Long-term depression links amyloid-β to the pathological hyperphosphorylation of tau
| Autor: | Henry B. C. Taylor, Nigel J. Emptage, Alexander Jeans |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Tau protein Glutamic Acid Hyperphosphorylation tau Proteins amyloid-β In Vitro Techniques Hippocampal formation Hippocampus Receptors N-Methyl-D-Aspartate General Biochemistry Genetics and Molecular Biology Pathogenesis Alzheimer Disease Report Animals long-term depression tau Rats Wistar Long-term depression Amyloid beta-Peptides biology phosphorylation Chemistry Long-Term Synaptic Depression Glutamate receptor Excitatory Postsynaptic Potentials Peptide Fragments Mice Inbred C57BL neurotransmitter release Synapses biology.protein Phosphorylation NMDA receptor Female Alzheimer’s disease Neuroscience |
| Zdroj: | Cell Reports |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2021.109638 |
| Popis: | Summary 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. Graphical abstract Highlights • Amyloid-β oligomers mediate increased neuronal glutamate release probability (Pr) • Increased Pr enhances the magnitude of hippocampal long-term depression (LTD) • Enhanced LTD drives the accumulation of pathologically hyperphosphorylated tau • This mechanism links the two key pathogenic proteins of Alzheimer’s disease How amyloid-β triggers the recruitment and hyperphosphorylation of tau in Alzheimer’s disease remains unclear. Taylor et al. show that an oligomeric amyloid-β-mediated increase in glutamate release probability enhances the magnitude of Hebbian long-term depression (LTD) in the hippocampus, which in turn drives the accumulation of pathologically hyperphosphorylated tau. |
| Databáze: | OpenAIRE |
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