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

Abstract

Tau protein participates in microtubule stabilization, axonal transport, and protein trafficking. Loss of normal tau function will exert a negative effect. However, current knowledge on the impact of tau deficiency on the motor behavior and related neurobiological changes is controversial. In this study, we examined motor functions and analyzed several proteins implicated in the maintenance of midbrain dopaminergic (DA) neurons (mDANs) function of adult and aged tau+/+, tau+/−, tau−/− mice. We found tau deficiency could not induce significant motor disorders. However, we discovered lower expression levels of transcription factors Orthodenticle homeobox 2 (OTX2) of mDANs in older aged mice. Compared with age-matched tau+/+ mice, there were 54.1% lower (p = 0.0192) OTX2 protein (OTX2-fluorescence intensity) in VTA DA neurons of tau+/−mice and 43.6% lower (p = 0.0249) OTX2 protein in VTA DA neurons of tau−/−mice at 18 months old. Combined with the relevant reports, our results suggested that tau deficiency alone might not be enough to mimic the pathology of Parkinson’s disease. However, OTX2 down-regulation indicates that mDANs of tau-deficient mice will be more sensitive to toxic damage from MPTP.

Genetic ablation of tau improves mitochondrial function and cognitive abilities in the hippocampus

“… Three month old wild-type (WT) and homozygous tau KO (tau-/-) mice were obtained from The Jackson Laboratory (strain name: B6.129-Mapttm1Hnd/J Bar Harbor, ME, Stock no 007251). Tau -/- mice are viable and successful reproducible, and have a normal life-span reaching 20 month-old [26] , [82] . The animals were handled according to the guidelines of the National Institute of Health (NIH, Baltimore, MD).…”

Tau knockout exacerbates degeneration of parvalbumin‐positive neurons in substantia nigra pars reticulata in Parkinson's disease‐related α‐synuclein A53T mice

“…The triple transgenic mice gained significantly less body weight compared with nTg mice since 1‐month‐old ( P < .001, Figure 1A). Since our previous study have demonstrated that variations in tau expression levels did not affect the body weight in mice at different age stages, 20 these results suggest that α‐syn A53T mutation is the key gene that gives rise to a significant decrease in body weight in transgenic mice. In the rotarod test, compared to nTg mice, all triple transgenic mice exhibited significant impairment in motor coordination and balance from 2‐month‐old, while Pitx3‐A53T α‐Syn × Tau +/− mice seemed to perform worse than the other triple transgenic mice at 6‐month‐old (Figures 1B and S1A).…”

“…Furthermore, the pathways traced by all mice showed that Pitx3‐A53T α‐Syn × Tau −/− mice exhibited anxiety‐like behavior, as they spent significant shorter time in central zone during habituation compared with nTg mice (the ratio of time in central zone was 5.8% and 15.9%, respectively), while Tau −/− mice showed normal pathways compared with nTg mice (Figures 1E,F and S1B). Additionally, there were no obvious differences among Pitx3 × hTau , Tau +/− , Tau −/− , and nTg mice in the rotarod and open‐field tests (Figure S1), indicating that different expression levels of tau could not independently induce the motor abnormalities 20 . Taken together, these results suggested that tau deficiency could exacerbate movement impairment in the α‐syn A53T conditional transgenic mice.…”

“…Additionally, there were no obvious differences among Pitx3 × hTau, Tau +/− , Tau −/− , and nTg mice in the rotarod and open-field tests ( Figure S1), indicating that different expression levels of tau could not independently induce the motor abnormalities. 20 Taken together, these results suggested that tau deficiency could exacerbate movement impairment in the α-syn A53T conditional transgenic mice. Moreover, at 18-month-old, all mice maintained a low level of activity and there were no significant differences in movement among genotypes.…”

“…We crossbred Pitx3-tTA mice with inducible responder tetO-A53T, tetO × hTau mice, or Tau −/− mice to generate the triple transgenic mice, achieving high-level expression of α-syn A53T in the mDANs with different tau gene dosage, including overexpressed human tau (Pitx3-A53T α-Syn × hTau), tau wild-type (Pitx3-A53T α-Syn × Tau +/+ ), tau heterozygote (Pitx3-A53T α-Syn × Tau +/− ), and tau knockout (Pitx3-A53T α-Syn × Tau −/− ). While the single transgenic mice were performed normally as non-transgenic (nTg) mice, as shown in our previous studies, 16,20 nTg littermates were used as controls in this study for simplicity.…”