Doxycycline for Alzheimer's Disease: Fighting β-Amyloid Oligomers and Neuroinflammation

Alzheimer's disease (AD) is the most widespread form of dementia, affecting about 45 million people worldwide. Although the beta-amyloid peptide (A beta) remains the most acknowledged culprit of AD, the multiple failures of A beta-centric therapies call for alternative therapeutic approaches. Conceivably, the complexity of the AD neuropathological scenario cannot be solved with single-target therapies, so multiple-target approaches are needed. Core targets of AD to date are soluble oligomeric A beta species and neuroinflammation, in an intimate detrimental dialogue. A beta oligomers, the most neurotoxic species, appear to induce synaptic and cognitive dysfunction through the activation of glial cells. Anti-inflammatory drugs can prevent the action of A beta oligomers. Neuroinflammation is a chronic event whose perpetuation leads to the continuous release of pro-inflammatory cytokines, promoting neuronal cell death and gross brain atrophy. Among the possible multi-target therapeutic alternatives, this review highlights the antibiotic tetracyclines, which besides antimicrobial activity also have pleiotropic action against amyloidosis, neuroinflammation, and oxidative stress. A particular focus will be on doxycycline (Doxy), a second-generation tetracycline that crosses the bloodbrain barrier more easily and has a safer clinical profile. Doxy emerged as a promising preventive strategy in prion diseases and gave compelling pre-clinical results in mouse models of AD against A beta oligomers and neuroinflammation. This strongly supports its therapeutic potential and calls for deciphering its exact mechanisms of action so as to maximize its effects in the clinic.