Understanding the Pathophysiological Actions of Tau Oligomers: A Critical Review of Current Electrophysiological Approaches

Abstract

Tau is a predominantly neuronal protein that is normally bound to microtubules, where it acts to modulate neuronal and axonal stability. In humans, pathological forms of tau are implicated in a range of diseases that are collectively known as tauopathies. Kinases and phosphatases are responsible for maintaining the correct balance of tau phosphorylation to enable axons to be both stable and labile enough to function properly. In the early stages of tauopathies, this balance is interrupted leading to dissociation of tau from microtubules. This leaves microtubules prone to damage and phosphorylated tau prone to aggregation. Initially, phosphorylated tau forms oligomers, then fibrils, and ultimately neurofibrillary tangles (NFTs). It is widely accepted that the initial soluble oligomeric forms of tau are probably the most pathologically relevant species but there is relatively little quantitative information to explain exactly what their toxic effects are at the individual neuron level. Electrophysiology provides a valuable tool to help uncover the mechanisms of action of tau oligomers on synaptic transmission within single neurons. Understanding the concentration-, time-, and neuronal compartment-dependent actions of soluble tau oligomers on neuronal and synaptic properties are essential to understanding how best to counteract its effects and to develop effective treatment strategies. Here, we briefly discuss the standard approaches used to elucidate these actions, focusing on the advantages and shortcomings of the experimental procedures. Subsequently, we will describe a new approach that addresses specific challenges with the current methods, thus allowing real-time toxicity evaluation at the single-neuron level.

Rutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimer’s disease

“…Tau oligomers are widely regarded as the most toxic and pathogenic form of tau [ 11 , 27 ]. To assess the effect of rutin on the level of tau oligomers, we further determined the oligomer levels in mouse brain lysates by dot-blot using fibrillar oligomer-specific antibody OC.…”

Tau: A Signaling Hub Protein

“…While these studies provide evidence that tau modulates synaptic function, the precise mechanisms and/or requirement of tau for LTP and LTD requires further investigation. In the context of disease, other studies documented the effects of pathological tau species on synaptic function (Tracy and Gan, 2018 ; Hanger et al, 2019 ; Hill et al, 2020 ). Indeed, oligomeric tau, mutant forms of tau associated with inherited tauopathies, abnormally phosphorylated tau species, acetylated tau, and caspase-cleaved tau were shown to impair LTP and/or LTD function, promoting abnormal AMPAR trafficking through various mechanisms (Yoshiyama et al, 2007 ; Hoover et al, 2010 ; Warmus et al, 2014 ; Min et al, 2015 ; Fá et al, 2016 ; Tracy et al, 2016 ; Zhao et al, 2016 ; Puzzo et al, 2017 ; Ondrejcak et al, 2018 ).…”

Oligomer-Targeting Prevention of Neurodegenerative Dementia by Intranasal Rifampicin and Resveratrol Combination – A Preclinical Study in Model Mice

“…For example, synaptic dysfunction, which is assumed an immediate early symptom in AD, is caused by soluble Aβ oligomers ( Cline et al, 2018 ; Li and Selkoe, 2020 ), and Aβ oligomers trigger the pathological cascade of AD including tau hyperphosphorylation, glial activation, and neuronal loss ( Tomiyama et al, 2010 ; Cline et al, 2018 ). Tau oligomers ( Maeda and Takashima, 2019 ; Hill et al, 2020 ) and α-synuclein oligomers ( Bengoa-Vergniory et al, 2017 ; Kayed et al, 2020 ) are also suggested to play a crucial role in the pathogenesis of tauopathy and α-synucleinopathy, respectively.…”