Alzheimers Disease & Dementia

Biography

Biography: Claude Michel Wischik

Abstract

Following our discovery of a fragment from the repeat domain of tau protein as a structural constituent of the PHF-core in Alzheimer’s disease, we developed an assay that captured several key features of the aggregation process.  Tau-tau binding through the core tau fragment can be blocked by variants of the methylthioninium (MT) moiety found to dissolve proteolytically stable PHFs isolated from AD brain. The PHF-core tau fragment induces templated proteolytic processing of normal tau, is inherently capable of auto-catalytic self-propagation, can be assembled into characteristic PHFs in vitro, and assembly can be blocked by MT-like compounds. The potential utility of these compounds for reduction of pathology and reversal of behavioral deficits was confirmed in tau transgenic mouse models using a stable reduced form of the molecule (hydromethylthionine) which is better absorbed and tolerated. Similar benefits have been shown in a synuclein aggregation assay in vitro and in a transgenic synuclein mouse model. These findings led to the first clinical trials to test hydro methyl thionine therapy in Alzheimer’s disease as a way to block this cascade. Although hydro methyl thionine appears to be beneficial as monotherapy, there is a negative interaction with standard symptomatic treatments for the AD which had now been confirmed in a tau transgenic mouse model. In clinical practice, hydro methyl thionine therapy will be optimally useful as first-line monotherapy. The efficacy of hydro methyl thionine as a-synuclein aggregation inhibitor suggests that it may also be useful in Parkinson’s disease and Dementia of the Lewy Body type.