Résumé
Alzheimer's disease (AD) is a neurodegenerative disease and the most common form of dementia, neuropathologically characterized by senile plaques and neurofibrillary tangles (NFTs). Early advancements in AD research led to the identification of amyloid-β, derived from the cleavage of the amyloid precursor protein (APP), as the main component of senile plaques, and Tau protein as the main component of NFTs. The amyloid pathology has long been considered the predominant factor in AD, known as the amyloid hypothesis. However, recent advances have redefined this initial hypothesis. In this review, we demonstrate that AD is a complex, multifactorial pathology involving other pathophysiological mechanisms such as inflammation, oxidative stress, and the alteration of fundamental cellular processes like autophagy and mitochondrial function. Furthermore, we highlight that AD is a multiproteinopathy, characterized by the accumulation and dissemination of amyloid peptide and Tau protein in the brain, suggesting a potential synergy between these two pathologies. Drawing on a substantial body of human data and disease models, we highlight the latest evidence of the complex interaction between Aβ and Tau, explaining the failures of therapies targeting only Aβ or Tau. Consequently, we have developed a new AD model in zebrafish, allowing us to study the in vivo interaction between Tau and Aβ and enabling the screening of combined therapies targeting both proteinopathies simultaneously.