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Degeneration of cholinergic neurons in the basal forebrain (BF) contributes to cognitive impairment in Alzheimer's disease (AD) and other disorders. Atrophy of BF volume measured by structural MRI is thought to represent the loss of cholinergic neurons in this structure. As there are multiple types of neurons in the BF as well as glia and axons, whether this MRI measure actually reflects the change of cholinergic neurons has not been verified. In this study, we assessed BF cholinergic neuron number by histological counts and compared with the volume measurements by in vivo MRI in 3xTg mice, a model of familial AD. Both manual and template-based segmentation revealed atrophy of the medial septum (MS), consistent with a significant reduction in cholinergic neuron number. However, MRI-measured volume reduction did not correlate with the reduced cholinergic neuron number. To directly test whether specific loss of cholinergic neurons results in BF atrophy, we selectively ablated the cholinergic neurons in the MS. However, no detectable change in MRI volume was observed between lesioned and unlesioned mice. The results indicate that although loss of cholinergic neurons within the BF likely contributes to volume loss, this volume change cannot be taken as a direct biomarker of cholinergic neuron number.

Cholinergic signaling plays a crucial role in the regulation of adult hippocampal neurogenesis and hippocampus-dependent cognitive and mood-related functions. However, the contribution of basal forebrain medial septum (MS) and diagonal band of Broca (DBB) cholinergic neurons that innervate the hippocampus and the identity of the cholinergic receptor(s) that regulate the production and maturation of new neurons are not completely understood. Using a targeted, selective ablation approach, we show that MS/DBB cholinergic neurons support both the survival and morphological maturation of adult-born neurons in the mouse hippocampus. We demonstrate that the muscarinic acetycholine receptor subtype M4 (M4 mAChR) is expressed on a population of quiescent neural precursor cells (NPCs) and that its pharmacological stimulation via intra-hippocampal or systemic administration of M4-selective modulators leads to their activation, thereby enhancing neurogenesis in vivo. Furthermore, we show that the activation of M4 mAChR-expressing quiescent NPCs ameliorates the MS/DBB cholinergic lesion-induced decrease in hippocampal neurogenesis. In contrast, the impairment in the morphological maturation of adult-born neurons due to MS/DBB cholinergic neuron loss is further exacerbated by the systemic administration of an M4-selective allosteric potentiator. These findings reveal novel and stage-specific roles of cholinergic signaling in regulating adult hippocampal neurogenesis. They also uncouple the positive role of selective M4 potentiators in enhancing the production of new neurons from the M4-induced inhibition of their morphological maturation, at least in the context of cholinergic dysfunction.Significance statementCholinergic signaling plays an important role in the regulation of adult hippocampal neurogenesis and cognitive function, with impairments in these processes reported as early pathogenic events in age-related dementia. Here, we uncover the presence of cholinergic-responsive hippocampal precursor cells that are are directly activated by selective stimulation of the muscarinic receptor subtype M4. Furthermore, M4-mediated stimulation rescues the decrease in the level of hippocampal neurogenesis following the sepal-hippocampal cholinergic neuron loss. We also reveal that septal-hippocampal cholinergic dysfunction impairs the structural maturation of hippocampal adult-born neurons, an effect which is further exacerbated by M4 receptor modulators. These findings reveal stage-specific roles of cholinergic signaling in regulating functionally relevant adult hippocampal neurogenesis.

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 [

Emerging evidence suggests that people with severe mental illness (SMI) have an increased risk of frailty. We conducted a systematic review to investigate the prevalence and correlates of frailty, as well as the efficacy of frailty interventions, in this population.We searched databases from inception to 21 September 2021 for studies that assessed or intervened for frailty in relation to an SMI diagnosis. A narrative synthesis explored the characteristics and adverse health outcomes associated with frailty and the efficacy of interventions. The prevalence of frailty was investigated, and its relationship with age was analysed by a meta-regression.Twenty-five studies involving 2499 patients, primarily older adults, were included in the narrative synthesis. Frailty was associated with higher rates of physical comorbidity, cognitive deficits, falls and mortality among those with SMI. The efficacy of a yoga intervention was investigated in one study, without sustained reductions in frailty. The prevalence of frailty varied between 10.2 and 89.7% and was high in comparison to the general population.The prevalence of frailty was high in those with SMI and ranged widely due to heterogeneity of study populations. Assessing frailty enables the identification of patients who could benefit from interventions and assists in treatment-related decision making. Further research is required to develop appropriate frailty interventions for this population.

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.

