Furthermore, recovery after stroke will, in most cases, imply compensatory shifts in cross-regional interactions (Gerloff et al., 2006, van Meer et al., 2010 and Carter et al., 2012). Envelope ICMs involving somatomotor, executive, and attention networks

are well investigated in stroke and during recovery and have been shown to be predictive for both behavioral deficits and adaptive reorganization after stroke (Carter et al., 2010 and Wang et al., 2010). This holds, in particular, for interhemispheric coupling in these networks (Carter et al., 2012). In contrast, evidence regarding changes in phase ICMs is limited to a few recent studies. Alpha-band ICMs have been observed to be decreased in perilesional and increased HIF inhibitor review in contralesional regions, and this interhemispheric difference has been found to predict cognitive and motor performance as well as aspects of poststroke recovery (Westlake et al., 2012 and Dubovik et al., 2012). Moreover, ongoing beta-band interhemispheric coupling was found to change under the influence of rehabilitation training (Pellegrino et al., 2012). In PD, numerous studies have addressed changes in ICMs. Substantial Pomalidomide price evidence has accumulated demonstrating that phase ICMs are altered in specific ways in PD and that they correlate with

clinical symptoms and behavior. Many of the studies in PD patients involve recordings from basal ganglia structures during stereotactic surgery for deep brain stimulation. These provide clear evidence for abnormal beta-band ICMs in corticobasal ganglia loops (Figure 5A), which correlate with severity of bradykinesia and rigidity, the key clinical symptoms in PD (Brown, 2003 and Stein and Bar-Gad, 2013). Accordingly, their suppression by dopaminergic medication or deep brain stimulation ameliorates

the patient’s condition. These findings have also been confirmed by MEG studies of phase ICMs in PD (Stoffers et al., 2008 and Litvak et al., 2011). Interestingly, dopaminergic therapy and reduction of motor impairment are associated with the emergence of a gamma-band ICM between cortex and basal ganglia (Brown, 2003 and Jenkinson et al., 2013) (Figure 5B). Overall, these studies have led to the notion of movement-permissive (gamma-band) versus movement-prohibitive (beta-band) ICMs (Brown, 2003) (Figure 5C). More generally, it has been suggested that these ICMs permit or prohibit TCL a change in the sensorimotor or cognitive set (Engel and Fries, 2010). Studies on envelope ICMs using fMRI have observed increased coupling between cortex and basal ganglia in PD that is attenuated by dopamine (Kwak et al., 2010 and Baudrexel et al., 2011). Whether this might relate to power envelope correlations of the abundant beta-band activity has apparently not yet been tested. In schizophrenia, functional disconnection in brain networks has been considered an important pathophysiological mechanism already early on (Friston and Frith, 1995).

A clue to what this alternative learning mechanism might be was provided by a recent study in which healthy subjects were exposed to an incremental rotation but were provided only with binary reward rather than vector error (Izawa and Shadmehr, 2011). Under these circumstances, subjects showed exploratory trial-and-error behavior rather Everolimus mouse than typical monotonic adaptation behavior and also did not show a change in perceived hand

position. These two sets of results in humans are consistent with the idea that errors can be reduced through cerebellar-independent non-forward model-based processes as long as the errors lie within the envelope of exploratory variability. A study of saccadic gain adaptation in monkeys also showed a small amount of residual adaptation to a gain change after lesions of the oculomotor posterior vermis (Barash et al., 1999). The authors of this study could only speculate as to the locus for this residual capacity to reduce errors, suggesting it might be mediated by the cerebellar nuclei. We would suggest that this result in monkeys is reminiscent of Bosutinib clinical trial the human reaching studies reported above and that the mechanism might

be outside the cerebellum. Support for this idea comes from studies in monkeys, in which intermediate and lateral deep cerebellar nuclei ablations were performed and yet slow recovery of limb ataxia was still seen, which was reversed with lesions to sensory cortex (Mackel, 1987). Compared to the cerebellum, the precise role of the basal ganglia in motor learning remains unclear and contradictory. Like

the cerebellum, both the anatomy and neurotransmitter localization for the basal ganglia (BG) are highly conserved in all vertebrates, again suggesting a preserved form of computation (Reiner et al., 1998). Of particular interest, is the fact that basal ganglia output evolved from principally Oxalosuccinic acid targeting the tectum in amphibians to also targeting cortical regions in reptiles and in subsequent vertebrates (Reiner et al., 1998). In addition, there is no evidence for either cortical or significant dopaminergic inputs to striatum in amphibians. Amphibians have simpler musculoskeletal systems and execute a simpler repertoire of movements than reptiles; their movements are tectally mediated, stereotypical, and stimulus locked (Reiner et al., 1998). This phylogenetic transition between amphibians and reptiles with respect to the connections of the BG is interesting for a number of reasons. First, it suggests that the BG perform a function that does not have an obligate relationship to cortex.

