Age-appropriate cognition and subtle dopamine-independent motor deficits in aged Tau knockout mice

Abstract

The microtubule-associated protein tau is expressed throughout the nervous system, most highly in neurons but also in glial cells. Its functions in adult and aging mammals remain to be defined. Previous studies in mouse models found either protective or detrimental effects of genetic tau ablation. While tau ablation prevented synaptic, network and cognitive dysfunctions in several models of Alzheimer’s disease and made mice more resistant to epileptic seizures, a recent study described a parkinsonian phenotype in aging Tau knockout mice. Here we tested cognition and motor functions in Tau+/+, Tau+/− and Tau−/− mice around 1 and 2 years of age. Tau ablation did not impair cognition and caused only minor motor deficits that were much more subtle than those associated with the aging process. Tau ablation caused a mild increase in body weight, which correlated with and may have contributed to some of the motor deficits. However, tau ablation did not cause significant dopaminergic impairments, and dopamine treatment did not improve the motor deficits, suggesting that they do not reflect extrapyramidal dysfunction.

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

“…In combination with our previous observation that tau ablation increases body weight in aging mice 88, these findings raise the intriguing possibility that tau also contributes to AD‐related phenotypes through signaling pathways that regulate body weight.…”

“…After 2–3 days of single housing, mice were spatially trained to locate a hidden platform for 4–9 days, probed for spatial memory retention 24 h after the last hidden training trial, and then trained to find a cued platform, as described 88. Briefly, training with the hidden platform was continued until the mean latency of NTG mice reached ~20 s. Twenty‐four hours after the last training session, the mice were tested in a 60‐s probe trial followed by training to locate a visibly cued platform to exclude general performance deficits.…”

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

“…Lei et al ., 2012 and Morris et al ., 2013), we performed a battery of motor‐related behavioral tests in adult (4–6 months old) and old (17–22 months old) male Tau−/− and Tau+/+ animals. Motor function/coordination and locomotor activity were assessed in the rotarod and open‐field tests, respectively.…”

“…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).…”

“…However, chronic loss of Tau has been described to result in subtle or mild motor deficits in increasingly aged animals (reviewed by Gotz et al., 2013). Indeed, one study revealed loss of substantia nigra (SN) dopaminergic neurons in middle‐aged Tau−/− animals (Lei et al ., 2012), while in another study, using aged Tau−/− of the same strain, similar motor deficits were shown but in a SN‐/dopamine‐independent manner (Morris et al ., 2013), raising uncertainty on the underlying mechanisms of the motor deficits in Tau−/− animals. Surprisingly, the involvement of the PNS has not been assessed in any of the previous studies given the fact that Tau reduction is found in peripheral nerves (e.g., sciatic nerve) of patients with AD (Holzer et al ., 1999).…”