Abstract
Tauopathies are neurodegenerative disorders with increasing incidence and still without cure. The extensive time required for development and approval of novel therapeutics highlights the need for testing and repurposing known safe molecules. Since doxycycline impacts α-synuclein aggregation and toxicity, herein we tested its effect on tau. We found that doxycycline reduces amyloid aggregation of the 2N4R and K18 isoforms of tau protein in a dose-dependent manner. Furthermore, in a cell free system doxycycline also prevents tau seeding and in cell culture reduces toxicity of tau aggregates. Overall, our results expand the spectrum of action of doxycycline against aggregation-prone proteins, opening novel perspectives for its repurposing as a disease-modifying drug for tauopathies.
Highlights
Tauopathies are a group of neurodegenerative diseases characterized by clinical heterogeneity and progressive deposition of amyloid aggregates of abnormally hyper-phosphorylated tau protein within specific brain regions (Lee et al, 2001)
The ability of doxycycline to interfere with 2N4R tau aggregation was studied in the presence of heparin, a classical model system which induces the formation of tau fibrillary elements similar to neurofibrillary tangles (NFT) (Goedert et al, 1996; Pérez et al, 2002)
We monitored the extent of tau fibril formation in the absence or presence of doxycycline using Congo Red (CR) binding assay, which served as a complementary measure to detect the presence of amyloid fibril structures in tau samples (Klunk et al, 1989, 1999)
Summary
Tauopathies are a group of neurodegenerative diseases characterized by clinical heterogeneity and progressive deposition of amyloid aggregates of abnormally hyper-phosphorylated tau protein within specific brain regions (Lee et al, 2001). Tau is the major microtubule associated protein (MAP), and plays a crucial role in regulating its dynamics, concomitant axonal transport and neurite outgrowth (Iqbal et al, 2010). Six tau isoforms are expressed in the human brain as a consequence of the alternative splicing. This in turn, leads to the expression of the tau proteins 0N3R, 1N3R, 2N3R, 0N4R, 1N4R, and 2N4R, N being the number of 29 amino acid inserts in the N-terminal region of tau and R the microtubule binding repeats (Iqbal et al, 2010).
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