The p75 neurotrophin receptor (p75

Schwann cell reprogramming and differentiation are crucial prerequisites for neuronal regeneration and re-myelination to occur following injury to peripheral nerves. The neurotrophin receptor p75NTR 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 p75NTR knockout mouse models and cannot dissect the specific role of p75NTR expressed by Schwann cells. In this present study, a conditional knockout model selectively deleting p75NTR expression in Schwann cells was generated, where p75NTR expression is replaced with that of an mCherry reporter. Silencing of Schwann cell p75NTR expression was confirmed in the sciatic nerve in vivo and in vitro, without altering axonal expression of p75NTR. 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 p75NTR reduced motor nerve conduction velocity after crush injury. Our data indicate that the absence of Schwann cell p75NTR 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 p75NTR in the peripheral nervous system, suggesting that the Schwann cell-axon unit functions as a syncytium, with the previous published involvement of p75NTR in remyelination most likely depending on axonal/neuronal p75NTR and/or mutual glial-axonal interactions.

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.

The production and circuit integration of new neurons is one of the defining features of the adult mammalian hippocampus. A wealth of evidence has established that adult hippocampal neurogenesis is exquisitely sensitive to neuronal activity-mediated regulation. How these signals are interpreted and contribute to neurogenesis and hippocampal functions has been a subject of immense interest. In particular, neurotransmitters, in addition to their synaptic roles, have been shown to offer important trophic support. Amongst these, acetylcholine, which has a prominent role in cognition, has been implicated in regulating neurogenesis. In this review, we appraise the evidence linking the contribution of cholinergic signalling to the regulation of adult hippocampal neurogenesis and hippocampus-dependent functions. We discuss open questions that need to be addressed to gain a deeper mechanistic understanding of the role and translational potential of acetylcholine and its receptors in regulating this form of cellular neuroplasticity.

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

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 degeneration of cholinergic basal forebrain (cBF) neurons in Alzheimer's disease (AD) leads to the cognitive impairment associated with this condition. cBF neurons express the p75 neurotrophin receptor (p75NTR), which mediates cell death, and the extracellular domain of p75NTR can bind to amyloid beta (Aβ) and promote its degradation. Here, we investigated the contribution of cBF neuronal p75NTR to the progression of AD by removing p75NTR from cholinergic neurons in the APP/PS1 familial AD mouse strain. Conditional loss of p75NTR slowed cognitive decline and reduced both Aβ accumulation into plaques and gliosis. Expression of the amyloid protein precursor and its cleavage enzymes ADAM10 and BACE1 were unchanged. There was also no upregulation of p75NTR in non-cholinergic cell types. This indicates that a direct interaction between cBF-expressed p75NTR and Aβ does not contribute significantly to the regulation of Aβ load. Rather, loss of p75NTR from cBF neurons, which results in increased cholinergic innervation of the cortex, appears to regulate alternative, more dominant, Aβ clearance mechanisms.

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.

Neurotrophins play a critical role in neuronal development and survival, as well as maintenance of the adult nervous system. Neurotrophins can mediate their effects by signalling locally at the nerve terminal, or signalling retrogradely from the axonal terminal to the cell soma to regulate gene expression. Given that the axon terminals of many nerve cells can be up to a metre away from their soma, neurons have evolved specialized long-range signalling platforms that depend on a highly regulated network of intracellular membrane compartments termed "signalling endosomes". Endosomal trafficking of activated receptors controls not only the axonal retrograde signals but also local receptor recycling and degradation. Endosomal trafficking involving the sorting and compartmentalizing of different signals, which are subsequently distributed to the appropriate cellular destination, can at least partially explain how neurotrophins generate a diverse array of signalling outcomes. Although signalling endosomes provide a useful model for understanding how different cell surface receptor-mediated signals are generated and transported, the precise role, identity and functional definition of a signalling endosome remains unclear. In this review we will discuss the regulation of local versus long-range neurotrophin signalling, with a specific focus on recent developments in the role of endosomes in regulating the fate of Trk receptors.

Background: Drug development for Alzheimer disease (AD) is challenged by the success in animal models tested in the Morris water maze (MWM) and the subsequent failures to meet primary outcome measures in phase II or III clinical trials in patients. The human variant of MWM (hMWM) enables us to examine allocentric and egocentric navigation as in the MWM. Objective: It was the aim of this study to examine the utility of a computerized hMWM to assess the effects of donepezil in mild AD. Methods: Donepezil 5 mg/day was started after initial hMWM testing in the treated group (n = 12), and after 28 days, the dose was increased to 10 mg/day. The performance after 3 months was compared to that of a non-treated group (n = 12). Results: Donepezil stabilized or improved the spatial navigation performance after 3 months, especially in the allocentric delayed recall subtask (p = 0.014). Conclusions: The computerized hMWM has the potential to measure the effects of donepezil in mild AD. It is a sensitive cognitive outcome measure in AD clinical trials.