4A). Similarly, induction of TRPV6 gene expression was observed from low concentrations of calcitriol (590 pmol/L and ≥2480 pmol/L). Calbindin-D9k gene expression was unchanged by the administration of calcitriol or eldecalcitol (Fig. 4B). In the kidneys, TRPV5 mRNA expression Selleckchem Tyrosine Kinase Inhibitor Library was significantly elevated at the highest concentration

of eldecalcitol (15,800 pmol/L) and at high concentrations of calcitriol (≥1170 pmol/L) (Fig. 4C). Calbindin-D28k mRNA was increased at the higher blood concentrations of eldecalcitol (≥7520 pmol/L) and calcitriol (≥1170 pmol/L) (Fig. 4D). In bone, blood concentrations of calcitriol correlated with RANKL and FGF-23 gene expression; however, only the highest Osimertinib concentration of eldecalcitol (15,800 pmol/L) induced RANKL and FGF-23 gene expression (Fig. 4E). Blood concentration of calcitriol

correlated with VDR gene expression in the kidneys and bone (Fig. 5B and C), but calcitriol did not affect VDR gene expression in the intestine (Fig. 5A). Induction of VDR gene expression in the intestine and kidneys were associated with increasing concentration of eldecalcitol in the blood (Fig. 5A and B). In bone, significant induction of VDR gene expression was observed only at the highest concentration of eldecalcitol (Fig. 5C). Taken together, these results show that, in comparison to calcitriol, relatively higher concentrations of eldecalcitol in the blood were required to stimulate expression of vitamin D target genes in the kidneys (VDR, TRPV5, and calbindin-D28k) and bone (VDR, RANKL, and FGF-23). In order to compare the true biological activity of calcitriol and eldecalcitol in vivo, the blood concentration required to elicit a 50% response in each activity was calculated from the raw data above. The ratio of biological activity was obtained by dividing

the 50% response concentration of calcitriol by that of eldecalcitol. Based on these calculations, eldecalcitol was approximately 1/4 to 1/7 as active as calcitriol in increasing serum calcium and FGF-23, in stimulating urinary calcium excretion, and in suppressing Oxymatrine plasma PTH ( Table 1). Eldecalcitol was approximately 1/3 to 1/8 as active as calcitriol in stimulating expression of target genes in the kidneys (VDR, TRPV5, and calbindin-D28k) and bone (VDR, FGF-23, and RANKL). The biological activities of eldecalcitol in increasing intestinal TRPV6 and VDR gene expression were comparable to those of calcitriol ( Fig. 4 and Fig. 5). The half-life of eldecalcitol in the blood is much longer than it is for calcitriol [23]. Although eldecalcitol strongly induces CYP24A1 in the intestine and kidneys [24], eldecalcitol itself is hardly degraded by CYP24A1 [25]. At the same time, eldecalcitol strongly suppresses CYP27B1 in the kidneys.

To test this possibility, we assessed the ability of SnoN1 RNAi to reverse the SnoN2 RNAi-induced branching phenotype in neurons. Simultaneous expression of SnoN1 shRNAs and SnoN2 shRNAs induced knockdown of both SnoN1 and SnoN2 isoforms in neurons (Figure 1I). SnoN1 knockdown in the background of SnoN2 RNAi restored both the percentage of branched neurons and the number of axon branches per neuron to baseline levels (Figures 1J and 1K and Figure S1C) suggesting that SnoN1 RNAi suppresses the CP-868596 SnoN2 RNAi-induced branching phenotype. Although the combined knockdown

of SnoN1 and SnoN2 also reduced axon length (Figures S1C and S1D), suppression of axon branching occurred at a faster pace than the reduction of axon length (see right panel in Figure 1K and Figure S1D). In addition, branching was suppressed in the subpopulation of SnoN1, SnoN2 double knockdown neurons that harbor short axons as effectively as in those with long axons (Figure S1G). These data suggest that the ability of SnoN1 RNAi to suppress SnoN2

