Tau Aggregation Inhibiting Peptides as Potential Therapeutics for Alzheimer Disease

Abstract

Alzheimer disease (AD) is the most common progressive neurodegenerative disorder. AD causes enormous personal and economic burden to society as currently only limited palliative therapeutic options are available. The pathological hallmarks of the disease are extracellular plaques, composed of fibrillar amyloid-β (Aβ), and neurofibrillary tangles inside neurons, composed of Tau protein. Until recently, the search for AD therapeutics was focussed more on the Aβ peptide and its pathology, but the results were unsatisfying. As an alternative, Tau might be a promising therapeutic target as its pathology is closely correlated to clinical symptoms. In addition, pathological Tau aggregation occurs in a large group of diseases, called Tauopathies, and in most of them Aβ aggregation does not play a role in disease pathogenesis. The formation of Tau aggregates is triggered by two hexapeptide motifs within Tau; PHF6* and PHF6. Both fragments are interesting targets for the development of Tau aggregation inhibitors (TAI). Peptides represent a unique class of pharmaceutical compounds and are reasonable alternatives to chemical substances or antibodies. They are attributed with high biological activity, valuable specificity and low toxicity, and often are developed as drug candidates to interrupt protein-protein interactions. The preparation of peptides is simple, controllable and the peptides can be easily modified. However, their application may also have disadvantages. Currently, a few peptide compounds acting as TAI are described in the literature, most of them developed by structure-based design or phage display. Here, we review the current state of research in this promising field of AD therapy development.

Keywords: Aggregation inhibitors; Alzheimer disease; Peptides; Tau; Tauopathies.

Fig. 1

(D)-Peptide generation for application as Tau aggregation inhibitors (TAI). A Methods for identification of TAI peptides. (1) Phage display procedure. Target molecule immobilized on solid phase is incubated with a phage display library. Specific library phages bind to the target molecule and unbound phages are removed by washing. Bound library phages are eluted and then amplified in E. coli. Finally, the amplified phages are used in the next biopanning round. After serval rounds, phage DNA can be analyzed to obtain therapeutic peptides. (2) Principle of mirror image phage display. Target molecule is used as D-enantiomer in the selection process. Biopanning is performed with phages presenting L-peptides. Finally, the D-enantiomeric form of the selected L-peptide is synthesized. (3) Another method of peptide identification offers in silico modelling using a variety of software. B Binding sites of established peptides summarized in this article