Marta Zagrebelsky

Prior studies reported an association between the levels of brain-derived neurotrophic factor (BDNF) circulating in the bloodstream and those of different inflammatory factors. However, their causal relationship remains unclear. Here, we performed a Mendelian randomization (MR) study to investigate the causal relationships between plasma BDNF levels and 91 circulating inflammatory proteins to shed light on the possible role of BDNF in the pathogenesis and progression of inflammation-related neurological diseases in order to distinguish correlation from possible causal effects. Data for plasma BDNF levels were derived from a genome-wide association study (GWAS) encompassing 3,301 European participants. Genetic association estimates for 91 inflammation proteins were extracted from a GWAS meta-analysis that enrolled 14,824 European participants. The primary MR analysis employed the inverse variance weighted (IVW) method and was corroborated by additional methods including MR-Egger, weighted median, weighted mode, and simple mode. Analyses of sensitivity were performed by evaluating the heterogeneity, horizontal pleiotropy, and robustness of the results. Genetic evidence indicated that elevated plasma BDNF levels possibly contribute to decreased concentrations of 13 inflammation proteins (OR: 0.951–0.977), including beta-nerve growth factor (Beta-NGF), caspase 8 (CASP-8), interleukin-15 receptor subunit alpha (IL-15RA), interleukin-17 A (IL-17 A), interleukin-17 C (IL-17 C), interleukin-2 (IL-2), interleukin-20 (IL-20), interleukin-20 receptor subunit alpha (IL-20RA), interleukin-24 (IL-24), interleukin-33 (IL-33), leukemia inhibitory factor (LIF), neurturin (NRTN), as well as neurotrophin-3 (NT-3). The associations between BDNF and IL-33 remained statistically significant after FDR correction (FDR > 0.05). Furthermore, reverse MR analysis showed that C-C motif chemokine 23 (CCL23), CUB domain-containing protein 1 (CDCP1), and NRTN is suggestive for a positive causal effect on BDNF plasma levels (OR: 1.240–1.422). Moreover, 5 proteins are likely to be associated with lower plasma levels of BDNF (OR: 0.742–0.971), including adenosine deaminase (ADA), cystatin D (CST5), interleukin-13 (IL-13), interleukin-17 A (IL-17 A), and vascular endothelial growth factor A (VEGF-A). Genetically determined plasma BDNF levels influence IL-33 and are possibly associated with 12 circulating inflammatory proteins. The data suggest that 8 inflammatory proteins exhibit either negative or protective roles to BDNF levels, respectively. Of these, 5 are negatively associated with BDNF levels, while 3 play protective roles. These findings may offer new theoretical and empirical insights into the pathogenesis and progression of inflammation-related neurological diseases.

Introduction: Alzheimer’s disease (AD), is characterized by a gradual cognitive decline associated with the accumulation of Amyloid beta (Aβ)-oligomers, progressive neuronal degeneration and chronic neuroinflammation. Among the receptors shown to bind and possibly transduce the toxic effects of Aβ-oligomers is the p75 neurotrophin receptor (p75^NTR). Interestingly, p75^NTR mediates several crucial processes in the nervous system, including neuronal survival and apoptosis, maintenance of the neuronal architecture, and plasticity. Furthermore, p75^NTR is also expressed in microglia, the resident immune cells of the brain, where it is markedly increased under pathological conditions. These observations indicate p75^NTR as a potential candidate for mediating Aβ-induced toxic effects at the interface between the nervous and the immune system, thereby potentially participating in the crosstalk between these two systems.Methods: Here we used APP/PS1 transgenic mice (APP/PS1tg) and compared the Aβ-induced alterations in neuronal function, chronic inflammation as well as their cognitive consequences between 10 months old APP/PS1tg and APP/PS1tg x p75^NTRexonIV knockout mice.Results: Electrophysiological recordings show that a loss of p75^NTR rescues the impairment in long-term potentiation at the Schaffer collaterals in the hippocampus of APP/PS1tg mice. Interestingly, however loss of p75^NTR does not influence the severity of neuroinflammation, microglia activation or the decline in spatial learning and memory processes observed in APP/PS1tg mice.Conclusion: Together these results indicate that while a deletion of p75^NTR rescues the synaptic defect and the impairment in synaptic plasticity, it does not affect the progression of the neuroinflammation and the cognitive decline in a mouse model for AD.

Signaling of BDNFviaits TrkB receptor is crucial in regulating several critical aspects of the architecture and function of neurons both during development and in the adult central nervous system. Indeed, several neurological conditions, such as neurodevelopmental and neurodegenerative disorders are associated with alterations both in the expression levels of BDNF and TrkB, and in their intracellular signaling. Thus, the possibility of promoting BDNF/TrkB signaling has become relevant as a potential therapeutic intervention for neurological disorders. However, the clinical potential of BDNF itself has been limited due to its restricted diffusion rate in biological tissue, poor bioavailability and pharmacological properties, as well as the potential for unwanted side effects due to its ability to also signalviathe p75^NTRpathway. Several small molecule and biologic drug candidate TrkB agonists have been developed and are reported to have effects in rescuing both the pathological alterations and disease related symptoms in mouse models of several neurological diseases. However, recent side-by-side comparative studies failed to show their specificity for activating TrkB signaling cascades, suggesting the need for the generation and validation of improved candidates. In the present study, we examine the ability of the novel, fully human TrkB agonist antibody ZEB85 to modulate the architecture, activity and synaptic plasticity of hippocampal murine neurons under physiological conditions. Moreover, we show here that ZEB85 prevents β-amyloid toxicity in cultured hippocampal neurons, in a manner which is comparable to BDNF.

