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The p75 neurotrophin receptor (p75NTR ) is required for maintaining peripheral sensory neuron survival and function; however, the underlying cellular mechanism remains unclear. The general view is that expression of p75NTR by the neuron itself is required for maintaining sensory neuron survival and myelination in the peripheral nervous system (PNS). Adopting a neuronal-specific conditional knockout strategy, we demonstrate the partial depletion of p75NTR in neurons exerts little influence upon maintaining sensory neuron survival and peripheral nerve myelination in health and after demyelinating neuropathy. Our data show that the density and total number of dorsal root ganglion (DRG) neurons in 2-month-old mice is not affected following the deletion of p75NTR in large-diameter myelinating neurons, as assessed by stereology. Adopting experimental autoimmune neuritis induced in adult male mice, an animal model of demyelinating peripheral neuropathy, we identify that deleting p75NTR in myelinating neurons exerts no influence upon the disease progression, the total number of DRG neurons, and the extent of myelin damage in the sciatic nerve, indicating that the expression of neuronal p75NTR is not essential for maintaining peripheral neuron survival and myelination after a demyelinating insult in vivo. Together, results of this study suggest that the survival and myelination of peripheral sensory neurons is independent of p75NTR expressed by a subtype of neurons in vivo. Thus, our findings provide new insights into the mechanism underpinning p75NTR -mediated neuronal survival in the PNS.

Inappropriate expansion of antibody-secreting cells (ASCs) is typical of systemic lupus erythematosus (SLE), but the regulatory signaling of pathogenic ASCs is unclear. The present study shows that brain-derived neurotrophic factor precursor (proBDNF) and its high-affinity pan-75 neurotrophin receptor (p75NTR) are highly expressed in CD19+CD27hiCD38hi ASCs in patients with SLE and in CD19+CD44hiCD138+ ASCs in lupus-like mice. The increased proBDNF+ ASCs were positively correlated with clinical symptoms and higher titers of autoantibodies in SLE. Administration of monoclonal antibodies against proBDNF or specific knockout of p75NTR in CD19+ B cells exerted a therapeutic effect on lupus mice by limiting the proportion of ASCs, reducing the production of autoantibodies and attenuating kidney injury. Blocking the biological function of proBDNF or p75NTR also inhibits ASC differentiation and antibody production in vitro. Together, these findings suggest that proBDNF-p75NTR signaling plays a critical pathogenic role in SLE through promoting ASC dysfunction., Description, ProBDNF/p75NTR signaling drives systemic lupus erythematosus by dysregulating antibody-secreting cells.

The mechanism by which antidepressants elicit clinical improvements has proven elusive. In a recent publication in Cell, Casarotto et al. (2021) reveal a surprising direct interaction between antidepressants and TrkB. This link provides an important mechanistic insight into synaptic remodeling that may assist in the design of improved antidepressant therapeutics.

Dysfunction of the cholinergic basal forebrain (BF) neurotransmitter system, including cholinergic axon denervation of the cortex, plays an important role in cognitive decline and dementia. A validated method to directly quantify cortical cholinergic terminal integrity enables exploration of the involvement of this system in diverse cognitive profiles associated with dementia, particularly at a prodromal stage. In this study, we used the radiotracer [

Brain-derived neurotrophic factor (BDNF) signaling plays a major role in the regulation of hippocampal neurogenesis in the adult brain. While the majority of studies suggest that this is due to its effect on the survival and differentiation of newborn neurons, it remains unclear whether this signaling directly regulates neural precursor cell (NPC) activity and which of its two receptors, TrkB or the p75 neurotrophin receptor (p75NTR ) mediates this effect. Here, we examined both the RNA and protein expression of these receptors and found that TrkB but not p75NTR receptors are expressed by hippocampal NPCs in the adult mouse brain. Using a clonal neurosphere assay, we demonstrate that pharmacological blockade of TrkB receptors directly activates a distinct subpopulation of NPCs. Moreover, we show that administration of ANA-12, a TrkB-selective antagonist, in vivo either by systemic intraperitoneal injection or by direct infusion within the hippocampus leads to an increase in the production of new neurons. In contrast, we found that NPC-specific knockout of p75NTR had no effect on the proliferation of NPCs and did not alter neurogenesis in the adult hippocampus. Collectively, these results demonstrate a novel role of TrkB receptors in directly regulating the activity of a subset of hippocampal NPCs and suggest that the transient blockade of these receptors could be used to enhance adult hippocampal neurogenesis.

