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DURING development, neuronal survival is regulated by the limited availability of neurotrophins, which are proteins of the nerve growth factor (NGF) family. Activation of specific trk tyrosine kinase receptors by the neurotrophins blocks programmed cell death. The trk A-specific ligand NGF has also been shown to activate the non-tyrosine kinase receptor p75, a member of the tumour necrosis factor (TNF) receptor and Fas (APO-1/CD95) family. Here we report that, early in development, endogenous NGF causes the death of retinal neurons that express p75 but not trk A. These results indicate that, as with cells of the immune system, the death of neurons in the central nervous system can also be induced by ligands, and that the effect of NGF on cell fate depends on the type of receptor expressed by developing neurons.

Traumatic brain injury (TBI) is one of the leading causes of mortality and disability worldwide without any validated biomarker or set of biomarkers to help the diagnosis and evaluation of the evolution/prognosis of TBI patients. To achieve this aim, a deeper knowledge of the biochemical and pathophysiological processes triggered after the trauma is essential. Here, we identified the serum amyloid A1 protein-Toll-like receptor 4 (SAA1-TLR4) axis as an important link between inflammation and the outcome of TBI patients. Using serum and mRNA from white blood cells (WBC) of TBI patients, we found a positive correlation between serum SAA1 levels and injury severity, as well as with the 6-month outcome of TBI patients. SAA1 levels also correlate with the presence of TLR4 mRNA in WBC. In vitro, we found that SAA1 contributes to inflammation via TLR4 activation that releases inflammatory cytokines, which in turn increases SAA1 levels, establishing a positive proinflammatory loop. In vivo, post-TBI treatment with the TLR4-antagonist TAK242 reduces SAA1 levels, improves neurobehavioral outcome, and prevents blood–brain barrier disruption. Our data support further evaluation of (i) post-TBI treatment in the presence of TLR4 inhibition for limiting TBI-induced damage and (ii) SAA1-TLR4 as a biomarker of injury progression in TBI patients.

E2F4 is a transcription factor involved in cellular homeostasis and a substrate of the stress-activated kinase p38MAPK, which phosphorylates a conserved Thr248/Thr250 motif. A non-phosphorylatable mutant, E2F4DN (Thr248Ala/Thr250Ala), has demonstrated preclinical efficacy in a murine model of Alzheimer's disease (AD), but its mechanism of action remains unknown. We hypothesized that cell stress-induced phosphorylation disrupts E2F4's homeostatic function, whereas exogenous E2F4DN restores it. To begin testing this hypothesis, we treated differentiated N2a neuroblastoma cells (N2a neuron-like cells) with camptothecin (CPT) to induce genotoxic stress. CPT activated p38MAPK within 8 h, leading to phosphorylation of E2F4 at Thr248/Thr250. We then overexpressed E2F4DN or a phosphomimetic variant, E2F4CA (Thr248Glu/Thr250Glu), and assessed apoptosis via procaspase-3 cleavage. The pro-apoptotic factor E2F1 strongly induced caspase-3 activation in this model system. This effect was partially mimicked by E2F4CA, while E2F4DN markedly suppressed it. Notably, E2F4DN, but not E2F4CA, upregulated the antiapoptotic factor Cited2, and knockdown experiments suggest it may contribute to E2F4DN's protective effect. Overall, these findings indicate that E2F4DN counteracts p38MAPK-driven neuronal apoptosis and helps preserve neuronal homeostasis, at least in part, through Cited2 upregulation. This provides mechanistic insight into the neuroprotective role of E2F4DN as a potential therapy for AD.E2F4 is a transcription factor involved in cellular homeostasis and a substrate of the stress-activated kinase p38MAPK, which phosphorylates a conserved Thr248/Thr250 motif. A non-phosphorylatable mutant, E2F4DN (Thr248Ala/Thr250Ala), has demonstrated preclinical efficacy in a murine model of Alzheimer's disease (AD), but its mechanism of action remains unknown. We hypothesized that cell stress-induced phosphorylation disrupts E2F4's homeostatic function, whereas exogenous E2F4DN restores it. To begin testing this hypothesis, we treated differentiated N2a neuroblastoma cells (N2a neuron-like cells) with camptothecin (CPT) to induce genotoxic stress. CPT activated p38MAPK within 8 h, leading to phosphorylation of E2F4 at Thr248/Thr250. We then overexpressed E2F4DN or a phosphomimetic variant, E2F4CA (Thr248Glu/Thr250Glu), and assessed apoptosis via procaspase-3 cleavage. The pro-apoptotic factor E2F1 strongly induced caspase-3 activation in this model system. This effect was partially mimicked by E2F4CA, while E2F4DN markedly suppressed it. Notably, E2F4DN, but not E2F4CA, upregulated the antiapoptotic factor Cited2, and knockdown experiments suggest it may contribute to E2F4DN's protective effect. Overall, these findings indicate that E2F4DN counteracts p38MAPK-driven neuronal apoptosis and helps preserve neuronal homeostasis, at least in part, through Cited2 upregulation. This provides mechanistic insight into the neuroprotective role of E2F4DN as a potential therapy for AD.