A tight regulation of the balance between inhibitory and excitatory synaptic transmission is a prerequisite for synaptic plasticity in neuronal networks. In this context, the neurite growth inhibitor membrane protein Nogo-A modulates synaptic plasticity, strength, and neurotransmitter receptor dynamics. However, the molecular mechanisms underlying these actions are unknown. We show that Nogo-A loss-of-function in primary mouse hippocampal cultures by application of a function-blocking antibody leads to higher excitation following a decrease in GABA_ARs at inhibitory and an increase in the GluA1, but not GluA2 AMPAR subunit at excitatory synapses. This unbalanced regulation of AMPAR subunits results in the incorporation of Ca²⁺-permeable GluA2-lacking AMPARs and increased intracellular Ca²⁺ levels due to a higher Ca²⁺ influx without affecting its release from the internal stores. Increased neuronal activation upon Nogo-A loss-of-function prompts the phosphorylation of the transcription factor CREB and the expression of c-Fos. These results contribute to the understanding of the molecular mechanisms underlying the regulation of the excitation/inhibition balance and thereby of plasticity in the brain.

Dendritic spines are tiny membrane specialization forming the postsynaptic part of most excitatory synapses. They have been suggested to play a crucial role in regulating synaptic transmission during development and in adult learning processes. Changes in their number, size, and shape are correlated with processes of structural synaptic plasticity and learning and memory and also with neurodegenerative diseases, when spines are lost. Thus, their alterations can correlate with neuronal homeostasis, but also with dysfunction in several neurological disorders characterized by cognitive impairment. Therefore, it is important to understand how different stages in the life of a dendritic spine, including formation, maturation, and plasticity, are strictly regulated. In this context, brain-derived neurotrophic factor (BDNF), belonging to the NGF-neurotrophin family, is among the most intensively investigated molecule. This review would like to report the current knowledge regarding the role of BDNF in regulating dendritic spine number, structure, and plasticity concentrating especially on its signaling via its two often functionally antagonistic receptors, TrkB and p75^NTR. In addition, we point out a series of open points in which, while the role of BDNF signaling is extremely likely conclusive, evidence is still missing.

The brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endogenous BDNF levels is the administration of the BDNF-inducing drug Fingolimod, an agonist of the sphingosine-1-phosphate receptor. Fingolimod treatment was shown to rescue diverse symptoms associated with several neurological conditions (i.e., Alzheimer disease, Rett syndrome). However, the cellular mechanisms through which Fingolimod mediates its BDNF-dependent therapeutic effects remain unclear. We show that Fingolimod regulates the dendritic architecture, dendritic spine density and morphology of healthy mature primary hippocampal neurons. Moreover, the application of Fingolimod upregulates the expression of activity-related proteins c-Fos and pERK1/2 in these cells. Importantly, we show that BDNF release is required for these actions of Fingolimod. As alterations in neuronal structure underlie cognitive impairment, we tested whether Fingolimod application might prevent the abnormalities in neuronal structure typical of two neurodevelopmental disorders, namely Rett syndrome and Cdk5 deficiency disorder. We found a significant rescue in the neurite architecture of developing cortical neurons from Mecp2 and Cdkl5 mutant mice. Our study provides insights into understanding the BDNF-dependent therapeutic actions of Fingolimod.

Purkinje cells (PCs) are primarily affected in neurodegenerative spinocerebellar ataxias (SCAs). For generating animal models for SCAs, genetic regulatory elements specifically targeting PCs are required, thereby linking pathological molecular effects with impaired function and organismic behavior. Because cerebellar anatomy and function are evolutionary conserved, zebrafish represent an excellent model to study SCAsin vivo. We have isolated a 258 bp cross-species PC-specific enhancer element that can be used in a bidirectional manner for bioimaging of transgene-expressing PCs in zebrafish (both sexes) with variable copy numbers for tuning expression strength. Emerging ectopic expression at high copy numbers can be further eliminated by repurposing microRNA-mediated posttranslational mRNA regulation.Subsequently, we generated a transgenic SCA type 13 (SCA13) model, using a zebrafish-variant mimicking a human pathological SCA13^R420Hmutation, resulting in cell-autonomous progressive PC degeneration linked to cerebellum-driven eye-movement deficits as observed in SCA patients. This underscores that investigating PC-specific cerebellar neuropathologies in zebrafish allows for interconnecting bioimaging of disease mechanisms with behavioral analysis suitable for therapeutic compound testing.SIGNIFICANCE STATEMENTSCA13 patients carrying aKCNC3^R420Hallele have been shown to display mid-onset progressive cerebellar atrophy, but genetic modeling of SCA13 by expressing this pathogenic mutant in different animal models has not resulted in neuronal degeneration so far; likely because the transgene was expressed in heterologous cell types. We developed a genetic system for tunable PC-specific coexpression of several transgenes to manipulate and simultaneously monitor cerebellar PCs. We modeled a SCA13 zebrafish accessible for bioimaging to investigate disease progression, revealing robust PC degeneration, resulting in impaired eye movement. Our transgenic zebrafish mimicking both neuropathological and behavioral changes manifested in SCA-affected patients will be suitable for investigating causes of cerebellar diseasesin vivofrom the molecular to the behavioral level.