Intraneuronal Aβ accumulation causes tau hyperphosphorylation via endolysosomal leakage.

Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) peptide plaques and intracellular neurofibrillary tangles formed by hyperphosphorylated tau. Many attempts have been made to clarify the link between Aβ and tau in the pathogenesis, but conclusive data describing a pathway for this connection are still lacking. We developed a neuronal model of Aβ-induced toxicity and studied downstream effects of intraneuronal Aβ42 accumulation on tau hyperphosphorylation using confocal microscopy and live cell imaging. Aβ42 added to the medium was endocytosed into neurons, inducing the formation of endolysosomal protofibrils and endolysosomal leakage, which in turn promoted tau hyperphosphorylation. Asparaginyl endopeptidase (AEP) was released from the disrupted lysosomes, and inhibition of this peptidase activity reduced tau hyperphosphorylation. The data suggest a mechanism of AD in which Aβ42 accumulates and aggregates gradually in neurons over time, leading to endolysosomal leakage and release of AEP, which subsequently triggers tau hyperphosphorylation. Aβ42 endocytosis leads to its endolysosomal accumulation in neurons over time. Aβ42 polymerizes into protofibrils and causes endolysosomal leakage. Tau hyperphosphorylation is induced by endolysosomal asparagine endopeptidase leakage. Tau hyperphosphorylation is inhibited by an asparagine endopeptidase inhibitor.