Abstract
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.
Highlights
Tau is a microtubule-associated protein abundant in the Central Nervous System (CNS) with its most well-characterized biological function being microtubules polymerization [1, 2]
The insertion of a transgene that encodes the longest isoform of human Tau (2N4R) triggered insulin resistance in Tau knockout (TauKO) animals. human Tau protein under the prion promoter (hTau) mice displayed insulin resistance in the Insulin Tolerance Test (ITT) (Figures 1A,B), increased fasting plasma insulin levels (Figure 1C) and higher HOMA-IR index (Figure 1D) when compared to WT and TauKO
The present study provides evidence for a role of tau protein in anxiety and memory
Summary
Tau is a microtubule-associated protein abundant in the Central Nervous System (CNS) with its most well-characterized biological function being microtubules polymerization [1, 2]. Hyperphosphorylated tau is the main component of Neurofibrillary tangles (NFT) in Alzheimer‘s Disease (AD) brains [3]. In AD, the six Braak stages of the pathology are based on the sequential appearance of NFT in the brain in a hierarchical pattern that correlates with disease severity [4, 5]. Tau pathology in the form of NFT correlates with memory loss in normal aging and mild cognitive impairment (MCI) [6, 7]. Soluble tau oligomer species isolated from AD patient brains have been implicated in memory impairment, synaptic dysfunction and disease propagation [8,9,10].
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