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In Alzheimer's disease, soluble oligomers of the amyloid-β peptide (Aβo) trigger a cascade of events that includes abnormal hyperphosphorylation of the protein tau, which is essential for pathogenesis. However, the mechanistic link between these two key pathological proteins remains unclear. Using hippocampal slices, we show here that an Aβo-mediated increase in glutamate release probability causes enhancement of synaptically evoked N-methyl-d-aspartate subtype glutamate receptor (NMDAR)-dependent long-term depression (LTD). We also find that elevated glutamate release probability is required for Aβo-induced pathological hyperphosphorylation of tau, which is likewise NMDAR dependent. Finally, we show that chronic, repeated chemical or optogenetic induction of NMDAR-dependent LTD alone is sufficient to cause tau hyperphosphorylation without Aβo. Together, these results support a possible causal chain in which Aβo increases glutamate release probability, thus leading to enhanced LTD induction, which in turn drives hyperphosphorylation of tau. Our data identify a mechanistic pathway linking the two critical pathogenic proteins of AD.

Original publication




Journal article


Cell Rep

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Alzheimer’s disease, amyloid-β, long-term depression, neurotransmitter release, phosphorylation, tau, Alzheimer Disease, Amyloid beta-Peptides, Animals, Excitatory Postsynaptic Potentials, Female, Glutamic Acid, Hippocampus, In Vitro Techniques, Long-Term Synaptic Depression, Male, Mice, Inbred C57BL, Peptide Fragments, Phosphorylation, Rats, Wistar, Receptors, N-Methyl-D-Aspartate, Synapses, tau Proteins