Retinal ganglion cells (RGCs) are neurons that relay visual signals from the retina to the brain. The RGC cell bodies reside in the retina and their fibers form the optic nerve. Full transection (axotomy) of the optic nerve is an extra-retinal injury model of RGC degeneration. Optic nerve transection permits time-kinetic studies of neurodegenerative mechanisms in neurons and resident glia of the retina, the early events of which are reported here. One day after injury, and before atrophy of RGC cell bodies was apparent, glia had increased levels of phospho-Akt, phospho-S6, and phospho-ERK1/2; however, these signals were not detected in injured RGCs. Three days after injury there were increased levels of phospho-Rb and cyclin A proteins detected in RGCs, whereas these signals were not detected in glia. DNA hyperploidy was also detected in RGCs, indicative of cell cycle re-entry by these post-mitotic neurons. These events culminated in RGC death, which is delayed by pharmacological inhibition of the MAPK/ERK pathway. Our data show that a remote injury to RGC axons rapidly conveys a signal that activates retinal glia, followed by RGC cell cycle re-entry, DNA hyperploidy, and neuronal death that is delayed by preventing glial MAPK/ERK activation. These results demonstrate that complex and variable neuro-glia interactions regulate healthy and injured states in the adult mammalian retina.

E2F4 is a transcription factor involved in cellular homeostasis and a substrate of the stress-activated kinase p38 , which phosphorylates a conserved Thr248/Thr250 motif. A non-phosphorylatable mutant, E2F4DN (Thr248Ala/Thr250Ala), has demonstrated preclinical efficacy in a murine model of Alzheimer's disease (AD), but its mechanism of action remains unknown. We hypothesized that cell stress-induced phosphorylation disrupts E2F4's homeostatic function, whereas exogenous E2F4DN restores it. To begin testing this hypothesis, we treated differentiated N2a neuroblastoma cells (N2a neuron-like cells) with camptothecin (CPT) to induce genotoxic stress. CPT activated p38 within 8 h, leading to phosphorylation of E2F4 at Thr248/Thr250. We then overexpressed E2F4DN or a phosphomimetic variant, E2F4CA (Thr248Glu/Thr250Glu), and assessed apoptosis via procaspase-3 cleavage. The pro-apoptotic factor E2F1 strongly induced caspase-3 activation in this model system. This effect was partially mimicked by E2F4CA, while E2F4DN markedly suppressed it. Notably, E2F4DN, but not E2F4CA, upregulated the antiapoptotic factor Cited2, and knockdown experiments suggest it may contribute to E2F4DN's protective effect. Overall, these findings indicate that E2F4DN counteracts p38 -driven neuronal apoptosis and helps preserve neuronal homeostasis, at least in part, through Cited2 upregulation. This provides mechanistic insight into the neuroprotective role of E2F4DN as a potential therapy for AD.