Alzheimer's disease (AD) is associated with the cleavage of the amyloid precursor protein (APP) to produce the toxic amyloid-β (Aβ) peptide. Accumulation of Aβ, together with the concomitant inflammatory response, ultimately leads to neuronal death and cognitive decline. Despite AD progression being underpinned by both neuronal and immunological components, therapeutic strategies based on dual targeting of these systems remains unexplored. Here, we report that inactivation of the p110δ isoform of phosphoinositide 3-kinase (PI3K) reduces anterograde axonal trafficking of APP in hippocampal neurons and dampens secretion of the inflammatory cytokine tumor necrosis factor-alpha by microglial cells in the familial AD APPswe/PS1ΔE9(APP/PS1) mouse model. Moreover, APP/PS1 mice with kinase-inactive PI3Kδ (δD910A) had reduced Aβ peptides levels and plaques in the brain and an abrogated inflammatory response compared with APP/PS1 littermates. Mechanistic investigations reveal that PI3Kδ inhibition decreases the axonal transport of APP by eliciting the formation of highly elongated tubular-shaped APP-containing carriers, reducing the levels of secreted Aβ peptide. Importantly, APP/PS1/δD910Amice exhibited no spatial learning or memory deficits. Our data highlight inhibition of PI3Kδ as a new approach to protect against AD pathology due to its dual action of dampening microglial-dependent neuroinflammation and reducing plaque burden by inhibition of neuronal APP trafficking and processing.SIGNIFICANCE STATEMENTDuring Alzheimer's disease (AD), the accumulation of the toxic amyloid-β (Aβ) peptide in plaques is associated with a chronic excessive inflammatory response. Uncovering new drug targets that simultaneously reduce both Aβ plaque load and neuroinflammation holds therapeutic promise. Using a combination of genetic and pharmacological approaches, we found that the p110δ isoform of phosphoinositide 3-kinase (PI3K) is involved in anterograde trafficking of the amyloid precursor protein in neurons and in the secretion of tumor necrosis factor-alpha from microglial cells. Genetic inactivation of PI3Kδ reduces Aβ plaque deposition and abrogates the inflammatory response, resulting in a complete rescue of the life span and spatial memory performance. We conclude that inhibiting PI3Kδ represents a novel therapeutic approach to ameliorate AD pathology by dampening plaque accumulation and microglial-dependent neuroinflammation.

Increasing spatial and temporal resolutions of functional MRI (fMRI) measurement has been shown to benefit the study of neural dynamics and functional interaction. However, acceleration of rodent brain fMRI using parallel and simultaneous multi-slice imaging techniques is hampered by the lack of high-density phased-array coils for the small brain. To overcome this limitation, we adapted phase-offset multiplanar and blipped-controlled aliasing echo planar imaging (EPI) to enable simultaneous multi-slice fMRI of the mouse brain using a single loop coil on a 9.4T scanner. Four slice bands of 0.3 × 0.3 × 0.5 mm3 resolution can be simultaneously acquired to cover the whole brain at a temporal resolution of 300 ms or the whole cerebrum in 150 ms. Instead of losing signal-to-noise ratio (SNR), both spatial and temporal SNR can be increased due to the increased k-space sampling compared to a standard single-band EPI. Task fMRI using a visual stimulation shows close to 80% increase of z-score and 4 times increase of activated area in the visual cortex using the multiband EPI due to the highly increased temporal samples. Resting-state fMRI shows reliable detection of bilateral connectivity by both single-band and multiband EPI, but no significant difference was found. Without the need of a dedicated hardware, we have demonstrated a practical method that can enable unparallelly fast whole-brain fMRI for preclinical studies. This technique can be used to increase sensitivity, distinguish transient response or acquire high spatiotemporal resolution fMRI.

There is in vitro evidence that sorting nexin family member 27 (SNX27), a member of the retromer complex, changes the distribution of the amyloid-beta (Aβ) precursor protein (APP) to promote its recycling and thereby prevent the production of Aβ, the toxic protein associated with Alzheimer's disease (AD). In this study, we analyzed the phenotype of the familial AD APP/PS mouse strain lacking one copy of the SNX27 gene. The reduction in SNX27 expression had no significant effect on the in vivo accumulation of soluble, total, or plaque-deposited Aβ, which is overproduced by the familial APP/PS transgenes. Hippocampal structure and cholinergic basal forebrain neuronal health were also unaffected. Nonetheless, mild positive and negative effects of age and/or genotype on spatial navigation performance were observed in SNX27+/− and SNX27+/−APP/PS mice, respectively. These data suggest that downregulation of SNX27 alone does not have long-term negative consequences on spatial memory, but that cognitive dysfunction in the context of high Aβ deposition is exacerbated by the cellular or molecular changes induced by reduced SNX27 function.

Cholinergic basal forebrain (cBF) neurons are particularly vulnerable to degeneration following trauma and in neurodegenerative conditions. One reason for this is their characteristic expression of the p75 neurotrophin receptor (p75 ), which is upregulated and mediates neuronal death in a range of neurological and neurodegenerative conditions, including dementia, stroke, and ischaemia. The signalling pathway by which p75 signals cell death is incompletely characterised, but typically involves activation by neurotrophic ligands and signalling through c-jun kinase, resulting in caspase activation via mitochondrial apoptotic signalling pathways. Less well appreciated is the link between conditions of oxidative stress and p75 death signalling. Here, we review the literature describing what is currently known regarding p75 death signalling in environments of oxidative stress and hypoxia to highlight the overlap in signalling pathways and the implications for p75 signalling in cBF neurons. We propose that there is a causal relationship and define key questions to test this assertion.

