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

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.
PMID: 32091331 [PubMed - as supplied by publisher]

Source: Current Alzheimer Research - February 23, 2020 Category: Neurology Authors: Riedel G, Klein J, Niewiadomska G, Kondak C, Schwab K, Lauer D, Magbagbeolu M, Steczkowska M, Zadrozny M, Wydrych M, Cranston A, Melis V, Santos RX, Theuring F, Harrington CR, Wischik CM Tags: Curr Alzheimer Res Source Type: research