Extracellular truncated tau causes early presynaptic dysfunction associated with Alzheimer’s disease and other tauopathies

Abstract

The largest part of tau secreted from AD nerve terminals and released in cerebral spinal fluid (CSF) is C-terminally truncated, soluble and unaggregated supporting potential extracellular role(s) of NH2 -derived fragments of protein on synaptic dysfunction underlying neurodegenerative tauopathies, including Alzheimer’s disease (AD). Here we show that sub-toxic doses of extracellular-applied human NH2 tau 26-44 (aka NH 2 htau) -which is the minimal active moiety of neurotoxic 20-22kDa peptide accumulating in vivo at AD synapses and secreted into parenchyma- acutely provokes presynaptic deficit in K+ -evoked glutamate release on hippocampal synaptosomes along with alteration in local Ca2+ dynamics. Neuritic dystrophy, microtubules breakdown, deregulation in presynaptic proteins and loss of mitochondria located at nerve endings are detected in hippocampal cultures only after prolonged exposure to NH 2 htau. The specificity of these biological effects is supported by the lack of any significant change, either on neuronal activity or on cellular integrity, shown by administration of its reverse sequence counterpart which behaves as an inactive control, likely due to a poor conformational flexibility which makes it unable to dynamically perturb biomembrane-like environments. Our results demonstrate that one of the AD-relevant, soluble and secreted N-terminally truncated tau forms can early contribute to pathology outside of neurons causing alterations in synaptic activity at presynaptic level, independently of overt neurodegeneration.

MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways

“…It is now widely appreciated that Tau exists both inside and outside of neurons [ 5 , 28 , 47 ]. Under normal circumstances, the majority of extracellular Tau is C-terminal truncated [ 28 , 38 , 61 ], but it has been speculated that, in disease, the C-terminally truncated forms of Tau are released and may contribute to the seeding and spreading of tau aggregates [ 16 ]. Since miR-132 diminishes C-terminal Tau fragments inside primary neurons, we next asked whether it may also affect the release of Tau.…”

Tau Proteolysis in the Pathogenesis of Tauopathies: Neurotoxic Fragments and Novel Biomarkers

“…Tau 26 - 230 is produced due to cleavage at D25-Q26 by caspase-3 [ 41 ] and by calpain-1 [ 33 ] or –2 [ 34 ] at R230-T231. When applied extracellularly to rat hippocampal neuronal cultures, the smallest sequence of the tau 26 - 230 fragment known to drive neurotoxicity, tau 26 - 44 , could impair presynaptic signalling, reduce presynaptic protein levels, and breakdown MTs and neurites, in its native monomeric form without the need for aggregation and neurodegeneration [ 102 ]. Importantly, the effects could not be replicated with the reverse sequence, tau 44 - 26 [ 102 ].…”

“…When applied extracellularly to rat hippocampal neuronal cultures, the smallest sequence of the tau 26 - 230 fragment known to drive neurotoxicity, tau 26 - 44 , could impair presynaptic signalling, reduce presynaptic protein levels, and breakdown MTs and neurites, in its native monomeric form without the need for aggregation and neurodegeneration [ 102 ]. Importantly, the effects could not be replicated with the reverse sequence, tau 44 - 26 [ 102 ]. Tau 26 - 44 represents a therapeutic target, as passive immunisation with N-terminally targeting antibodies reduced tau hyperphosphorylation and improved cognition in 3xTgAD mice (APP; KM670/671NL, MAPT; P301L and presenilin 1; M146V) [ 103 ].…”

“…However, tau 26 - 230 did not correlate with full-length tau, indicating that this fragment is not produced due to degradation of full-length protein in the CSF but is actively secreted into the CSF upon neuronal injury [ 128 ]. Tau 26 - 44 [ 102 ], is also seen at the lower end of detection in a range of CSF samples containing both normal and elevated total tau levels [ 125 ]. However, the most quantifiable tau peptides in CSF contain the mid-region (residues 156–224) of the protein, likely due to resistance to degradation by proteases, while the N- and C-terminal peptides usually fall below the limit of detection [ 125 ], likely due to the multiple proteolytic cleavage events that occur in these regions reducing the N- and C-terminal peptide levels.…”

Correlated Disorder in Myelinated Axons Orientational Geometry and Structure

“…Biological tissues are typically intrinsically heterogeneous; indeed, nowadays new features and properties have been visualized using scanning methods with high spatial resolutions, such as by Atomic Force Microscopy [38][39][40], Confocal Microscopy [40], Scanning Electron Microscopy [35] and Scanning micro X-ray diffraction [15][16][17][18][19][20][21]. Correlated spatial structural fluctuations in biological systems have been correlated with the emergence of quantum coherence in biological matter [35,41], in photosystems [42] and intrinsically disordered proteins [43,44], as well as in lamellar oxides showing quantum coherence [45][46][47][48], where non-Euclidean spatial geometries for signal transmission are able to emerge from a correlated disorder [22,48].…”