Neurons of the peripheral nervous system have long been known to require survival factors to prevent their death during development. But why they selectively become dependent on secretory molecules has remained a mystery, as is the observation that in the central nervous system, most neurons do not show this dependency. Using engineered embryonic stem cells, we show here that the neurotrophin receptors TrkA and TrkC (tropomyosin receptor kinase A and C, also known as Ntrk1 and Ntrk3, respectively) instruct developing neurons to die, both in vitro and in vivo . By contrast, TrkB (also known as Ntrk2), a closely related receptor primarily expressed in the central nervous system, does not. These results indicate that TrkA and TrkC behave as dependence receptors, explaining why developing sympathetic and sensory neurons become trophic-factor-dependent for survival. We suggest that the expansion of the Trk gene family that accompanied the segregation of the peripheral from the central nervous system generated a novel mechanism of cell number control. Neuronal cells on a knife-edge Neurons of the peripheral nervous system need trophic factors — natural growth factors that sustain cell proliferation and development — if they are to survive. Most neurons in the central nervous system can do without such support. Why are peripheral neurons so needy? Using engineered embryonic stem cells, Nikoletopoulou et al . show that the neurotrophin receptors TrkA and TrkC act as 'dependence receptors' in developing neurons, triggering cell death in the absence of protective factors. TrkB, a closely related receptor primarily expressed in the central nervous system, does not. This suggests that the expansion of the Trk gene family that accompanied the segregation of the peripheral and central nervous systems may have generated a mechanism for cell number control. Neurons of the peripheral nervous system need survival factors to prevent their death during development. Most in the central nervous system do not. Why are peripheral neurons so needy? Here it is shown that the neurotrophin receptors TrkA and TrkC, expressed at high levels by many peripheral nervous system neurons, behave as dependence receptors: they instruct neurons to die if there is no ligand around. By contrast, TrkB, expressed mainly in the central nervous system, does not signal death in the absence of ligand.

The development of neuroprotective therapies is a sought-after goal. By screening combinatorial chemical libraries using in vitro assays, we identified the small molecule BN201 that promotes the survival of cultured neural cells when subjected to oxidative stress or when deprived of trophic factors. Moreover, BN201 promotes neuronal differentiation, the differentiation of precursor cells to mature oligodendrocytes in vitro, and the myelination of new axons. BN201 modulates several kinases participating in the insulin growth factor 1 pathway including serum–glucocorticoid kinase and midkine, inducing the phosphorylation of NDRG1 and the translocation of the transcription factor Foxo3 to the cytoplasm. In vivo, BN201 prevents axonal and neuronal loss, and it promotes remyelination in models of multiple sclerosis, chemically induced demyelination, and glaucoma. In summary, we provide a new promising strategy to promote neuroaxonal survival and remyelination, potentially preventing disability in brain diseases.

Traumatic brain injury (TBI) is increasingly recognised as being responsible for a substantial proportion of the global burden of disease. Neurosurgical interventions are an important aspect of care for patients with TBI, but there is little epidemiological data available on this patient population. We aimed to characterise differences in casemix, management, and mortality of patients receiving emergency neurosurgery for TBI across different levels of human development. We did a prospective observational cohort study of consecutive patients with TBI undergoing emergency neurosurgery, in a convenience sample of hospitals identified by open invitation, through international and regional scientific societies and meetings, individual contacts, and social media. Patients receiving emergency neurosurgery for TBI in each hospital's 30-day study period were all eligible for inclusion, with the exception of patients undergoing insertion of an intracranial pressure monitor only, ventriculostomy placement only, or a procedure for drainage of a chronic subdural haematoma. The primary outcome was mortality at 14 days postoperatively (or last point of observation if the patient was discharged before this time point). Countries were stratified according to their Human Development Index (HDI)—a composite of life expectancy, education, and income measures—into very high HDI, high HDI, medium HDI, and low HDI tiers. Mixed effects logistic regression was used to examine the effect of HDI on mortality while accounting for and quantifying between-hospital and between-country variation. Our study included 1635 records from 159 hospitals in 57 countries, collected between Nov 1, 2018, and Jan 31, 2020. 328 (20%) records were from countries in the very high HDI tier, 539 (33%) from countries in the high HDI tier, 614 (38%) from countries in the medium HDI tier, and 154 (9%) from countries in the low HDI tier. The median age was 35 years (IQR 24–51), with the oldest patients in the very high HDI tier (median 54 years, IQR 34–69) and the youngest in the low HDI tier (median 28 years, IQR 20–38). The most common procedures were elevation of a depressed skull fracture in the low HDI tier (69 [45%]), evacuation of a supratentorial extradural haematoma in the medium HDI tier (189 [31%]) and high HDI tier (173 [32%]), and evacuation of a supratentorial acute subdural haematoma in the very high HDI tier (155 [47%]). Median time from injury to surgery was 13 h (IQR 6–32). Overall mortality was 18% (299 of 1635). After adjustment for casemix, the odds of mortality were greater in the medium HDI tier (odds ratio [OR] 2·84, 95% CI 1·55–5·2) and high HDI tier (2·26, 1·23–4·15), but not the low HDI tier (1·66, 0·61–4·46), relative to the very high HDI tier. There was significant between-hospital variation in mortality (median OR 2·04, 95% CI 1·17–2·49). Patients receiving emergency neurosurgery for TBI differed considerably in their admission characteristics and management across human development settings. Level of human development was associated with mortality. Substantial opportunities to improve care globally were identified, including reducing delays to surgery. Between-hospital variation in mortality suggests changes at an institutional level could influence outcome and comparative effectiveness research could identify best practices. National Institute for Health Research Global Health Research Group.