In Alzheimer's disease (AD) glial fibrillary acidic protein (GFAP) is expressed by reactive astrocytes surrounding β-amyloid (Aβ) plaques, whereas brain-derived neurotrophic factor (BDNF) levels are typically reduced. We compared the expression of GFAP, BDNF, and its precursor proBDNF in the dorsal hippocampus of two transgenic AD mouse models. APPSwe YAC mice expressing the APPSwe transgene on a yeast artificial chromosome (YAC) were assessed at age 4 and 21 months, and APPSwe/PS1dE9 mice co-expressing mutant amyloid precursor protein (APPSwe) and presenilin-1 (PS1dE9) were assessed at age 4 and 9 months. Significantly increased (1.4-fold) GFAP expression was observed in APPSwe YAC c.f. wild-type (Wt) mice aged 21 months, when Aβ deposition was first evident in these mice. In APPSwe/PS1dE9 mice aged 4 and 9 months, GFAP expression was significantly increased (1.6- and 3.1-fold, respectively) c.f. Wt mice, and was associated with robust Aβ deposition at 9 months. BDNF expression was significantly lower in 4- and 21-month old APPSwe YAC mice (0.8- and 0.6-fold, respectively) c.f. age-matched Wt mice, whereas proBDNF expression was significantly higher (10-fold) in the APPSwe YAC c.f. Wt mice aged 21 months. In APPSwe/PS1dE9 mice aged 4 months, BDNF expression was significantly lower (0.4-fold) c.f. age-matched Wt mice and was equivalent to that in 9-month old mice of both genotypes; proBDNF expression mirrored that of BDNF in this strain. These findings support a role for reactive astrocytes and neuroinflammation, rather than BDNF, in the spatial memory deficits previously reported for APPSwe YAC and APPSwe/PS1dE9 mice.

Epidemiological studies indicate that obstructive sleep apnoea is a strong risk factor for the development of Alzheimer’s disease but the mechanisms of the risk remain unclear. We developed a method of modelling obstructive sleep apnoea in mice that replicates key features of human obstructive sleep apnoea: altered breathing during sleep, sleep disruption, moderate intermittent hypoxemia and cognitive impairment. When we induced obstructive sleep apnoea in a familial Alzheimer’s disease model, the mice displayed exacerbation of cognitive impairment and pathological features of Alzheimer’s disease, including increased levels of amyloid-beta and inflammatory markers, as well as selective degeneration of cholinergic basal forebrain neurons. These pathological features were not induced by chronic hypoxia or sleep disruption alone. Our results also revealed that the neurodegeneration was mediated by the oxygen-sensitive p75 neurotrophin receptor and hypoxia inducible factor 1 alpha activity. Furthermore, restoring blood oxygen levels during sleep to prevent intermittent hypoxia prevented the pathological changes induced by the OSA. These findings provide a signalling mechanism by which obstructive sleep apnoea induces cholinergic basal forebrain degeneration and could thereby increase the risk of developing Alzheimer’s disease, as well as providing a rationale for testing a range of possible prophylactic treatment options for people with obstructive sleep apnoea and hypoxia including increased compliance of continuous positive airway pressure therapy.

Cholinergic basal forebrain (cBF)-derived neurotransmission plays a crucial role in regulating neuronal function throughout the cortex, yet the mechanisms controlling cholinergic innervation to downstream targets have not been elucidated. Here we report that removing the p75 neurotrophin receptor (p75NTR) from cBF neurons induces a significant impairment in fear extinction consolidation. We demonstrate that this is achieved through alterations in synaptic connectivity and functional activity within the medial prefrontal cortex. These deficits revert back to wild-type levels upon re-expression of the active domain of p75NTR in adult animals. These findings demonstrate a novel role for cholinergic neurons in fear extinction consolidation and suggest that neurotrophic signaling is a key regulator of cholinergic-cortical innervation and function.

Cholinergic basal forebrain (cBF) neurons are defined by their expression of the p75 neurotrophin receptor (p75NTR) and tropomyosin-related kinase (Trk) neurotrophin receptors in addition to cholinergic markers. It is known that the neurotrophins, particularly nerve growth factor (NGF), mediate cholinergic neuronal development and maintenance. However, the role of neurotrophin signalling in regulating adult cBF function is less clear, although in dementia, trophic signalling is reduced and p75NTR mediates neurodegeneration of cBF neurons. Here we review the current understanding of how cBF neurons are regulated by neurotrophins which activate p75NTR and TrkA, B or C to influence the critical role that these neurons play in normal cortical function, particularly higher order cognition. Specifically, we describe the current evidence that neurotrophins regulate the development of basal forebrain neurons and their role in maintaining and modifying mature basal forebrain synaptic and cortical microcircuit connectivity. Understanding the role neurotrophin signalling plays in regulating the precision of cholinergic connectivity will contribute to the understanding of normal cognitive processes and will likely provide additional ideas for designing improved therapies for the treatment of neurological disease in which cholinergic dysfunction has been demonstrated.

During development, the p75 neurotrophin receptor (p75NTR) is widely expressed in the nervous system where it regulates neuronal differentiation, migration and axonal outgrowth. p75NTR also mediates the survival and death of newly born neurons, with functional outcomes being dependent on both timing and cellular context. Here we show that knockout of p75NTR from embryonic day 10 (E10) in neural progenitors using a conditional Nestin-Cre; p75NTR floxed mouse causes increased apoptosis of progenitor cells, particularly in the neocortex, ganglionic eminences and preoptic area of embryonic mice. By E14.5, the number of Tbr2-positive progenitor cells was significantly reduced and the rate of neurogenesis was halved. Furthermore, in adult knockout mice, there were fewer upper layer cortical pyramidal neurons, cortical interneurons, cholinergic basal forebrain neurons, and striatal neurons, corresponding to a relative reduction in volume of the cortex and basal ganglia. Thalamic midline fusion during early postnatal development was also impaired in the Nestin-Cre p75NTR floxed mice, indicating a novel role of p75NTR in the formation of this structure. The phenotype of this strain demonstrates that p75NTR regulates multiple aspects of brain development, including cortical progenitor cell survival, and that expression during early neurogenesis is required for appropriate formation of telencephalic structures.

