Long-term depression links amyloid-β to the pathological hyperphosphorylation of tau.

Henry B C Taylor,Nigel J Emptage,Alexander F Jeans

doi:10.1016/j.celrep.2021.109638

Henry B C Taylor, Nigel J Emptage + Show 1 more

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https://doi.org/10.1016/j.celrep.2021.109638

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Journal: Cell Reports	Publication Date: Aug 1, 2021
Citations: 18	License type: cc-by

Affiliation: University of Oxford

Abstract

SummaryIn 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.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia, with approximately 5.8 million people currently living with the disease in the United States alone
Abo enhance the probability of neurotransmitter release at CA3-CA1 synapses We carried out most of our experiments in organotypic hippocampal slices because they are amenable to the chronic manipulations used in this study (Gogolla et al, 2006)
We monitored the rate of stimulus-evoked dye unloading, which is a reliable indicator of probability of evoked release (Zakharenko et al, 2001), at individual CA3-CA1 synapses, finding that it was increased following Abo exposure (average time constant of fluorescence decay (t) per punctum: control, 400.5 ± 14.6 s, n = 217 puncta from 6 slices; Abo, 268.3 ± 7.0 s, n = 283 puncta from 6 slices) (Figures 1B–1E)

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia, with approximately 5.8 million people currently living with the disease in the United States alone. The dominant hypothesis explaining AD pathogenesis, the amyloid cascade hypothesis, proposes that changes in the level and/or activity of Ab, in particular the accumulation of toxic small, soluble oligomers of Ab (Abo), trigger a cascade of events, including pathological changes in tau, that drive disease development (Hardy and Higgins, 1992). Despite nearly 30 years having passed since the amyloid hypothesis was published, the mechanism by which the two signature proteins of AD co-operate to bring about pathogenesis remains a critical knowledge gap in the field (Pickett et al, 2019). It is still not known how Ab recruits tau or how tau recruitment might lead to its hyperphosphorylation

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