RNAi-induced axon branching is not due to the reduction in axon length. SnoN2 knockdown but not SnoN1 knockdown also stimulated branching of dendrites without changing dendrite length (Figures S1J–S1L) and SnoN1 RNAi suppressed the SnoN2 RNAi-induced dendrite-branching phenotype without reducing dendrite length (Figures S1M and S1N). These data further support the conclusion that CSF-1R inhibitor SnoN1 RNAi suppresses SnoN2

knockdown-induced neuronal branching independently of reducing process length. Collectively, our findings suggest that SnoN1 and SnoN2 exert opposing effects on neuronal branching. Growing evidence suggests that impaired neuronal migration in vivo is often associated with increased branching in primary neurons (Bielas et al., 2007, Guerrier et al., 2009, Kappeler et al., 2006 and Nagano et al., 2004). We therefore explored whether SnoN1 and SnoN2 might have isoform-specific functions in the control of granule neuron migration and positioning in the cerebellar cortex. We used an in vivo electroporation method in postnatal rat pups to characterize neuronal migration and positioning within second the developing rat cerebellar cortex (Konishi et al., 2004). Because the electroporation procedure targets cells in the EGL (data not shown), all transfected neurons are granule neurons. We injected rat pups at postnatal day 3 (P3) with a plasmid encoding the U6 promoter and cmv-driven green fluorescent protein (U6-cmvGFP) and returned pups to moms (Figure 2A). Animals were then sacrificed 3, 5, or 7 days after electroporation and coronal sections of the cerebellar cortex were subjected to immunohistochemistry with the GFP antibody.

The limited occupancy of the postsynaptic site by individual axons (see, for example, Figures 1A–1D and 1J) further supports this idea because at most neuromuscular junctions at birth, there is

certainly room for many axons to establish synapses. But this estimate assumes that there is no dominant axon at each junction that occupies a large percentage of the territory, and our calculation is also based on the assumption that the number of innervating axons projecting to the muscle remains constant. We therefore needed to obtain a more direct measure of the number axons converging at neuromuscular junctions at birth. We wanted in addition to assay each of these contacts in terms of its size. Thin-section serial scanning

electron microscopy click here of perinatal neuromuscular junctions provided this information (see Experimental Procedures). Seven hundred serial sections (30 nm in thickness) were imaged in the region of the endplate band and three neuromuscular junctions on adjacent muscle fibers were completely reconstructed (Figure 4A, top panel). Because, as already mentioned, single motor unit labeling showed that axons sent only one branch to each junction they innervated (see Figures 1A–1D), it was possible to count the number of different axons converging at the junction by looking at the number of axons entering the junctional site. We counted 7, 8, and 11 axons entering the three adjacent find protocol junctions (Figure 4 and see Figure S1D available online). In each case, all the axons were bundled in a single fascicle and entered the junctional site from the same direction. All (26/26) of the axons entering the junctions were unmyelinated, although a few myelinated motor or sensory axons were visible in the nerve fascicles coursing through the muscle. To quantify how many of the converging axons were actually establishing synaptic contact with the

underlying muscle fiber, we identified all the sites where vesicle-filled profiles of axons were juxtaposed with the muscle fiber membrane with no intervening glial cell or an open gap of greater than 1 μm. In these three reconstructed junctions, 23/26 these (∼88%) of the axons had sites of contact with muscle fiber membrane (Figure 4A, bottom). The individual terminal arbors of each of the 11 axons innervating one of these junctions are shown in Figure 4B. The three axons that did not have contact with muscle fibers (see, for example, axons 10 and 11 in Figure 4B) terminated in vesicle- and mitochondria-filled bulbs emerging from quite thin axonal branches. Each of the axons that did not contact the muscle fiber was in close proximity to sheathing Schwann cells that contained axosomes (Figure S1C; the yellow-tinted Schwann cell is also shown in panels (ii) and (iv) in Figure 4C).