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.

Alzheimer's disease (AD) is a progressive, irreversible neurodegenerative disease that destroys memory and cognitive function. Aggregates of hyperphosphorylated tau protein are a prominent feature in the brain of patients with AD, and are a major contributor to neuronal toxicity and disease progression. However, the factors that initiate the toxic cascade that results in tau hyperphosphorylation in sporadic AD are unknown. Here we investigated whether degeneration of basal forebrain cholinergic neurons (BFCNs) and/or a resultant decrease in neurotrophin signaling cause aberrant tau hyperphosphorylation. Our results reveal that the loss of BFCNs in pre-symptomatic pR5 (P301L) tau transgenic mice results in a decrease in hippocampal brain-derived neurotrophic factor levels and reduced TrkB receptor activation. However, there was no exacerbation of the levels of phosphorylated tau or its aggregation in the hippocampus of susceptible mice. Furthermore the animals' performance in a hippocampal-dependent learning and memory task was unaltered, and no changes in hippocampal synaptic markers were observed. This suggests that tau pathology is likely to be regulated independently of BFCN degeneration and the corresponding decrease in hippocampal neurotrophin levels, although these features may still contribute to disease etiology.

Programmed cell death or apoptosis is a genetically based mechanism that has evolved to eliminate superfluous cells. Upon activation of the extrinsic apoptotic pathway, an extracellular apoptotic signal is transmitted to the cytosol via transmembrane death receptors (DRs) of the tumor necrosis factor receptor superfamily. The apoptotic signal emanating from the DRs initiates one of the two cascades that activate multiple caspases, which eventually dismantle the cell from the inside. However, despite their name, most DRs are also engaged in non-apoptotic signaling pathways, with recent research revealing their important role in a number of biological processes, including development and inflammation.

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.

The common neurotrophin receptor (p75(NTR) ) regulates various functions in the developing and adult nervous system. Cell survival, cell death, axonal and growth cone retraction, and regulation of the cell cycle can be regulated by p75(NTR) -mediated signals following activation by either mature or pro-neurotrophins and in combination with various co-receptors, including Trk receptors and sortilin. Here, we review the known functions of p75(NTR) by cell type, receptor-ligand combination, and whether regulated intra-membrane proteolysis of p75(NTR) is required for signalling. We highlight that the generation of the intracellular domain fragment of p75(NTR) is associated with many of the receptor functions, regardless of its ligand and co-receptor interactions.

Alzheimer's disease (AD) is characterized clinically by an insidious decline in cognition. Much attention has been focused on proposed pathogenic mechanisms that relate Aβ plaque and neurofibrillary tangle pathology to cognitive symptoms, but compelling evidence now identifies early synaptic loss and dysfunction, which precede plaque and tangle formation, as the more probable initiators of cognitive impairment. Glutamate-mediated transmission is severely altered in AD. Glutamate receptor expression is most markedly altered in regions of the AD brain that show the greatest pathological changes. Signaling via glutamate receptors controls synaptic strength and plasticity, and changes in these parameters are likely to contribute to memory and cognitive deficits in AD. Glutamate receptor expression and activity are modulated by interactions with post-synaptic scaffolding proteins that augment the strength and direction of signal cascades initiated by glutamate receptor activity. Scaffold proteins offer promising targets for more focused and effective drug therapy. In consequence, interest is developing into the roles these proteins play in neurological disease. In this review we discuss disruptions to excitatory neurotransmission at the level of glutamate receptor-post-synaptic scaffolding protein interactions that may contribute to synaptic dysfunction in AD.

The generation of amyloid-beta peptide (A) and its accumulation in amyloid plaques are generally recognized as key characteristics of Alzheimer’s disease. A number of reports have indicated that A can regulate the proliferation of neural precursor cells and adult neurogenesis, suggesting that this may underpin the cognitive decline and compromised olfaction also associated with the condition. Here we report that A1–42 treatment both in vitro and in vivo, as well as endogenous generation of A in C100 and APP/PS1 transgenic models of Alzheimer’s disease, stimulate neurogenesis of young adult subventricular zone precursors. The neurogenic effect of A1–42 was found to require expression of the p75 neurotrophin receptor (p75 NTR ) by the precursor cells, and activation of p75 NTR by metalloprotease cleavage. However, precursors from 12-month-old APP/PS1 mice failed to respond to A1–42. Our results suggest that overstimulation of p75 NTR -positive progenitors during early life might result in depletion of the stem cell pool and thus a more rapid decline in basal neurogenesis. This, in turn, could lead to impaired neurogenic function in later life. © 2008 Elsevier Inc. All rights reserved.