Schwann cell reprogramming and differentiation are crucial prerequisites for neuronal regeneration and re-myelination to occur following injury to peripheral nerves. The neurotrophin receptor p75(NTR) has been identified as a positive modulator for Schwann cell myelination during development and implicated in promoting nerve regeneration after injury. However, most studies base this conclusion on results obtained from complete p75(NTR) knockout mouse models and cannot dissect the specific role of p75(NTR) expressed by Schwann cells. In this present study, a conditional knockout model selectively deleting p75(NTR) expression in Schwann cells was generated, where p75(NTR) expression is replaced with that of an mCherry reporter. Silencing of Schwann cell p75(NTR) expression was confirmed in the sciatic nerve in vivo and in vitro, without altering axonal expression of p75(NTR). No difference in sciatic nerve myelination during development or following sciatic nerve crush injury was observed, as determined by quantification of both myelinated and unmyelinated nerve fiber densities, myelinated axonal diameter and myelin thickness. However, the absence of Schwann cell p75(NTR) reduced motor nerve conduction velocity after crush injury. Our data indicate that the absence of Schwann cell p75(NTR) expression in vivo is not critical for axonal regrowth or remyelination following sciatic nerve crush injury, but does play a key role in functional recovery. Overall, this represents the first step in redefining the role of p75(NTR) in the peripheral nervous system, suggesting that the Schwann cell-axon unit functions as a syncytium, with the previous published involvement of p75(NTR) in remyelination most likely depending on axonal/neuronal p75(NTR) and/or mutual glial-axonal interactions. Funding Agencies|Aarhus University Research Foundation [AUFF-E-2015-FLS-8-4]; Novo Nordisk Foundation [NNF14OC0011633]; Dagmar Marshals Fund; Australian National Health and Medical Research Council [APP1058647]

Summary Major depression is a prevalent and long-lasting psychiatric illness with severe functional impairment and high suicide rate. We have previously shown that the ventrolateral orbital cortex (VLO) plays a key role in the stress responses in mice, but the underlying mechanisms remains unclear. Here, we used proteomic method to identify differentially expressed proteins in VLO of chronic unpredictable mild stress (CUMS) mice. Of 4,953 quantified proteins, 45 proteins were differentially expressed following CUMS. The integrated pathway analyses identified 14-3-3ε and TrkB signaling as differentially downregulated in association with stress-induced depressive-like behaviors. 14-3-3ε overexpression in VLO relieved the depressive-like behaviors by rescue of Bad-mediated apoptosis. Moreover, treatment with the 14-3-3ε stabilizer FC-A precluded neuronal apoptotic signaling in VLO of depressed mice. Because 14-3-3ε provides significant protection against chronic stress, boosting 14-3-3ε expression, pharmacological stabilization of 14-3-3s (e.g. with FC-A) is identified as an exciting therapeutic target for major depression., Graphical abstract, Highlights • Novel screening of chronic mild stress-induced depression phenotypes in mice • Proteomics identify 14-3-3ε as a key modulator of depressive behaviors in VLO • 14-3-3ε partially reversed depressive behaviors through neural apoptotic pathway • 14-3-3ε stabilizer FC-A ameliorates depression phenotypes after chronic mild stress, Neuroscience; Cell Biology; Proteomics

Axonal retrograde transport of signalling endosomes from the nerve terminal to the soma underpins survival. As each signalling endosome carries a quantal amount of activated receptors, we hypothesized that it is the frequency of endosomes reaching the soma that determines the scale of the trophic signal. Here we show that upregulating synaptic activity markedly increased the flux of plasma membrane-derived retrograde endosomes (labelled using cholera toxin subunit-B: CTB) in hippocampal neurons cultured in microfluidic devices, and live Drosophila larval motor neurons. Electron and super-resolution microscopy analyses revealed that the fast-moving sub-diffraction-limited CTB carriers contained the TrkB neurotrophin receptor, transiently activated by synaptic activity in a BDNF-independent manner. Pharmacological and genetic inhibition of TrkB activation selectively prevented the coupling between synaptic activity and the retrograde flux of signalling endosomes. TrkB activity therefore controls the encoding of synaptic activity experienced by nerve terminals, digitalized as the flux of retrogradely transported signalling endosomes., Signalling endosomes are known to be essential for neuronal survival. Here the authors show that, in cultured hippocampal neurons and live Drosophila larval motor neurons, neuronal activity increases the retrograde flux of signalling endosomes, and this coupling depends on TrkB activation.