Application of exogenous BDNF to the optic tectum rapidly and profoundly impacts the retinotectal circuit. In vivo imaging of puncta of the synaptic vesicle protein GFP-synaptobrevin in Xenopus retinotectal Dabrafenib price axons has revealed a rapid increase in axonal branching and presynaptic punctum number within minutes to hours of BDNF application ( Alsina et al.,

2001 and Hu et al., 2005). A BDNF-mediated increase in the number of PSD95-GFP positive postsynaptic specializations appears to occur subsequent to presynaptic changes, becoming evident only many hours after neurotrophin application ( Sanchez et al., 2006). Functionally, a rapid increase in mEPSC frequency, but not amplitude, has been reported in response to application of BDNF to the tectum ( Du and Poo, 2004). Our experimental protocol differed from these approaches in two important ways. First, the elevation of BDNF levels in our experiments relied on activity-dependent synthesis and release of endogenous protein rather than application of exogenous neurotrophin. Second, the BDNF-mediated changes that we described occurred only in response to specific

LTP- and LTD-inducing electrical and visual stimulation protocols. Thus, the specific timing and location of neurotrophin delivery may determine its effects on the circuit. This is consistent Fulvestrant solubility dmso with the report that the human BDNF val66met polymorphism which impairs dendritic trafficking and activity-dependent, but not constitutive secretion of BDNF results in abnormal hippocampal function ( Egan et al., 2003). While our own experiments do not distinguish between

pre- and postsynaptic sites of action of the BDNF synthesized in response to visual conditioning stimuli, the efficacy with which MO knockdown of tectal BDNF synthesis fully prevented facilitation of both LTP and LTD clearly points to the postsynaptic cell as the source of newly synthesized BDNF. Retinotectal LTP experiments by Du and colleagues (2009) using MO antisense Endonuclease against TrkB targeted to presynaptic retinal or postsynaptic tectal neurons suggested that BDNF signaling onto both synaptic partners contributed to BDNF-dependent LTP expression. Quite remarkably, this same study also observed a retrograde change in synaptic transmission back in the retina within minutes of BDNF applied exclusively to the tectum. It is clear from our optic chiasm stimulation experiments that endogenous BDNF directly facilitated plasticity at the retinotectal synapse. While we cannot exclude the additional possibility that the newly synthesized BDNF may also have had retrograde effects in the retina that could have contributed to the refinement of visually evoked and behavioral responses that we observed, we did not detect changes in proBDNF levels in the retinae of tadpoles that had undergone visual conditioning (Figure S1).

This suggests that mechanisms other than Homer1a regulate surface mGluR expression during homeostatic scaling, and that changes in surface expression of mGluR5 are not critical for AMPAR trafficking. mGluR5 endocytosis has been reported to occur by both activity-dependent and activity-independent Gefitinib clinical trial pathways (Dhami and Ferguson, 2006). Mechanisms that

control mGluR trafficking in homeostatic scaling and the physiological significance remain to be determined. Group I mGluRs are implicated in several diseases of cognition. For example, mGluR5 signaling is increased in mouse models of fragile X mental retardation syndrome (Huber et al., 2002) and may be relevant in developing therapies (Bear, 2005). Group I mGluR are considered important targets for treatment Ku-0059436 purchase of depression, schizophrenia, and Alzheimer disease (Conn et al., 2009).

Drug addiction is also dependent on mGluR5 signaling as mGluR5 KO mice show a reduced behavioral response to cocaine (Chiamulera et al., 2001) and mGluR5 inverse agonists prevent self administration in monkeys (Lee et al., 2005). The present study focuses attention on the possible role of homeostatic scaling in the pathogenesis of these disorders, and identifies an important physiology to consider in the chronic use of mGluR pharmaceuticals. The following antibodies were previously described or obtained commercially: mGluR1 (mouse monoclonal) from BD Biosciences; mGluR5 from Upstate; N-GluA2 from Chemicon; horse radish peroxidase (HRP)

conjugated HA antibody, HRP-conjugated myc antibody, myc (mouse monoclonal) from Santa Cruz; actin (mouse monoclonal) from Sigma Aldrich. GluA2CPY was described previously (Hayashi and Huganir, 2004). Homer1, Homer2, and Homer3 were generated and described before. The following almost drugs and chemicals were purchased from Tocris Biosciences: tetrodotoxin, bicuculline, Bay 36-7620, MPEP, LY367385, and (S)-MCPG, CPCCOEt. The Homer1a targeting construct was generated by fusing 2.7 kb of genomic DNA, including intron 4 (part thereof) and exon 5 of the Homer1 gene, with part of the rat Homer1c cDNA (2 kb), containing exons 6–10, the hGH polyadenylation site and a “floxed” Pgk-neo cassette, followed by 7.2 kb of Homer1 gene sequence. The linearized (NotI, KpnI) targeting construct was electroporated into ES ([129X1/SvJ × 129S1] F1) cells. G418 resistant ES cell clones were screened by PCR and Southern blotting for homologous recombination. Correctly targeted ES cells were injected into blastocysts, and chimeras were mated with C57BL/6 mice to produce heterozygous Homer1a knockouts. Neuronal cortical cultures from embryonic day 18 (E18) pups were prepared as reported previously (Rumbaugh et al., 2003), with minor alterations. For biochemistry experiments, 1 × 106 neurons were added to each well of a 6-well plate (Corning) coated with poly-L-lysine.

