Tau Reduction Does Not Prevent Motor Deficits in Two Mouse Models of Parkinson's Disease

Abstract

Many neurodegenerative diseases are increasing in prevalence and cannot be prevented or cured. If they shared common pathogenic mechanisms, treatments targeting such mechanisms might be of benefit in multiple conditions. The tau protein has been implicated in the pathogenesis of diverse neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Tau reduction prevents cognitive deficits, behavioral abnormalities and other pathological changes in multiple AD mouse models. Here we examined whether tau reduction also prevents motor deficits and pathological alterations in two mouse models of PD, generated by unilateral striatal injection of 6-hydroxydopamine (6-OHDA) or transgene-mediated neuronal expression of human wildtype α-synuclein. Both models were evaluated on Tau +/+, Tau +/– and Tau –/– backgrounds in a variety of motor tests. Tau reduction did not prevent motor deficits caused by 6-OHDA and slightly worsened one of them. Tau reduction also did not prevent 6-OHDA-induced loss of dopaminergic terminals in the striatum. Similarly, tau reduction did not prevent motor deficits in α-synuclein transgenic mice. Our results suggest that tau has distinct roles in the pathogeneses of AD and PD and that tau reduction may not be of benefit in the latter condition.

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

“…(2000) reports signs of muscle weakness (tested by wire‐hanging) and reduced balance coordination in 2‐month‐old Tau−/− , but Morris et al . (2011) showed normal motor function of young (3–5 months old) and adult animals of another Tau −/− mouse line in a variety of motor tests (B6 background; Dawson et al . (2001)) in agreement with this study findings.…”

Tau Deficiency Down-Regulated Transcription Factor Orthodenticle Homeobox 2 Expression in the Dopaminergic Neurons in Ventral Tegmental Area and Caused No Obvious Motor Deficits in Mice

“…To date, four different tau −/− mouse models have been reported (Ke et al, 2012), and three of them have been used in previous studies to explore the pathomechanisms of tau-mediated neurodegeneration using assessments of cognitive and motor functions of mice (Ikegami et al, 2000; Roberson et al, 2007; Dawson et al, 2010; Morris et al, 2011; Lei et al, 2012; Morris et al, 2013; Ahmed et al, 2014; Lei et al, 2014, 2015; Ma et al, 2014). However, the conclusions about whether tau deficiency affects motor behaviors of adult and aged mice are still a matter of debate.…”

“…For example, Ikegami and colleagues have reported that young (10–11 weeks of age) tau − / − mice (generated by Harada) (Harada et al, 1994) showed hyperactivity in the open-field test, muscle weakness in the wire-hanging test and reduced balance in the rod-walking test (Ikegami et al, 2000). But other groups have reported that adult (3–7 months of age) tau − / − mice (two different strains generated by Dawson and Tucker, respectively) (Dawson et al, 2001; Tucker et al, 2001) showed no differences in gross motor functions (Roberson et al, 2007; Lei et al, 2012; Ahmed et al, 2014) or only developed minor motor deficits in the open-field test and balance beam test (Morris et al, 2011) when compared to age-matched wild-type mice. Besides, Lei and colleagues have observed that aged (12–24 months of age) tau − / − mice (generated by Dawson) (Dawson et al, 2001) showed reduced coordination and balance in the rotarod and pole test, decreased locomotion in the open-field test, and abnormal gait pattern in the gait analysis (Lei et al, 2012, 2014).…”

“…These results indicate that OTX2 might be an effective protective factor for neurons against the toxic effect of MPTP or other toxins, and could be used as a therapeutic target in Parkinson’s disease. Hence, the reduction of OTX2 in the VTA might render the mDANs of tau-deficient mice more susceptible to other insults (Morris et al, 2011) or induce other detrimental effects through its downstream targets.…”

“…To date, four independent tau-knock-out ( tau − / − ) mouse models have been generated (Harada et al, 1994; Dawson et al, 2001; Tucker et al, 2001; Hashimoto et al, 2008) and three of them have been used to study the role of tau deficiency in neurodegeneration by examining the motor and cognitive behaviors of mice (Ikegami and Harada, 2000; Roberson et al, 2007; Dawson et al, 2010; Morris et al, 2011, 2013; Lei et al, 2012, 2014, 2015; Ahmed et al, 2014; Ma et al, 2014). However, most of the findings on the relationship between tau deficiency and the development of overt motor deficits in mice were largely contradictory.…”