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by aggregation of toxic forms of amyloid β peptide (Aβ). Treatment strategies have largely been focused on inhibiting the enzymes (β- and γ-secretases) that liberate Aβ from the amyloid precursor protein (APP). While evidence suggests that individuals who exercise regularly are at reduced risk for AD and studies of animal models demonstrate that running can ameliorate brain Aβ pathology and associated cognitive deficits, the underlying mechanisms are unknown. However, considerable evidence suggests that brain-derived neurotrophic factor (BDNF) mediates beneficial effects of exercise on neuroplasticity and cellular stress resistance. Here we tested the hypothesis that BDNF promotes non-amyloidogenic APP processing. Using a transgenic mouse model of Alzheimer’s disease and cultured human neural cells, we demonstrate that exercise and BDNF reduce production of toxic Aβ peptides through a mechanism involving enhanced α-secretase processing of APP. This anti-amyloidogenic APP processing involves subcellular redistribution of α-secretase and an increase in intracellular neuroprotective APP peptides capable of binding and inhibiting BACE1. Moreover, our results suggest that BDNF’s ability to promote neurite outgrowth is primarily exerted through pathways other than APP processing. Exercise and other factors that enhance BDNF signaling may therefore have both therapeutic and prophylactic value in the battle against AD.

The brains of patients suffering from Alzheimer's disease (AD) have three classical pathological hallmarks: amyloid-beta (Aβ) plaques, tau tangles, and neurodegeneration, including that of cholinergic neurons of the basal forebrain. However the relationship between Aβ burden and basal forebrain degeneration has not been extensively studied. To investigate this association, basal forebrain volumes were determined from magnetic resonance images of controls, subjects with amnestic mild cognitive impairment (aMCI) and AD patients enrolled in the longitudinal Alzheimer's Disease Neuroimaging Initiative (ADNI) and Australian Imaging, Biomarkers and Lifestyle (AIBL) studies. In the AIBL cohort, these volumes were correlated within groups to neocortical gray matter retention of Pittsburgh compound B (PiB) from positron emission tomography images as a measure of Aβ load. The basal forebrain volumes of AD and aMCI subjects were significantly reduced compared to those of control subjects. Anterior basal forebrain volume was significantly correlated to neocortical PiB retention in AD subjects and aMCI subjects with high Aβ burden, whereas posterior basal forebrain volume was significantly correlated to neocortical PiB retention in control subjects with high Aβ burden. Therefore this study provides new evidence for a correlation between neocortical Aβ accumulation and basal forebrain degeneration. In addition, cluster analysis showed that subjects with a whole basal forebrain volume below a determined cut-off value had a 7 times higher risk of having a worse diagnosis within ~18 months., Highlights • The link between amyloid (Aβ) and basal forebrain degeneration in AD is unclear. • We find that basal forebrain volumes are correlated with neocortical Aβ burden. • Basal forebrain volume correlates with Aβ burden in at-risk control subjects. • Basal forebrain atrophy delineates subjects at increased risk of progressing to AD.

Loss of basal forebrain cholinergic neurons is an early and key feature of Alzheimer's disease, and magnetic resonance imaging (MRI) volumetric measurement of the basal forebrain has recently gained attention as a potential diagnostic tool for this condition. The aim of this study was to determine whether loss of basal forebrain cholinergic neurons underpins changes which can be detected through diffusion MRI using diffusion tensor imaging (DTI) and probabilistic tractography in a mouse model. To cause selective basal forebrain cholinergic degeneration, the toxin saporin conjugated to a p75 neurotrophin receptor antibody (mu-p75-SAP) was used. This resulted in ~25% loss of the basal forebrain cholinergic neurons and significant loss of terminal cholinergic projections in the hippocampus, as determined by histology. To test whether lesion of cholinergic neurons caused basal forebrain, hippocampal, or whole brain atrophy, we performed manual segmentation analysis, which revealed no significant atrophy in lesioned animals compared to controls (Rb-IgG-SAP). However, analysis by DTI of the basal forebrain area revealed a significant increase in fractional anisotropy (FA; +7.7%), mean diffusivity (MD; +6.1%), axial diffusivity (AD; +8.5%) and radial diffusivity (RD; +4.0%) in lesioned mice compared to control animals. These parameters strongly inversely correlated with the number of choline acetyl transferase-positive neurons, with FA showing the greatest association (r(2)=0.72), followed by MD (r(2)=0.64), AD (r(2)=0.64) and RD (r(2)=0.61). Moreover, probabilistic tractography analysis of the septo-hippocampal tracts originating from the basal forebrain revealed an increase in streamline MD (+5.1%) and RD (+4.3%) in lesioned mice. This study illustrates that moderate loss of basal forebrain cholinergic neurons (representing only a minor proportion of all septo-hippocampal axons) can be detected by measuring either DTI parameters of the basal forebrain nuclei or tractography parameters of the basal forebrain tracts. These findings provide increased support for using DTI and probabilistic tractography as non-invasive tools for diagnosing and/or monitoring the progression of conditions affecting the integrity of the basal forebrain cholinergic system in humans, including Alzheimer's disease.