It is widely acknowledged that neurogenesis occurs in the adult hippocampus under normal conditions and that the rate can be regulated by environmental factors, including antidepressant drugs, with concomitant effects on behaviour. Using a quick and sensitive flow cytometry method that can assess changes in the number of bromodeoxyuridine (BrdU)-positive cells in hippocampus, in combination with traditional histological cell counts in the dentate gyrus, we report that mice lacking the p75 neurotrophin receptor gene (p75(NTR-/-)) have significantly reduced hippocampal neurogenesis. Chronic treatment with the antidepressant fluoxetine stimulated hippocampal cell proliferation in p75(NTR-/-) animals, but it did not result in an increase above basal levels of the number of newly born neurons in the dentate gyrus. These results indicate that p75(NTR) acts as a regulator of fluoxetine-stimulated as well as basal adult hippocampal neurogenesis.

Although changes to neural circuitry are believed to underlie behavioural characteristics mediated by the hippocampus, the contribution of neurogenesis to this process remains controversial. This is partially because the molecular regulators of neurogenesis remain to be fully elucidated, and experiments generically preventing neurogenesis have, for the most part, depended on paradigms involving irradiation. Here we show that mice lacking the p75 neurotrophin receptor (p75(NTR-/-)) have 25% fewer neuroblasts and 50% fewer newborn neurons in the dentate gyrus, coincident with increased rates of cell death of newly born cells and a significantly smaller granular cell layer and dentate gyrus, than those of p75(NTR+/+) mice. Whereas p75(NTR-/-) mice had increased latency to feed in a novelty-suppressed feeding paradigm they had increased mobility in another test of "depression", the tail-suspension test. p75(NTR-/-) mice also had subtle behavioural impairment in Morris water maze tasks compared to wild-type animals. No difference between genotypes was found in relation to anxiety or exploration behaviour based on the elevated-plus maze, light-dark, hole-board, T-maze or forced-swim tests. Overall, this study demonstrates that p75(NTR) is an important regulator of hippocampal neurogenesis, with concomitant effects on associated behaviours. However, the behavioural attributes of the p75(NTR-/-) mice may be better explained by altered circuitry driven by the loss of p75(NTR) in the basal forebrain, rather than direct changes to neurogenesis.

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.

It has recently been shown that the p75 neurotrophin receptor (p75(NTR)), which is known to mediate neural cell death during development of the nervous system and in a range of adult neurodegenerative conditions, undergoes a regulated process of cell surface receptor cleavage, regulated intramembrane proteolysis (RIP). Here we show that neuronal death signaling occurs only following extracellular metalloprotease cleavage of p75(NTR) and palmitoylation of the resultant C-terminal fragment, causing its translocation to cholesterol-rich domains of the plasma membrane. Furthermore, death signaling is promoted by inhibition of intracellular gamma-secretase cleavage, a process which also occurs within the cholesterol-rich domains. In the presence of TrkA signaling, C-terminal fragment localization in these cholesterol-rich domains is prevented, thereby blocking neuronal death. Thus p75(NTR) activates neuronal death pathways in conditions where the balance of normal RIP is shifted toward extracellular domain cleavage due to increased metalloprotease activity, decreased TrkA activity or compromised gamma-secretase activity, all of which are features of neurodegenerative conditions such as 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.

The pan neurotrophin receptor (p75(NTR)) is best known for mediating neural cell death during development as well as in the adult following injury, the latter making it a target for the treatment of neurodegenerative disease. Although p75(NTR) has been studied for over 30 years, a number of recent discoveries have changed our understanding of its regulation. Here we provide a brief overview of the p75(NTR) protein, its post-translational modifications, and the phenotype of p75(NTR)-deficient mice as a starting point for researchers unfamiliar with this complex receptor. The accepted mechanisms underlying the ability of p75(NTR) to regulate cell death as well as a number of other neural functions, most notably neuronal differentiation, neurite outgrowth and synaptic plasticity, are also summarised.

Zinc release is a primary mediator of neuronal death. Here we show that zinc-mediated death of neurons in vitro is dependent on nerve growth factor (NGF) stimulation and does not occur in response to exposure to leukemia inhibitory factor. NGF priming is regulated, not by the traditional neurotrophin death receptor, p75NTR, but by TrkA, in a protein- and mRNA synthesis-dependent manner. Furthermore, Trk signaling promotes raised free intracellular zinc, mediating neuronal death after extracellular application of zinc. Thus, regulators of Trk signaling provide attractive targets for future treatment of zinc-associated neurological diseases, including stroke, epilepsy and brain trauma.

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 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.