Project Summary/Abstract
Alzheimer’s disease (AD) and other tau-related neurodegenerative diseases are characterized by
neurofibrillary tangles which are composed of aggregates of the microtubule associated protein tau. The
accumulation of these tangles contributes to neuronal death and cognitive decline. While millions nationally are
plagued by Alzheimer’s, therapeutic efforts focusing on one of the main hallmarks of the disease, amyloid-beta
(Aβ) plaques, have remained unsuccessful. The lack of correlation between treatment and robust cognitive
improvement during these clinical trials highlight the urgent need to elucidate the preclinical mechanistic
changes driving disease manifestation. The physiological roles of tau include the stabilization of microtubules,
and bundling of F-actin filaments. While tau-microtubule interactions are well-studied, tau interactions with F-
actin are more poorly understood, but are reported to drive the development of pathological species such as
Hirano bodies, actin inclusions found in AD brains and other tauopathies. Tau can form other functional or
pathological interactions, including recently reported binding to post-synaptic density protein 95 (PSD-95),
which was shown to interfere with functional hyperemia and promote the neurotoxicity induced by amyloid-
beta. Tau is also modified by a rich array of post-translational modifications (PTMs), which have been shown to
alter normal and pathological tau interactions. This proposal will test the central hypothesis that tau PTMs
within the critical PHF6 and PHF6* hexapeptide motifs modulate tau interactions with binding partners
such as PSD-95 and F-actin and thereby contribute to the role of these partners, as well of changes in
tau structure and function, in specific processes associated with disease manifestation. Using
biophysical methods, including nuclear magnetic resonance (NMR) spectroscopy, I will characterize the
interactions of tau with F-actin and PSD-95 and assess the effects of PTMs located within the PHF6 and
PHF6* motifs on these interactions. Our structural observations, complemented by functional studies
performed both by myself and our collaborators, will contribute to a deeper understanding of the mechanistic
changes in tau behavior that drive the manifestation of AD and other tauopathies, and facilitate the
development of novel therapeutic targets for the treatment of tau-based neurodegeneration.