Cleavage of transmembrane receptors by γ-secretase is the final step in the process of regulated intramembrane proteolysis (RIP) and has a significant impact on receptor function. Although relatively little is known about the molecular mechanism of γ-secretase enzymatic activity, it is becoming clear that substrate dimerization and/or the α-helical structure of the substrate can regulate the site and rate of γ-secretase activity. Here we show that the transmembrane domain of the pan-neurotrophin receptor p75(NTR), best known for regulating neuronal death, is sufficient for its homodimerization. Although the p75(NTR) ligands NGF and pro-NGF do not induce homerdimerization or RIP, homodimers of p75(NTR) are γ-secretase substrates. However, dimerization is not a requirement for p75(NTR) cleavage, suggesting that γ-secretase has the ability to recognize and cleave each receptor molecule independently. The transmembrane cysteine 257, which mediates covalent p75(NTR) interactions, is not crucial for homodimerization, but this residue is required for normal rates of γ-secretase cleavage. Similarly, mutation of the residues alanine 262 and glycine 266 of an AXXXG dimerization motif flanking the γ-secretase cleavage site within the p75(NTR) transmembrane domain alters the orientation of the domain and inhibits γ-secretase cleavage of p75(NTR). Nonetheless, heteromer interactions of p75(NTR) with TrkA increase full-length p75(NTR) homodimerization, which in turn potentiates the rate of γ-cleavage following TrkA activation independently of rates of α-cleavage. These results provide support for the idea that the helical structure of the p75(NTR) transmembrane domain, which may be affected by co-receptor interactions, is a key element in γ-secretase-catalyzed cleavage.

Alzheimer's disease is characterized by the accumulation of neurotoxic amyloidogenic peptide Aβ, degeneration of the cholinergic innervation to the hippocampus (the septohippocampal pathway), and progressive impairment of cognitive function, particularly memory. Aβ is a ligand for the p75 neurotrophin receptor (p75NTR), which is best known for mediating neuronal death and has been consistently linked to the pathology of Alzheimer's disease. Here we examined whether p75NTRis required for Aβ-mediated effects. Treatment of wild-type but not p75NTR-deficient embryonic mouse hippocampal neurons with human Aβ1–42peptide induced significant cell death. Furthermore, injection of Aβ1–42into the hippocampus of adult mice resulted in significant degeneration of wild-type but not p75NTR-deficient cholinergic basal forebrain neurons, indicating that the latter are resistant to Aβ-induced toxicity. We also found that neuronal death correlated with Aβ1–42peptide-stimulated accumulation of the death-inducing p75NTRC-terminal fragment generated by extracellular metalloprotease cleavage of full-length p75NTR. Although neuronal death was prevented in the presence of the metalloprotease inhibitor TAPI-2 (tumor necrosis factor-α protease inhibitor-2), Aβ1–42-induced accumulation of the C-terminal fragment resulted from inhibition of γ-secretase activity. These results provide a novel mechanism to explain the early and characteristic loss of cholinergic neurons in the septohippocampal pathway that occurs in Alzheimer's disease.

The pan neurotrophin receptor p75NTRsignals programmed cell death both during nervous system development and after neural trauma and disease in the adult. However, the molecular pathways by which death is mediated remain poorly understood. Here, we show that this cell death is initiated by activation of G-protein-coupled inwardly rectifying potassium (GIRK/Kir3) channels and a consequent potassium efflux. Death signals stimulated by neurotrophin-mediated cleavage of p75NTRactivate GIRK channels through the generation and binding of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2/PIP2] to GIRK channels. Both GIRK channel activity and p75NTR-mediated neuronal death are inhibited by sequestration of PtdIns(4,5)P2and application of GIRK channel inhibitors, whereas pertussis toxin treatment has no effect. Thus, p75NTRactivates GIRK channels without the need for Gi/o-proteins. Our results demonstrate a novel mode of activation of GIRK channels, representing an early step in the p75NTR-mediated cell death pathway and suggesting a function for these channels during nervous system development.

This Editorial highlights a study by Hermey and colleagues in the current issue of Journal of Neurochemistry. In their study, the authors provide novel insights into single-nucleotide polymorphisms associated with Alzheimer's disease and linked to the SorCS1 gene, toward a better understanding of the interaction of sorting receptor proteins which physically interact with the amyloid-beta protein precursor (APP). SorCS1, sortilin-related VPS10 domain-containing receptor 1; SorLA, sortilin-related Receptor with A-type Repeats. Read the full article 'SorCS1 variants and amyloid precursor protein (APP) are co-transported in neurons but only SorCS1c modulates anterograde APP transport' on page 60.

The basal forebrain degenerates in Alzheimer's disease (AD) and this process is believed to contribute to the cognitive decline observed in AD patients. Impairment in spatial navigation is an early feature of the disease but whether basal forebrain dysfunction in AD is responsible for the impaired navigation skills of AD patients is not known. Our objective was to investigate the relationship between basal forebrain volume and performance in real space as well as computer-based navigation paradigms in an elderly cohort comprising cognitively normal controls, subjects with amnestic mild cognitive impairment and those with AD. We also tested whether basal forebrain volume could predict the participants' ability to perform allocentric- vs. egocentric-based navigation tasks. The basal forebrain volume was calculated from 1.5 T magnetic resonance imaging (MRI) scans, and navigation skills were assessed using the human analog of the Morris water maze employing allocentric, egocentric, and mixed allo/egocentric real space as well as computerized tests. When considering the entire sample, we found that basal forebrain volume correlated with spatial accuracy in allocentric (cued) and mixed allo/egocentric navigation tasks but not the egocentric (uncued) task, demonstrating an important role of the basal forebrain in mediating cue-based spatial navigation capacity. Regression analysis revealed that, although hippocampal volume reflected navigation performance across the entire sample, basal forebrain volume contributed to mixed allo/egocentric navigation performance in the AD group, whereas hippocampal volume did not. This suggests that atrophy of the basal forebrain contributes to aspects of navigation impairment in AD that are independent of hippocampal atrophy.

