Doxycycline interferes with tau amyloid aggregation abolishing its associated neuronal toxicity

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 different isoforms of tau protein in a dose-dependent manner, remodeling the resultant species. Furthermore, doxycycline interacts with tau microtubule-binding domain preventing its aggregation. 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.

C9‐Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α‐Synuclein Aggregation and Neuroinflammation in Parkinson's Disease Degeneration

“…[16,23] Additionally, our previous research on the subject pointed to the importance of maintaining a specific structural motif in tetracyclines, which is crucial to interact with cross-β structures characteristic of amyloid aggregates of α-Syn. [19] The substitution at the C 9 position was already studied in the tetracycline class to modulate their antibiotic activity; [28][29][30][31] however, nothing was reported about 4-des-N-dimethylamino tetracyclines with substituents at the C 9 position. Indeed, to prepare these new analogs, the aromatic D ring appears to be well suited to achieve aromatic electrophilic substitutions at either positions C 9 or C 7 .…”

“…Fluorescence emission was recorded from 410 to 610 nm using a Fluoromax-4 spectrofluorometer. [19] Additional discussion and UV-absorbance and fluorescence spectra are available in supporting information.…”

“…[9][10][11] In particular, DOX was able to prevent or modulate the aggregation process of α-Syn, [12,13] reduce oxidative stress, repress neuroinflammatory processes, [13,14] in either ex vitro and in vitro assays as well as in vivo models that mimic PD neurodegenerative events. [12,[15][16][17] These pieces of evidence, along with DOX's ability to cross the blood-brain barrier [18] and its safe toxicological profile make this tetracycline a good candidate for neuroprotection in PD but also for Alzheimer's disease, [19,20] Huntington's disease [11] and other neurodegenerative disorders. [10,17,21] However, using DOX for long-term treatment of patients may lead to potential antibiotic resistance and microbiota disruption.…”

Possible Treatments for COVID Vaccine Induced Prion Disease

“…Doxycycline can penetrate the blood brain barrier [24]. This antibiotic blocks tau amyloid aggregation and its associated neuronal toxicity in vitro [25,26]. Doxycycline can inhibit the aggregation of Aβ42 amyloid fibrils and disassemble mature amyloid fibrils [27].…”