Neuronal and Glial Distribution of Tau Protein in the Adult Rat and Monkey.

Nicholas M Kanaan,Tessa Grabinski

doi:10.3389/fnmol.2021.607303

Abstract

Tau is a microtubule-associated protein for which the physiological functions remain a topic of vigorous investigation. Additionally, tau is a central player in the pathogenesis of several diseases such as Alzheimer’s disease and several frontotemporal dementias. A critical variable to understanding tau in physiological and disease contexts is its normal localization within cells of the adult CNS. Tau is often described as an axon-specific (or enriched) and neuron-specific protein with little to no expression in glial cells, all of which are untrue. Understanding normal tau distribution also impacts interpretation of experimental results and hypotheses regarding its role in disease. Thus, we set out to help clarify the normal localization of tau in the adult CNS of middle-aged rats and rhesus macaque using the hippocampus as a representative brain structure. The physiological concentration of tau in the rat hippocampus was 6.6 μM and in white matter was 3.6 μM as determined by quantitative sandwich ELISAs. We evaluated the cellular localization of tau using multiple tau-specific antibodies with epitopes to different regions, including Tau1, Tau5, Tau7, R1, and two novel primate-specific antibodies NT9 and NT15. In the rat and monkey, tau was localized within the somatodendritic and axonal compartments, as well as a subset of neuronal nuclei. Semi-quantitative fluorescence intensity measurements revealed that depending on the specific reagent used the somatodendritic tau is relatively equal to, higher than, or lower than axonal tau, highlighting differential labeling of tau with various antibodies despite its distribution throughout the neuron. Tau was strongly expressed in mature oligodendrocytes and displayed little to no expression in oligodendrocyte precursor cells, astrocytes or microglia. Collectively, the data indicate tau is ∼3 – 7 μM under physiological conditions, is not specifically enriched in axons, and is normally found in both neurons and mature oligodendrocytes in the adult CNS. The full landscape of tau distribution is not revealed by all antibodies suggesting availability of the epitopes is different within specific neuronal compartments. These findings set the stage for better understanding normal tau distributions and interpreting data regarding the presence of tau in different compartments or cell types within disease conditions.

Highlights

Tau was originally co-purified with microtubules from brain and was subsequently labeled as a microtubule-associated protein that primarily plays a role in stabilizing microtubules (Weingarten et al, 1975; Witman et al, 1976; Cleveland et al, 1977a,b)
We present a series of tau antibody stains in naïve adult rat and monkey brain tissue, with a focus on the HP as a representative region with relatively well-defined cell body, axon and dendritic regions
We demonstrated that tau is in-fact normally located within the somata, nuclei, dendrites and axons of neurons, as well as mature oligodendrocytes supporting a wider normal distribution of tau in the adult CNS (Figure 13)

Summary

Introduction

Tau was originally co-purified with microtubules from brain and was subsequently labeled as a microtubule-associated protein that primarily plays a role in stabilizing microtubules (Weingarten et al, 1975; Witman et al, 1976; Cleveland et al, 1977a,b). Evidence suggests tau is more likely involved in regulating microtubule dynamics (not stabilization), modulation of signaling pathways involved in axonal transport, and potentially additional roles including synaptic and nuclear functions, among others (Wang and Mandelkow, 2016; Combs et al, 2019; Mueller et al, 2021). It is critical that the field move forward with a clear understanding of basic biological characteristics of tau protein in the brain

Methods

Results

Conclusion