Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

Velázquez, Ramón; Ferreira, Eric; Tran, An; Turner, Emily C.; Belfiore, Ramona; Branca, Caterina; Oddo, Salvatore

doi:10.1111/acel.12775

Cited by 66 publications

(53 citation statements)

References 48 publications

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“…Tau protein plays a role in the regulation of synaptic function (11). Accordingly, a role for tau in synaptic plasticity has been suggested by reports showing deficits in hippocampal long-term potentiation (LTP) and/or long-term depression (LTD) (26,29,77), as well as reduced hippocampal brain-derived neurotrophic factor (BDNF) levels following tau deletion or knockdown in mice (22,78). Therefore, impairments in synaptic plasticity might be involved in the behavioral alterations reported in TauKO and hTau, in this study.…”

Section: Discussionmentioning

confidence: 99%

Behavioral Abnormalities in Knockout and Humanized Tau Mice

et al. 2020

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Microtubule-associated protein tau assists in stabilizing microtubules and has been particularly implicated in Alzheimer's disease (AD). Given the importance of tau to AD pathogenesis and therapies, it is important to understand non-classic physiological functions for this protein inside and outside the central nervous system (CNS). Our group has previously shown that tau ablation triggers glucose intolerance and pancreatic dysfunction in mice, suggesting that tau plays a role in peripheral metabolic regulation. Little is known about the role of tau in anxiety. Moreover, inconsistent results have been generated regarding the effects of tau deletion in memory. Here, we characterize systemic insulin resistance, anxiety-related behavior and memory in 15 to 20 weeks old Wild-Type (WT), Tau knockout (TauKO) and a distinct hTau mouse model consisting of tau knockout expressing the longest isoform (2N4R) of a non-mutant WT human Tau protein under the prion promoter (hTau). Our findings demonstrate that tau deletion leads to anxiety-related behavior, impaired contextual and cued fear memory. The presence of a human Tau transgene did not ameliorate the phenotypes observed in animals lacking the mouse tau protein and it elicited impairments in learning, memory, and peripheral insulin sensitivity. Our results suggest that tau protein plays a role in memory and anxiety-related behavior. Our findings also indicate that previously unrecognized functions for tau protein may be a complicating factor in using animal models on the TauKO background. Understanding the link between tau pathophysiology and cognitive and metabolic alterations is of great importance to establish the complete contribution of tau protein to AD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Behavioral Abnormalities in Knockout and Humanized Tau Mice

et al. 2020

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“…Tau plays an important role in axonal transport of vesicles, organelles as well as other cargoes, 22 as evident by acute reduction of hippocampal tau in adult mice resulting learning and memory deficits. 63 However, overexpression of tau, as observed early in some forms of tauopathies, 64 also impaired axonal transport before the breakdown of microtubules. 13,14,36,46,65 Interestingly, this inhibitory effect of excessive tau could be rescued by phosphorylation of tau.…”

Section: Discussionmentioning

confidence: 99%

T‐complex protein 1‐ring complex enhances retrograde axonal transport by modulating tau phosphorylation

Chen

Fang

Florio

et al. 2018

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The cytosolic chaperonin T-complex protein (TCP) 1-ring complex (TRiC) has been shown to exert neuroprotective effects on axonal transport through clearance of mutant Huntingtin (mHTT) in Huntington's disease. However, it is presently unknown if TRiC also has any effect on axonal transport in wild-type neurons. Here, we examined how TRiC impacted the retrograde axonal transport of brain-derived neurotrophic factor (BDNF). We found that expression of a single TRiC subunit significantly enhanced axonal transport of BDNF, leading to an increase in instantaneous velocity with a concomitant decrease in pauses for retrograde BDNF transport. The transport enhancing effect by TRiC was dependent on endogenous tau expression because no effect was seen in neurons from tau knockout mice. We showed that TRiC regulated the level of cyclin-dependent kinase 5 (CDK5)/p35 positively, contributing to TRiC-mediated tau phosphorylation (ptau). Expression of a single TRiC subunit increased the level of ptau while downregulation of the TRiC complex decreased ptau. We further demonstrated that TRiC-mediated increase in ptau induced detachment of tau from microtubules. Our study has thus revealed that TRiC-mediated increase in tau phosphorylation impacts retrograde axonal transport.

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“…The MWM task was conducted as previously described (Velazquez et al, ). To assess spatial learning, each animal was given four trials per day for a total of 5 days.…”

Section: Methodsmentioning

confidence: 99%

Lifelong choline supplementation ameliorates Alzheimer’s disease pathology and associated cognitive deficits by attenuating microglia activation

et al. 2019

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Currently, there are no effective therapies to ameliorate the pathological progression of Alzheimer's disease (AD). Evidence suggests that environmental factors may contribute to AD. Notably, dietary nutrients are suggested to play a key role in mediating mechanisms associated with brain function. Choline is a B‐like vitamin nutrient found in common foods that is important in various cell functions. It serves as a methyl donor and as a precursor for production of cell membranes. Choline is also the precursor for acetylcholine, a neurotransmitter which activates the alpha7 nicotinic acetylcholine receptor (α7nAchR), and also acts as an agonist for the Sigma‐1 R (σ1R). These receptors regulate CNS immune response, and their dysregulation contributes to AD pathogenesis. Here, we tested whether dietary choline supplementation throughout life reduces AD‐like pathology and rescues memory deficits in the APP/PS1 mouse model of AD. We exposed female APP/PS1 and NonTg mice to either a control choline (1.1 g/kg choline chloride) or a choline‐supplemented diet (5.0 g/kg choline chloride) from 2.5 to 10 months of age. Mice were tested in the Morris water maze to assess spatial memory followed by neuropathological evaluation. Lifelong choline supplementation significantly reduced amyloid‐β plaque load and improved spatial memory in APP/PS1 mice. Mechanistically, these changes were linked to a decrease of the amyloidogenic processing of APP, reductions in disease‐associated microglial activation, and a downregulation of the α7nAch and σ1 receptors. Our results demonstrate that lifelong choline supplementation produces profound benefits and suggest that simply modifying diet throughout life may reduce AD pathology.

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Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

Cited by 66 publications

References 48 publications

Behavioral Abnormalities in Knockout and Humanized Tau Mice

Behavioral Abnormalities in Knockout and Humanized Tau Mice

T‐complex protein 1‐ring complex enhances retrograde axonal transport by modulating tau phosphorylation

Lifelong choline supplementation ameliorates Alzheimer’s disease pathology and associated cognitive deficits by attenuating microglia activation

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