Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory

Abstract

Non-fibrillar soluble oligomeric forms of amyloid-β peptide (oAβ) and tau proteins are likely to play a major role in Alzheimer’s disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAβ initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aβ, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAβ levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAβ to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aβ on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aβ and tau pathology.

Soluble phospho-tau from Alzheimer’s disease hippocampus drives microglial degeneration

“…Thus, although the existence of extracellular tau is now considered crucial for AD propagation [1, 9, 56], phospho-tau could be predominantly accumulated in the cytosol. Therefore, it is likely that most of the phospho-tau in our S1 fractions were originally located intraneuronally.…”

Analysis of isoform-specific tau aggregates suggests a common toxic mechanism involving similar pathological conformations and axonal transport inhibition

“…More recently, we showed that several disease-related modifications of tau cause conformational display of the PAD in the amino terminus of tau and oligomeric tau aggregates impaired axonal transport confirming a link between pathological conformations and tau toxicity (Kanaan, et al, 2011,LaPointe, et al, 2009,Patterson, et al, 2011a,Patterson, et al, 2011b,Tiernan, et al, 2016). Moreover, many other studies suggest oligomeric tau is toxic to neurons in culture and in vivo (Castillo-Carranza, et al, 2014a,Castillo-Carranza, et al, 2014b,Fa, et al, 2016,Gerson, et al, 2016,Lasagna-Reeves, et al, 2010,Tian, et al, 2013,Usenovic, et al, 2015). Previous studies have focused only on the longest 4R tau isoform to study the effects of PAD exposure and oligomerization.…”

“…Indeed, multiple studies implicate oligomers as a primary toxic species of tau in several tauopathy model systems (Cardenas-Aguayo Mdel, et al, 2014,Castillo-Carranza, et al, 2014a,Fa, et al, 2016,Gerson, et al, 2016,Lewis and Dickson, 2015,Sahara, et al, 2013,Tian, et al, 2013,Usenovic, et al, 2015,Ward, et al, 2012). Here, the vast majority of aggregates produced by the 3R isoforms under the experimental conditions used were oligomeric, with only rare filaments being present in the sample.…”

Pseudophosphorylation of tau at S422 enhances SDS-stable dimer formation and impairs both anterograde and retrograde fast axonal transport

“…Other proposed mechanisms for neurotoxicity include enhanced formation of degradation-resistant multimers that could overwhelm protein degradation machinery (Myeku et al, 2015; Tai et al, 2012; Wang et al, 2009) and/or compromise chaperone activity (Patterson et al, 2011a), impairment of neurophysiological functions (Fá et al, 2016), or promotion of mitochondria dysfunction (Kopeikina et al, 2011). However, the relatively low concentrations of S422E tau and the short incubation time used presently would argue against these mechanisms as an explanation for the effects on FAT.…”