The basal forebrain degenerates in Alzheimer’s disease (AD) and this process is believed to contribute to the cognitive decline observed in AD patients. Impairment in spatial navigation is an early feature of the disease but whether basal forebrain dysfunction in AD is responsible for the impaired navigation skills of AD patients is not known. Our objective was to investigate the relationship between basal forebrain volume and performance in real space as well as computer-based navigation paradigms in an elderly cohort comprising cognitively normal controls, subjects with amnestic mild cognitive impairment and those with AD. We also tested whether basal forebrain volume could predict the participants’ ability to perform allocentric- vs. egocentric-based navigation tasks. The basal forebrain volume was calculated from 1.5 T MRI scans, and navigation skills were assessed using the human analog of the Morris water maze employing allocentric, egocentric and mixed allo/egocentric real space as well as computerized tests. When considering the entire sample, we found that basal forebrain volume correlated with spatial accuracy in allocentric (cued) and mixed allo/egocentric navigation tasks but not the egocentric (uncued) task, demonstrating an important role of the basal forebrain in mediating cue-based spatial navigation capacity. Regression analysis revealed that, although hippocampal volume reflected navigation performance across the entire sample, basal forebrain volume contributed to mixed allo/egocentric navigation performance in the AD group, whereas hippocampal volume did not. This suggests that atrophy of the basal forebrain contributes to aspects of navigation impairment in AD that are independent of hippocampal atrophy.

The p75 neurotrophin receptor (p75(NTR); also known as NGFR) can mediate neuronal apoptosis in disease or following trauma, and facilitate survival through interactions with Trk receptors. Here we tested the ability of a p75(NTR)-derived trophic cell-permeable peptide, c29, to inhibit p75(NTR)-mediated motor neuron death. Acute c29 application to axotomized motor neuron axons decreased cell death, and systemic c29 treatment of SOD1(G93A) mice, a common model of amyotrophic lateral sclerosis, resulted in increased spinal motor neuron survival mid-disease as well as delayed disease onset. Coincident with this, c29 treatment of these mice reduced the production of p75(NTR) cleavage products. Although c29 treatment inhibited mature- and pro-nerve-growth-factor-induced death of cultured motor neurons, and these ligands induced the cleavage of p75(NTR) in motor-neuron-like NSC-34 cells, there was no direct effect of c29 on p75(NTR) cleavage. Rather, c29 promoted motor neuron survival in vitro by enhancing the activation of TrkB-dependent signaling pathways, provided that low levels of brain-derived neurotrophic factor (BDNF) were present, an effect that was replicated in vivo in SOD1(G93A) mice. We conclude that the c29 peptide facilitates BDNF-dependent survival of motor neurons in vitro and in vivo.

Alzheimer's disease is characterized by the over-production and accumulation of amyloidogenic Abeta peptide, which can induce cell death in vitro. It has been suggested that the death signal could be transduced by the pan neurotrophin receptor (p75NTR). p75NTR is well known for its ability to mediate neuronal death in neurodegenerative conditions and is inextricably linked with changes that occur in Alzheimer's disease. Moreover, Abeta binds to p75NTR, activating signalling cascades. However, the complexity of p75NTR-mediated signalling, which does not always promote cell death, leaves open the possibly of Abeta promoting death via an alternative signalling pathway or the regulation of other p75NTR-mediated actions. This review focuses on the interactions between Abeta and p75NTR in the context of the broader p75NTR signalling field, and offers alternative explanations for how p75NTR might contribute to the aetiology of Alzheimer's disease.

This study characterized the ability of a new member of the p35 family, p49, to inhibit a number of mammalian and insect caspases. p49 blocked apoptosis triggered by treatment with Fas ligand (FasL), Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or ultraviolet (UV) radiation but provided negligible protection against apoptosis induced by the chemotherapeutic drug cisplatin. The caspase cleavage site in p49 was determined, and mutation of the P1 residue of this site abolished the ability of p49 to inhibit caspases, implying that p49 inhibits caspases through an analogous suicide-substrate mechanism to p35. Unlike p35, p49 inhibited the upstream insect caspase DRONC.

The role of the p75 neurotrophin receptor (p75NTR) in adult cholinergic basal forebrain (cBF) neurons is unclear due to conflicting results from previous studies and to limitations of existing p75NTR-knock-out mouse models. In the present study we used a novel conditional knock-out line (ChAT-cre p75in/in) to assess the role of p75NTRin the cBF by eliminating p75NTRin choline acetyl-transferase-expressing cells. We show that the absence of p75NTRresults in a lasting increase in cBF cell number, cell size, and cholinergic innervation to the cortex. Analysis of adult ChAT-cre p75in/inmice revealed that mutant animals show a similar loss of cBF neurons with age to that observed in wild-type animals, indicating that p75NTRdoes not play a significant role in mediating this age-related decline in cBF neuronal number. However, the increased cholinergic axonal innervation of the cortex, but not the hippocampus, corresponded to alterations in idiothetic but not allothetic navigation. These findings support a role for p75NTR-mediated regulation of cholinergic-dependent cognitive function, and suggest that the variability in previous reports of cBF neuron number may stem from limited spatial and temporal control of p75NTRexpression in existing knock-out models.