Axon injury in mature neurons triggers injury responses and repair pathways (Abe and Cavalli, 2008). These pathways activate regrowth programs whose effectiveness depends on both the intrinsic growth competence of the neuron (Sun and He, 2010) and the local extracellular environment (Busch and Silver, 2007). Much attention has focused on the regrowth-inhibiting properties of

CNS myelin components such as Nogo (Schwab, 2010). However, the roles of specific myelin components in vivo remain a Baf-A1 in vitro matter of debate (Cafferty et al., 2010 and Lee et al., 2010). Compared to the effects of extrinsic cues, less is known about intrinsic mechanisms affecting regrowth competence. Experimental paradigms such as the conditioning lesion show that neuronal sensitivity to extrinsic influences in regeneration is under the control of intrinsic pathways (Enes et al., 2010, Hannila and Filbin, 2008 and Ylera et al., 2009). Intrinsic triggers of regrowth include positive injury signaling pathways such as the MAP kinases Erk and JNK, which are activated by injury and retrogradely transported from sites of damage (Perlson et al., 2005). Differences

in regenerative ability at different stages also reflect alterations in intrinsic growth capacity (Moore et al., 2009). Analysis of regeneration-competent neurons in the vertebrate PNS and in model organisms has this website given insight into pathways that promote axon regrowth after injury (Ambron et al., 1996 and Chen et al., 2007). Several studies have used genomic or proteomic approaches to identify regeneration-associated genes (Michaelevski et al., 2010). As yet, a limited number of such genes have been tested for function in vivo. An important goal is to exploit new models for large-scale screening and gene discovery that will

open up additional therapeutic avenues. The nematode C. elegans is an emerging model for genetic and chemical screens for factors affecting axon regeneration after injury ( Ghosh-Roy and Chisholm, 2010, Samara et al., 2010 and Wang these and Jin, 2011). Axons labeled with GFP transgenes can be severed precisely with ultrafast laser irradiation ( Yanik et al., 2004). Although laser axotomy of single axons differs in the precise mechanism of damage from mechanical severing or crush injuries of vertebrate nerves, at least some regrowth mechanisms are conserved. In C. elegans, as in vertebrate neurons, the second messengers Ca2+ and cAMP are rate limiting for axonal regrowth ( Ghosh-Roy et al., 2010, Neumann et al., 2002 and Qiu et al., 2002). Pharmacological screening in C. elegans revealed a conserved role for protein kinase C in regenerative growth ( Samara et al., 2010). Finally, the Dual Leucine Zipper Kinase/DLK-1 cascade was first demonstrated in C. elegans as essential for axonal regrowth ( Hammarlund et al., 2009 and Yan et al., 2009) and is required for axon regeneration in Drosophila ( Xiong et al., 2010) and likely in mouse ( Itoh et al., 2009).

Symptomatic male mice have altered hippocampal NMDA Selleckchem CDK inhibitor receptor expression and impairments in LTP and LTD ( Asaka et al., 2006). Male mutant mice also display deficits in cued fear conditioning, while mutant mice of both sexes display deficits in object recognition and altered anxiety ( Stearns et al., 2007). The MeCP2 null mice generated by the Bird and

