Hyperphosphorylation and Cleavage at D421 Enhance Tau Secretion

It is well established that tau pathology propagates in a predictable manner in Alzheimer’s disease (AD). Moreover, tau accumulates in the cerebrospinal fluid (CSF) of AD’s patients. The mechanisms underlying the propagation of tau pathology and its accumulation in the CSF remain to be elucidated. Recent studies have reported that human tau was secreted by neurons and non-neuronal cells when it was overexpressed indicating that tau secretion could contribute to the spreading of tau pathology in the brain and could lead to its accumulation in the CSF. In the present study, we showed that the overexpression of human tau resulted in its secretion by Hela cells. The main form of tau secreted by these cells was cleaved at the C-terminal. Surprisingly, secreted tau was dephosphorylated at several sites in comparison to intracellular tau which presented a strong immunoreactivity to all phospho-dependent antibodies tested. Our data also revealed that phosphorylation and cleavage of tau favored its secretion by Hela cells. Indeed, the mimicking of phosphorylation at 12 sites known to be phosphorylated in AD enhanced tau secretion. A mutant form of tau truncated at D421, the preferential cleavage site of caspase-3, was also significantly more secreted than wild-type tau. Taken together, our results indicate that hyperphosphorylation and cleavage of tau by favoring its secretion could contribute to the propagation of tau pathology in the brain and its accumulation in the CSF

Reproducing Personality in Neuroscience

Using rsfMRI we want to reproduce the Big 5 personality traits and how they relate to functional connectivity

Comparison of functional connectivity maps between 3- and 5-year-olds.

<p>Comparison of functional connectivity maps between 3- and 5-year-olds.</p

Brain regions showing significant hemispheric asymmetry of functional connectivity with pSTG and IFG.

<p>Brain regions showing significant hemispheric asymmetry of functional connectivity with pSTG and IFG.</p

Average connectivity strength in the regions with significant functional hemispheric asymmetry of pSTG (3-year-olds, A; 5-year-olds, B) and of IFG (3-year-olds, C).

<p>The red color indicates connectivity strength calculated when seeded in the left pSTG/IFG; the blue color indicates connectivity strength calculated when seeded in the right pSTG/IFG. L., left hemisphere; R., right hemisphere; SPL, superior parietal lobe; SOG, superior occipital gyrus; MCC, middle cingulate cortex; MTG, middle temporal gyrus; STG, superior temporal gyrus; AnG, angular gyrus; IFG, inferior frontal gyrus; SFG, superior frontal gyrus; SMA, supplementary motor area. L, left hemisphere; R, right hemisphere.</p

Regions of interest for language network [39].

<p>Regions of interest for language network [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0165802#pone.0165802.ref039" target="_blank">39</a>].</p

Individual variation in intentionality in the mind-wandering state is reflected in the integration of the default-mode, fronto-parietal, and limbic networks

Mind-wandering has a controversial relationship with cognitive control. Existing psychological evidence supports the hypothesis that episodes of mind-wandering reflect a failure to constrain thinking to task-relevant material, as well the apparently alternative view that control can facilitate the expression of self-generated mental content. We assessed whether this apparent contradiction arises because of a failure to consider differences in the types of thoughts that occur during mind-wandering, and in particular, the associated level of intentionality. Using multi-modal magnetic resonance imaging (MRI) analysis, we examined the cortical organisation that underlies inter-individual differences in descriptions of the spontaneous or deliberate nature of mind-wandering. Cortical thickness, as well as functional connectivity analyses, implicated regions relevant to cognitive control and regions of the default-mode network for individuals who reported high rates of deliberate mind-wandering. In contrast, higher reports of spontaneous mind-wandering were associated with cortical thinning in parietal and posterior temporal regions in the left hemisphere (which are important in the control of cognition and attention) as well as heightened connectivity between the intraparietal sulcus and a region that spanned limbic and default-mode regions in the ventral inferior frontal gyrus. Finally, we observed a dissociation in the thickness of the retrosplenial cortex/lingual gyrus, with higher reports of spontaneous mind-wandering being associated with thickening in the left hemisphere, and higher repots of deliberate mind-wandering with thinning in the right hemisphere. These results suggest that the intentionality of the mind-wandering state depends on integration between the control and default-mode networks, with more deliberation being associated with greater integration between these systems. We conclude that one reason why mind-wandering has a controversial relationship with control is because it depends on whether the thoughts emerge in a deliberate or spontaneous fashion

Significant hemispheric asymmetry of pSTG in both age groups (first row) and of IFG in 3-year-olds (second row).

<p>The foci of the left hemisphere show significant asymmetric functional connectivity with their ipsilateral seeds, and the foci in the right hemisphere show significant asymmetric functional connectivity with their contralateral seeds, corrected for multiple comparisons (|<i>Z</i>| ≥ 2.58, voxel-wise <i>p</i> < .01, cluster-wise <i>p</i> < .05, GRF corrected). The red-yellow color bar indicates stronger connectivity for left seeds (i.e., left IFG, pSTG), while the blue color bar indicates stronger connectivity for right seeds (i.e., right IFG, pSTG). L, left hemisphere; R, right hemisphere.</p

Group comparison of hemispheric asymmetry between 3- and 5-year-olds for pSTG (A) and IFG (B).

<p>The red-yellow color bar indicates regions with stronger functional asymmetry in 5-year-olds than 3-year-olds, while the blue color bar indicates regions with stronger functional asymmetry in 3-year-olds than 5-year-olds. L, left hemisphere; R, right hemisphere.</p