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

Abstract

Summary In Alzheimer’s disease, soluble oligomers of the amyloid-β peptide (Aβ o ) 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 Aβ o -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 Aβ o -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 Aβ o . Together, these results support a possible causal chain in which Aβ o 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.

LTD-inducing low frequency stimulation enhances p-Tau181 and p-Tau217 in an age-dependent manner in live rats

“…Pyramidal neurons in hippocampal CA1 area is one of the fields that p-Tau first appears during Braak stage II of AD (Braak et al ., 2006). Although LFS-triggered tau phosphorylation at Ser396 (Kimura et al ., 2014; Regan et al ., 2015) and Ser202/Thr205 (Taylor et al ., 2021) in hippocampal slices has been previously reported, the effects of LTD-inducing LFS on the expression of p-Tau181, p-Tau217, and p-Tau231, recently proposed to be particularly sensitive markers of early AD, have yet to be described. Having developed stimulation protocols to reliably induce LTD at CA3 to CA1 synapses in live rats (Hu et al ., 2014; O’Riordan et al ., 2018a, b; Ondrejcak et al ., 2019), we confirmed (Hu et al ., 2014) that this protocol (LFS-900, 900 pulses at 1 Hz) triggered a robust persistent form of LTD that, like certain forms of long-term memory formation, is protein synthesis-dependent ( Figure S1 ).…”

“…Previous reports indicate that p-Tau396 can be enhanced by LFS-900 (1 Hz) in acute hippocampal slices (Kimura et al ., 2014; Regan et al ., 2015). In contrast, no change in p-Tau202/205 was triggered by LFS except under the extreme condition of 2 hours LTD induction over a period of 7 days in slice cultures (Taylor et al ., 2021). The experimental conditions used to detect changes in p-Tau396 in hippocampal slices differ very significantly from our live brain studies, including relatively young age and non-physiological temperature.…”

“…Synaptic plasticity mechanisms at excitatory glutamatergic synapses in hippocampus, including those underlying memory function (Connor & Wang, 2016; Magee & Grienberger, 2020). Interestingly, recent studies indicate that LTD induction enhances tau phosphorylation at Ser396 (p-Tau396) (Kimura et al , 2014; Regan et al , 2015) and Ser202/Thr205 (p-Tau202/205) (Taylor et al , 2021) in hippocampus in vitro . It is still unknown whether the expression levels of p-Tau181, p-Tau217, and p-Tau231 can also be enhanced by physiological LTD induction.…”

Long-Term Depression-Inducing Low Frequency Stimulation Enhances p-Tau181 and p-Tau217 in an Age-Dependent Manner in Live Rats

“…Activity-dependent persistent increases and decreases in synaptic strength, long-term potentiation (LTP), and long-term depression (LTD), respectively, are the main forms of synaptic plasticity in the hippocampus and are used to study the neurophysiological substrates of normal learning and memory function [27,28]. Interestingly, recent studies indicate that LTD induction enhances tau phosphorylation at Ser396 (p-Tau396) [29,30] and, when repeated chronically, Ser202/Thr205 (p-Tau202/205) [31] in hippocampus in vitro. It is still unknown whether the expression levels of p-Tau181, p-Tau217, and p-Tau231 can also be enhanced by physiological LTD induction.…”

Synthetic, Cell-Derived, Brain-Derived, and Recombinant β-Amyloid: Modelling Alzheimer’s Disease for Research and Drug Development

“…Most of the studies use synthetic Aβ oligomers to probe the role of tau in AD in acute slices. It was found that sAβ induced LTP block and LTD induction in rodent hippocampal slices via NMDAR-dependent hyperphosphorylation of tau by GSK-3 [ 97 , 98 ]. Oligomers of sAβ also induced tau dysfunction in acute human brain slices [ 99 ], and in all of the studies mentioned, the concentration of peptides was in the 100–500 nM range.…”