Fig. 1

The transcription of the amyloid precursor protein (APP) gene leads to the cleavage of APP by α- and γ-secretases in the non-amyloidogenic pathway (plasma membrane) or by β- and γ-secretases in the amyloidogenic pathway (endosomal/lysosomal system), resulting in the extracellular release of amyloid beta (Aβ) peptide. Aβ monomers have the potential to form Aβ oligomers, which can fibrillize into Aβ fibrils under normal physiological conditions. However, under pathological conditions associated with Alzheimer’s disease (AD), Aβ aggregates can induce Tau-dependent neurotoxicity. The transcription and translation of the MAPT gene results in the production of Tau protein, which undergoes diverse post-translational modifications (PTMs) in various forms within the cell. In normal physiological conditions, the microtubule-binding domain (MTBD) of Tau binds to microtubules, thereby stabilizing them. However, in the presence of AD pathology, Tau is hyperphosphorylated, a process that can be influenced by Aβ aggregates, resulting in a reduction in the affinity of Tau for microtubules and rendering them unstable. Furthermore, hyperphosphorylated Tau can form neurofibrillary tangles in the cytoplasm, leading to cellular toxicity