Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations

Abstract

Alzheimer's disease (AD) is the leading cause of dementia worldwide. In AD animal models, soluble tau aggregates have been shown to disrupt neuronal function, alter synaptic plasticity and impair cognitive function. In humans, small fractions of these toxic tau species are secreted into cerebrospinal fluid (CSF), some of which can be measured as diagnostic and prognostic biomarkers, starting from early stages of disease. However, the mechanisms of how these tau forms alter neuronal and network function are not fully understood. Here, we have developed and applied a novel approach to examine the electrophysiological effects of CSF from patients with a tau-positive biomarker profile. The method involves incubation of acutely-isolated wild-type mouse hippocampal brain slices with small volumes of diluted human CSF, followed by a suite of electrophysiological recording methods to evaluate their effects on neuronal function from single cells through to the network level. Comparison of the toxicity profiles of the same CSF samples, with and without immuno-depletion for tau, has enabled a pioneering demonstration that CSF-tau potently modulates neuronal function. We demonstrate that CSF-tau mediates an increase in neuronal excitability in single cells. We then observed, at the network level, increased input-output responses and enhanced paired-pulse facilitation as well as an increase in long-term potentiation. Finally, we show that CSF-tau modifies the generation and maintenance of hippocampal theta oscillations, which have important roles in learning and memory and are known to be altered in AD patients. Together, we describe a novel method for screening human CSF-tau to understand functional effects on neuron and network activity, which could have far-reaching benefits in understanding tau pathology, thus allowing for the development of better targeted treatments for tauopathies in the future.

Rapidly reversible persistent long-term potentiation inhibition by patient-derived brain tau and amyloid ß proteins

“…As shown here and previously [9–11,22], both oTau and SτAs mimic the LTP disruptive action of synaptotoxic tau in patient-derived brain extracts [9,11,22] and extracellular tau in secretomes of induced pluripotent stem cell-derived neurons from individuals with trisomy 21, the most common genetic cause of AD [36], but see [37]. Whether or not the responsible tau species are the same remains to be determined.…”

Lateral Entorhinal Cortex Dysfunction in Alzheimer’s disease Mice

“…Previous studies have shown that Aβ and tau can cause neuronal hyperexcitability leading to network dysfunction ( [40][41][42][43]) and memory deficits. We confirm that this is also the case in the LEC neurons of EC-App/Tau mice which not only show hyperexcitability, but also have low information content and high sparsity compared to the controls.…”