1: Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11213-8.

Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines.

Wischik CM, Edwards PC, Lai RY, Roth M, Harrington CR.

Cambridge Brain Bank Laboratory, University Department of Psychiatry, United
Kingdom.

In Alzheimer disease (AD) the microtubule-associated protein tau is redistributed
exponentially into paired helical filaments (PHFs) forming neurofibrillary
tangles, which correlate with pyramidal cell destruction and dementia. Amorphous
neuronal deposits and PHFs in AD are characterized by aggregation through the
repeat domain and C-terminal truncation at Glu-391 by endogenous proteases. We
show that a similar proteolytically stable complex can be generated in vitro
following the self-aggregation of tau protein through a high-affinity binding
site in the repeat domain. Once started, tau capture can be propagated by seeding
the further accumulation of truncated tau in the presence of proteases. We have
identified a nonneuroleptic phenothiazine previously used in man (methylene blue,
MB), which reverses the proteolytic stability of protease-resistant PHFs by
blocking the tau-tau binding interaction through the repeat domain. Although MB
is inhibitory at a higher concentration than may be achieved clinically, the
tau-tau binding assay was used to identify desmethyl derivatives of MB that have
Ki values in the nanomolar range. Neuroleptic phenothiazines are inactive. Tau
aggregation inhibitors do not affect the tau-tubulin interaction, which also
occurs through the repeat domain. Our findings demonstrate that biologically
selective pharmaceutical agents could be developed to facilitate the proteolytic
degradation of tau aggregates and prevent the further propagation of tau capture
in AD.

PMCID: PMC38310