Jaenisch laboratories display an early onset of symptoms and short life span that differentiates them from classic Rett syndrome and limits the analysis of symptoms. Two groups have developed models that attempted to address these limitations. The Zoghbi group generated the mutant mouse model MeCP2308/Y, possessing a premature stop after codon 308, where mutations have been frequently indentified in humans with Rett syndrome. These mice exhibit a milder phenotype, www.selleckchem.com/products/umi-77.html presumably because the truncated protein retains partial function, characterized by impaired motor function, reduced activity, stereotypic forelimb-clasping movement, and abnormal social interactions (Moretti et al., 2005). MeCP2308/Y mice also display

impaired LTP, increased basal synaptic transmission, and deficits in the induction of LTD, as well as corresponding disruptions in spatial memory, contextual fear conditioning, and long-term social memory (Moretti et al., 2006). Importantly, these mice possess hyperacetylation of H3 (Shahbazian et al., 2002). The Tam group generated another line of MeCP2 null mice (Mecp2tm1Tam) with a deletion of the methyl-binding domain. Behavioral testing of these mice revealed deficits in cerebellar learning and impairments in both cued and contextual fear conditioning and contextual association (Pelka et al., 2006). In Dichloromethane dehalogenase a collaborative effort, the Zoghbi and Sweatt laboratories showed that MeCP2-deficient animals have deficits in spatial learning, contextual fear conditioning, and LTP deficits (Moretti et al., 2006). Moreover, they also showed that overexpression of MeCP2 resulted in enhanced

fear conditioning and enhanced LTP (Collins et al., 2004). Since Rett syndrome is caused by mutations in MeCP2, enhancing MeCP2 levels could therefore be a therapeutic option. Overall, these findings strongly support the idea that MeCP2 might be involved in regulation of LTP and hippocampal-dependent memory formation. Rett syndrome has classically been viewed as a neurodevelopmental disorder, the underlying genetic basis of which is mutation/deletion of the MeCP2 gene and resultant disruption of normal MeCP2 function during prenatal and early postnatal development. This model is consistent with the fact that the mutated gene product is present throughout development. However, the mutant gene product is also present in the fully developed adult CNS.

JNK3 phosphorylates APP at the T668P site in its cytoplasmic domain both in vitro and in vivo. The fact that selleck JNK or JNK3 phosphorylates APP is also supported by a study, where double deletion of putative upstream JNK kinases, MKK4 and MKK7, from another FAD mouse line resulted in a reduction in T668P phosphorylation ( Mazzitelli et al., 2011). T668P phosphorylation was increased in AD brains, wherein the β-CTF rather than the full-length APP exhibited increased T668P phosphorylation compared to the control ( Lee et al., 2003). Supporting the notion that T668

phosphorylation contributes to APP processing, T668P to A668P mutation reduced Aβ peptide generation in vitro ( Lee et al., 2003). Our data also support this view: When JNK phosphorylated APP at T668P, the amount of CTF increased. This was in part due to the fact that JNK phosphorylation of T668P in APP facilitated rapid internalization of the receptor as indicated by a reduction in the amount of the full-length APP on the cell surface. Since JNK3 is not the only kinase that phosphorylates APP at T668P in vivo as indicated by our data, and JNK3 can also be activated in the axon Obeticholic Acid cost under pathological conditions ( Falzone et al., 2009; Morfini et al., 2009), we hypothesize that JNK3 is the predominant kinase that phosphorylates APP within particular endosomal compartments in the axon where APP encounters Chlormezanone BACE1 ( Abe et al.,

2009; Cavalli et al., 2005). Structurally, phosphorylation at T668P induces propyl isomerization, converting the p-T668P peptide from trans to cis configuration ( Ramelot and Nicholson, 2001). Pin1, a phosphorylation-dependent propyl isomerase, indeed binds p-T668P in vitro, thereby facilitating cis to trans conversion ( Pastorino et al., 2006). Since Pin1 deletion from an AD mouse line resulted in a 46% increase in Aβ peptide production, cis configuration induced by T668 phosphorylation

is believed to render APP vulnerable to amyloidogenic processing ( Pastorino et al., 2006). Our data and those of Lee et al. (2003) also support the idea that T668P phosphorylation is critical for Aβ peptide generation in vitro. Whether T668P phosphorylation causes greater Aβ peptide generation in vivo is, however, still unresolved. In normal aged mice, A668P knock-in mutation did not affect β CTF generation ( Sano et al., 2006), leading the authors to conclude that T668P phosphorylation plays no role in APP processing. Such a conclusion is premature especially with gain-of-function mutations such as phosphorylation, until the role of T668P phosphorylation is assessed in AD mouse models. A case in point is that although hyperphosphorylation of tau is clearly indicated as pathologic, deleting tau alone showed a relatively minor defect in axon degeneration ( Dawson et al., 2001; Gómez de Barreda et al., 2010; Harada et al., 1994).