JIA is the most common chronic inflammatory arthritis in children and young people and an estimated one-third of individuals will have persistent active disease into adulthood. There are a number of key differences in the clinical manifestations, assessment and management of JIA compared with adult-onset arthritis. Transition and transfer to adult services present significant challenges for many patients, their families and health care professionals. We describe key clinical issues relevant to adult rheumatology health care teams responsible for ongoing care of these young people.

Soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs) are crucial for exocytosis, trafficking, and neurite outgrowth, where vesicular SNAREs are directed toward their partner target SNAREs: synaptosomal-associated protein of 25 kDa and syntaxin. SNARE proteins are normally membrane bound, but can be cleaved and released by botulinum neurotoxins. We found that botulinum proteases types C and D can easily be transduced into endocrine cells using DNA-transfection reagents. Following administration of the C and D proteases into normally refractory Neuro2A neuroblastoma cells, the SNARE proteins were cleaved with high efficiency within hours. Remarkably, botulinum protease exposures led to cytotoxicity evidenced by spectrophotometric assays and propidium iodide penetration into the nuclei. Direct delivery of SNARE fragments into the neuroblastoma cells reduced viability similar to botulinum proteases' application. We observed synergistic cytotoxic effects of the botulinum proteases, which may be explained by the release and interaction of soluble SNARE fragments. We show for the first time that previously observed cytotoxicity of botulinum neurotoxins/C in neurons could be achieved in cells of neuroendocrine origin with implications for medical uses of botulinum preparations.

The p75 neurotrophin receptor (p75NTR) has been shown to mediate neuronal death through an unknown pathway. We microinjected p75NTR expression plasmids into sensory neurons in the presence of growth factors and assessed the effect of the expressed proteins on cell survival. We show that, unlike other members of the TNFR family, p75NTR signals death through a unique caspase-dependent death pathway that does not involve the "death domain" and is differentially regulated by Bcl-2 family members: the anti-apoptotic molecule Bcl-2 both promoted, and was required for, p75NTR killing, whereas killing was inhibited by its homologue Bcl-xL. These results demonstrate that Bcl-2, through distinct molecular mechanisms, either promotes or inhibits neuronal death depending on the nature of the death stimulus.

JIA is the most common chronic inflammatory arthritis in children and young people. More than one-third of individuals have persistent active disease into adulthood. In RA, there has been considerable interest in long-term cardiovascular outcomes. Increased cardiovascular mortality and morbidity have been observed and consensus guidelines recommend annual cardiovascular risk assessment for adults with RA. The increased risk is attributed to a higher prevalence of traditional cardiovascular risk factors and the role of systemic inflammation in the acceleration of atherosclerosis. The long-term risk of cardiovascular disease for individuals with JIA remains uncertain and guidance on risk assessment is not currently available. Given the potential for longer disease duration, it is possible that cardiovascular risk in this group surpasses that observed in adult-onset inflammatory arthritides. In this article, we consider the evidence for cardiovascular risk in JIA.

Transit of proteins through the endosomal organelle following endocytosis is critical for regulating the homeostasis of cell-surface proteins and controlling signal transduction pathways. However, the mechanisms that control these membrane-transport processes are poorly understood. The Phox-homology (PX) domain-containing proteins sorting nexin (SNX) 17, SNX27, and SNX31 have emerged recently as key regulators of endosomal recycling and bind conserved Asn-Pro-Xaa-Tyr–sorting signals in transmembrane cargos via an atypical band, 4.1/ezrin/radixin/moesin (FERM) domain. Here we present the crystal structure of the SNX17 FERM domain bound to the sorting motif of the P-selectin adhesion protein, revealing both the architecture of the atypical FERM domain and the molecular basis for recognition of these essential sorting sequences. We further show that the PX-FERM proteins share a promiscuous ability to bind a wide array of putative cargo molecules, including receptor tyrosine kinases, and propose a model for their coordinated molecular interactions with membrane, cargo, and regulatory proteins.

Axonal retrograde transport of signalling endosomes from the nerve terminal to the soma underpins survival. As each signalling endosome carries a quantal amount of activated receptors, we hypothesized that it is the frequency of endosomes reaching the soma that determines the scale of the trophic signal. Here we show that upregulating synaptic activity markedly increased the flux of plasma membrane-derived retrograde endosomes (labelled using cholera toxin subunit-B: CTB) in hippocampal neurons cultured in microfluidic devices, and live Drosophila larval motor neurons. Electron and super-resolution microscopy analyses revealed that the fast-moving sub-diffraction-limited CTB carriers contained the TrkB neurotrophin receptor, transiently activated by synaptic activity in a BDNF-independent manner. Pharmacological and genetic inhibition of TrkB activation selectively prevented the coupling between synaptic activity and the retrograde flux of signalling endosomes. TrkB activity therefore controls the encoding of synaptic activity experienced by nerve terminals, digitalized as the flux of retrogradely transported signalling endosomes.