The etiology of Alzheimer’s disease (AD) has been associated with impaired neurogenesis in the adult subventricular zone (SVZ), but the molecular mechanism leading to this impairment remains poorly understood. Neuronal dysfunction in the AD-affected brain might lead to reduced production of neuron-derived paracrine factors acting through receptors necessary for adult SVZ neurogenesis (ASN). To test this hypothesis, we focused on the TrkB receptor, which can transduce signals from the neurotrophins BDNF and NT4/5, since TrkB is known to regulate the ASN process and its function becomes altered in AD. Here we show that ASN is impaired in the SVZ of homozygous 5xFAD (h5xFAD) mice. This impairment is prevented by administering an AAV.PHP.eB vector that expresses in neurons the transcription factor E2F4 carrying the Thr249Ala/Th251Ala mutation (E2F4DN), a gene therapeutic approach previously demonstrated to exert multifactorial effects in this mouse model of AD. The use of culture media conditioned by primary cortical neurons expressing E2F4DN was able to recover the proliferative and differentiative capacity of neural stem cells (NSCs) isolated from h5xFAD mice. This effect was blocked by inhibiting the TrkB receptor. Accordingly, TrkB activation mimicked the effect of the E2F4DN-conditioned medium on the proliferative and differentiative capacity of h5xFAD NSCs, a finding consistent with the upregulation of NT4/5 expression in the E2F4DN-transduced neurons. We conclude that the activation of TrkB by neurotrophins released by E2F4DN-expressing neurons can recover the ASN phenotype in 5xFAD mice. Therefore, the multifactorial therapeutic capacity of E2F4DN includes the recovery of impaired ASN through the upregulation of TrkB signaling in NSCs.

Alzheimer's disease (AD) has a multifactorial etiology, which requires a single multi-target approach for an efficient treatment. We have focused on E2F4, a transcription factor that regulates cell quiescence and tissue homeostasis, controls gene networks affected in AD, and is upregulated in the brain of Alzheimer's patients and of APP/PS1 and 5xFAD transgenic mice. E2F4 contains an evolutionarily-conserved Thr-motif that, when phosphorylated, modulates its activity, thus constituting a potential target for intervention. Here we show that neuronal expression in 5xFAD mice of a dominant negative form of E2F4 lacking this Thr-motif (E2F4DN) potentiates a transcriptional program consistent with global brain homeostasis. The latter correlates with attenuation of both microglial immune response and astrogliosis, modulation of Aβ proteostasis, and blockade of neuronal tetraploidization. Moreover, E2F4DN prevents cognitive impairment and body weight loss, a known somatic alteration associated with AD. We propose E2F4DN-based gene therapy as a promising multifactorial approach against AD. Competing Interest Statement J.M. Frade is shareholder (8.96% equity ownership) of Tetraneuron, a biotech company exploiting his patent on the blockade of neuronal tetraploidization by E2F4DN as a therapeutic approach against Alzheimer's disease. N.L.S. received her salary from a R&D contract with Tetraneuron, and currently she works for this biotech company. M.R.L. and A.G.G. works for Tetraneuron.