Tau-Induced Defects in Synaptic Plasticity, Learning, and Memory Are Reversible in Transgenic Mice after Switching Off the Toxic Tau Mutant

Abstract

This report describes the behavioral and electrophysiological analysis of regulatable transgenic mice expressing mutant repeat domains of human Tau (Tau RD ). Mice were generated to express Tau RD in two forms, differing in their propensity for ␤-structure and thus in their tendency for aggregation ("pro-aggregant" or "anti-aggregant") (Mocanu et al., 2008). Only pro-aggregant mice show pronounced changes typical for Tau pathology in Alzheimer's disease (aggregation, missorting, hyperphosphorylation, synaptic and neuronal loss), indicating that the ␤-propensity and hence the ability to aggregate is a key factor in the disease. We now tested the mice with regard to neuromotor parameters, behavior, learning and memory, and synaptic plasticity and correlated this with histological and biochemical parameters in different stages of switching Tau RD on or off. The mice are normal in neuromotor tests. However, pro-aggregant Tau RD mice are strongly impaired in memory and show pronounced loss of long-term potentiation (LTP), suggesting that Tau aggregation specificallyperturbsthesebrainfunctions.Remarkably,whentheexpressionofhumanpro-aggregantTau RD isswitchedonforϳ10monthsand off for ϳ4 months, memory and LTP recover, whereas aggregates decrease moderately and change their composition from mixed human plus mouse Tau to mouse Tau only. Neuronal loss persists, but synapses are partially rescued. This argues that continuous presence of amyloidogenic pro-aggregant Tau RD constitutes the main toxic insult for memory and LTP, rather than the aggregates as such.

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

“…DOX also fully reversed the abnormal immunostaining with PHF1 (Fig 4D–F). This finding suggests that the increased PHF1 and HT7 immunoreactivities in hTau‐A152T (L1) mice reflect the accumulation of soluble tau species rather than insoluble tau aggregates, as insoluble tau aggregates persisted even after the suppression of human tau expression in other hTau transgenic models 31, 36.…”

“…However, both hTau‐A152T and hTau‐WT mice had age‐dependent increases in synaptic transmission strength and decreases in paired‐pulse facilitation at the mossy fiber/CA3 pyramidal cell synapse. In contrast, synaptic transmission and facilitation were unaltered or reduced at this synapse in hTau mice bearing FTDP‐17 mutations (P301L and ∆K280) that strongly promote tau aggregation 36, 78, 79, 80, 81. Whether and how these phenotypic differences relate to specific conformations and assemblies of tau 82 remains to be determined.…”

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…Long term potentiation (LTP), a measure of synaptic plasticity, is thought to be a mechanism underlying learning and memory. In mouse models of AD and HD, neurons derived from affected brain regions have defective LTP 25,26 . Furthermore, the activation of extrasynaptic NMDARs in a mouse model of AD promotes ß-secretase cleavage of APP, which results in increased levels of Aβ that are directly correlated with the severity of the cognitive deficit 27 .…”

“…Increased extrasynaptic NR2B-containing NMDARs 18,19 Increased phosphorylation of NMDARs 20,22 Affected neurons have defective LTP 25,26 Increased Ca 2+ influx 18 Defects in mitochondrial trafficking 18 …”

Brain 5‐lipoxygenase over‐expression worsens memory, synaptic integrity, and tau pathology in the P301S mice

“…As learning and memory task responses are known to be directly modulated by synaptic function and integrity, next we assessed two well‐established synaptic markers, synaptophysin, and PSD‐95 (Hoover et al ., 2010; Sydow et al ., 2011). Compared with P301S controls, the same mice over‐expressing 5LO displayed decreased levels of the presynaptic marker synaptophysin, while no differences were seen in levels of PSD‐95, indicating that 5LO can influence synaptic integrity particularly at the presynaptic level.…”