Motor and cognitive deficits in aged tau knockout mice in two background strains

Abstract

BackgroundWe recently reported that Parkinsonian and dementia phenotypes emerge between 7-12 months of age in tau-/- mice on a Bl6/129sv mixed background. These observations were partially replicated by another group using pure Bl6 background tau-/- mice, but notably they did not observe a cognitive phenotype. A third group using Bl6 background tau-/- mice found cognitive impairment at 20-months of age.ResultsTo reconcile the observations, here we considered the genetic, dietary and environmental variables in both studies, and performed an extended set of behavioral studies on 12-month old tau+/+, tau+/-, and tau-/- mice comparing Bl6/129sv to Bl6 backgrounds. We found that tau-/- in both backgrounds exhibited reduced tyrosine hydroxylase-positive nigral neuron and impaired motor function in all assays used, which was ameliorated by oral treatment with L-DOPA, and not confounded by changes in body weight. Tau-/- in the C57BL6/SV129 background exhibited deficits in the Y-maze cognition task, but the mice on the Bl6 background did not.ConclusionsThese results validate our previous report on the neurodegenerative phenotypes of aged tau-/- mice, and show that genetic background may impact the extent of cognitive impairment in these mice. Therefore excessive lowering of tau should be avoided in therapeutic strategies for AD.

Absence of Tau triggers age‐dependent sciatic nerve morphofunctional deficits and motor impairment

“…As Tau−/− mice are shown to exhibit motor deficits, it was of interest to monitor the impact of Tau ablation on the peripheral component of motor circuit; for that purpose, we studied the sciatic nerve, in the same mouse line and background (C57BL/6; Dawson et al., 2001) used in previous studies describing motor deficits after Tau ablation (Morris et al ., 2013; Lei et al ., 2014). It is important to note that the sciatic nerve is known to exhibit important morphological and functional changes with aging (Melcangi et al ., 2000).…”

“…Furthermore, in a later study, Lei et al . (2014) showed that motor deficits of old Tau−/− animals do not depend on background or have a sex‐dependent profile. In line with it, despite the fact that our study has used male animals and Morris study (2013) used a mixed (male and female) cohort, both studies exhibit motor deficits providing further support of no gender influence in the old Tau−/− motor deficits.…”

Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis

“…In addition, alterations that may be related to deficient synaptic plasticity (LTP and LTD) have been reported in Tau −/− mice (Ahmed et al , 2014; Kimura et al , 2014; Regan et al , 2015). In fact, hippocampal LTD is considered necessary for clearing old memories, and Tau −/− mice show impairments in learning flexibility and various types of hippocampal‐dependent memory (Ikegami et al , 2000; Ahmed et al , 2014; Lei et al , 2014; Ma et al , 2014; Regan et al , 2015). Remarkably, it has been described that granule neurons are important for flexibility of learning strategies (Garthe et al , 2009).…”

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…However, while young APP +/+ tau -/-mice (4-7 months old) exhibit better cognitive function [60,61], aged APP +/+ tau -/-mice (12 months old or older) showed enhanced degeneration [63], indicating that loss of tau function alone may be toxic. Further investigations found that loss of tau induces parkinsonism and dementia phenotypes [64][65][66], suggesting that excessive lowering of tau should be avoided in therapeutic strategies for AD.…”