Anneke Van der Jeugd

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

This report describes the behavioral and electrophysiological analysis of regulatable transgenic mice expressing mutant repeat domains of human Tau (TauRD). Mice were generated to express TauRD in two forms, differing in their propensity for β-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 Alzheimers disease (aggregation, missorting, hyperphosphorylation, synaptic and neuronal loss), indicating that the β-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 TauRD on or off. The mice are normal in neuromotor tests. However, pro-aggregant TauRD mice are strongly impaired in memory and show pronounced loss of long-term potentiation (LTP), suggesting that Tau aggregation specifically perturbs these brain functions. Remarkably, when the expression of human pro-aggregant TauRD is switched on for ∼10 months and off for ∼4 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 TauRD constitutes the main toxic insult for memory and LTP, rather than the aggregates as such.

From tau phosphorylation to tau aggregation: what about neuronal death?

Tau pathology is characterized by intracellular aggregates of abnormally and hyperphosphorylated tau proteins. It is encountered in many neurodegenerative disorders, but also in aging. These neurodegenerative disorders are referred to as tauopathies. Comparative biochemistry of the tau aggregates shows that they differ in both tau isoform phosphorylation and content, which enables a molecular classification of tauopathies. In conditions of dementia, NFD (neurofibrillary degeneration) severity is correlated to cognitive impairment and is often considered as neuronal death. Using tau animal models, analysis of the kinetics of tau phosphorylation, aggregation and neuronal death in parallel to electrophysiological and behavioural parameters indicates a disconnection between cognition deficits and neuronal cell death. Tau phosphorylation and aggregation are early events followed by cognitive impairment. Neuronal death is not observed before the oldest ages. A sequence of events may be the formation of toxic phosphorylated tau species, their aggregation, the formation of neurofibrillary tangles (from pre-tangles to ghost tangles) and finally neuronal cell death. This sequence will last from 15 to 25 years and one can ask whether the aggregation of toxic phosphorylated tau species is a protection against cell death. Apoptosis takes 24 h, but NFD lasts for 24 years to finally kill the neuron or rather to protect it for more than 20 years. Altogether, these data suggest that NFD is a transient state before neuronal death and that therapeutic interventions are possible at that stage.

Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model

One of the greatest challenges for the treatment of neurodegenerative disease is crossing the blood-brain barrier. Nisbet et al. demonstrate that non-invasive scanning ultrasound increases the delivery of tau-specific single-chain antibody fragments across the blood-brain barrier and into neurons of tau transgenic mice, reducing anxiety-like behaviour and tau pathology.

Progressive age-related cognitive decline in tau mice.

Age-related cognitive decline and neurodegenerative diseases are a growing challenge for society. Accumulation of tau pathology has been proposed to partially contribute to these impairments. This study provides a behavioral characterization during aging of transgenic mice bearing tau mutations. THY-Tau22 mice were evaluated at ages wherein tau neuropathology in this transgenic mouse model is low (3-4 months), moderate (6-7 months), or extensive (>9 months). Spatial memory was found to be impaired only after 9 months of age in THY-Tau22 mice, whereas non-spatial memory was affected as early as 6 months, appearing to offer an opportunity for assessing potential therapeutic agents in attenuating or preventing tauopathies through modulation of tau kinetics.

Impulsivity, decreased social exploration, and executive dysfunction in a mouse model of frontotemporal dementia

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder, a major subset of which is characterized by the accumulation of abnormal forms of the protein tau, leading to impairments in motor functions as well as language and behavioral alterations. Tau58-2/B mice express human tau with the P301S mutation found in familial forms of FTLD in neurons. By assessing three age cohorts of Tau58-2/B mice in a comprehensive behavioral test battery, we found that the tauopathy animals showed age-dependent signs of impulsivity, decreased social exploration and executive dysfunction. The deficit in executive function was first limited to decreased spatial working memory, but with aging this was extended to impaired instrumental short-term memory. Tau pathology was prominent in brain regions underlying these behaviors. Thus, Tau-58-2/B mice recapitulate neurological deficits of the behavioral variant of frontotemporal dementia (bvFTD), presenting them as a suitable model to test therapeutic interventions for the amelioration of this variant.