellular compartments at multiple levels of brain function. There is, therefore, no single locus for the negative interaction. Rather, the chronic neuronal activation induced by reducing cholinesterase function produces compensatory homeostatic downregulation in multiple neuronal systems. This reduces a broad range of treatment responses to LMTM associated with a reduction in tau aggregation pathology. Since the interference is dictated by homeostatic responses to prior symptomatic treatment, it is likely that there would be similar interference with other drugs tested as add-on to the existing symptomatic treatment, regardless of the intended therapeutic target or mode of action. The present findings outline key results that now provide a working model to explain interference by symptomatic treatment.

scholarly journals Structural Determinants of Tau Aggregation Inhibitor Potency

2013 ◽  
Vol 288 (45) ◽  
pp. 32599-32611 ◽  
Author(s):  
Kelsey N. Schafer ◽  
Katryna Cisek ◽  
Carol J. Huseby ◽  
Edward Chang ◽  
Jeff Kuret
Keyword(s):  
Structural Determinants ◽  
Aggregation Inhibitor ◽  
Tau Aggregation

Complex Disposition of Methylthioninium Redox Forms Determines Efficacy in Tau Aggregation Inhibitor Therapy for Alzheimer’s Disease

2014 ◽  
Vol 352 (1) ◽  
pp. 110-118 ◽  
Author(s):  
Thomas C. Baddeley ◽  
Jennifer McCaffrey ◽  
John M. D. Storey ◽  
John K. S. Cheung ◽  
Valeria Melis ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inhibitor Therapy ◽  
Aggregation Inhibitor ◽  
Tau Aggregation ◽  
Redox Forms

scholarly journals PE859, a Novel Tau Aggregation Inhibitor, Reduces Aggregated Tau and Prevents Onset and Progression of Neural Dysfunction In Vivo

PLoS ONE ◽  
2015 ◽  
Vol 10 (2) ◽  
pp. e0117511 ◽  
Author(s):  
Michiaki Okuda ◽  
Ichiro Hijikuro ◽  
Yuki Fujita ◽  
Xiaofeng Wu ◽  
Shinichi Nakayama ◽  
...  
Keyword(s):  
Aggregation Inhibitor ◽  
Tau Aggregation ◽  
Neural Dysfunction
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