Tau Pathology and Future Therapeutics

Abstract

The current review discusses microtubules and tau in the healthy brain and move on to the underling pathology of Alzheimer's disease (AD) with emphasis on tau and neurofibrillary tangles. Tangles have been associated with cognitive dysfunction causing neurodegeneration in the absence of plaques. AD, the most abundant tauopathy is characterized by β-amyloid plaques and tau tangles. An abundance of tau inclusions, in the absence of β-amyloid deposits, defines Pick's disease (frontotemporal lobar degeneration), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and other diseases. Our own focused research is on activity-dependent neuroprtective protein (ADNP). Our findings show that ADNP-deficiency leads to tauopathy which is inhibited by the ADNP derived drug candidate, davunetide (originally known as NAP). The current review further describes tau as a potential diagnostic marker followed by drug candidates that are aimed at fighting tau pathology. A recent historical perspective is the final comment of the manuscript. This paper is not a comprehensive review of the literature rather it gives my own point of view in the face of many publications and a great unmet need for future therapeutics. It is hoped that davunetide, a most advanced drug in clinical development will rapidly advance as a first effective treatment for a number of brain disorders broadly categorized as frontotemporal dementia (FTD) and serve as a prototype for future therapeutic development toward modification and remedy of currently intractable neurodegenerative diseases.

Clioquinol rescues Parkinsonism and dementia phenotypes of the tau knockout mouse

“…The link was supported by pathological findings including the interaction between α-synuclein and tau, and the presence of tau in the Lewy bodies of typical PD (Lei et al, 2010;Arima et al, 1999). Furthermore, tau mutations cause atypical PD syndromes, such as progressive supranuclear palsy, and corticobasal degeneration (Gozes, 2010). While the hyperphosphorylation of tau causes toxicity (Morris et al, 2011), increasing evidence also supports a possible role for functional loss of tau protein in both diseases, as soluble tau is reduced in the affected regions in both disorders (Lei et al, 2012;Kosik et al, 1989;Zhukareva et al, 2001).…”

“…Tau protein is extensively implicated in the pathogenesis of AD and considered as a potential drug target (Gozes, 2010). Recent genomewide association studies identified a significant association between the MAPT locus and sporadic PD (Lei et al, 2010;Nalls et al, 2014), indicating a possible pathological link between tau and PD.…”

Proposal for Alzheimer’s diagnosis using molecular buffer and bus network

“…Recent studies show tau as a potential diagnostic marker and a candidate for change and maintenance via drug application. [53][54][55] In this work, we propose the future design of Alzheimer's therapy in that the tangle protein and molecular motor can be trapped, transported, and received into the optical waveguide by optical tweezers. By utilizing the reasonable optical pulse input power, the dynamic tweezers can be controlled and stored within the system before reaching the final destination via the molecular buffer and bus network.…”

VIP–PACAP 2010: My Own Perspective on Modulation of Cognitive and Emotional Behavior

“…This selective review on VIP-PACAP-ADNP-NAP that highlights the current issue of the Journal of Molecular Neuroscience paves the path to new and original research. Our additional comprehensive reviews are accessible for perspective reading (Gozes 2007(Gozes , 2008Gozes 2010;Gozes et al 2005;Gozes et al 2009). New and exciting findings will be presented at the forthcoming VIP-PACAP and related peptides meeting in Eilat, Israel, 2011.…”