Involvement of JNK1 in neuronal polarization during brain development

The c-Jun N-terminal Kinases (JNKs) are a group of regulatory elements responsible for the control of a wide array of functions within the cell. In the central nervous system (CNS), JNKs are involved in neuronal polarization, starting from the cell division of neural stem cells and ending with their final positioning when migrating and maturing. This review will focus mostly on isoform JNK1, the foremost contributor of total JNK activity in the CNS. Throughout the text, research from multiple groups will be summarized and discussed in order to describe the involvement of the JNKs in the different steps of neuronal polarization. The data presented support the idea that isoform JNK1 is highly relevant to the regulation of many of the processes that occur in neuronal development in the CNS

Regulation of young-adult neurogenesis and neuronal differentiation by neural cell adhesion molecule 2 (NCAM2)

Adult neurogenesis persists in mammals in the neurogenic zones, where newborn neurons are incorporated into preexisting circuits to preserve and improve learning and memory tasks. Relevant structural elements of the neurogenic niches include the family of cell adhesion molecules (CAMs), which participate in signal transduction and regulate the survival, division, and differentiation of radial glial progenitors (RGPs). Here we analyzed the functions of neural cell adhesion molecule 2 (NCAM2) in the regulation of RGPs in adult neurogenesis and during corticogenesis. We characterized the presence of NCAM2 across the main cell types of the neurogenic process in the dentate gyrus, revealing different levels of NCAM2 amid the progression of RGPs and the formation of neurons. We showed that Ncam2 overexpression in adult mice arrested progenitors in an RGP-like state, affecting the normal course of young-adult neurogenesis. Furthermore, changes in Ncam2 levels during corticogenesis led to transient migratory deficits but did not affect the survival and proliferation of RGPs, suggesting a differential role of NCAM2 in adult and embryonic stages. Our data reinforce the relevance of CAMs in the neurogenic process by revealing a significant role of Ncam2 levels in the regulation of RGPs during young-adult neurogenesis in the hippocampus

A novel rhein-huprine hybrid ameliorates disease-modifying properties in preclinical mice model of Alzheimer's disease exacerbated with high fat diet

Background: Alzheimer's disease (AD) is characterized by a polyetiological origin. Despite the global burden of AD and the advances made in AD drug research and development, the cure of the disease remains elusive, since any developed drug has demonstrated effectiveness to cure AD. Strikingly, an increasing number of studies indicate a linkage between AD and type 2 diabetes mellitus (T2DM), as both diseases share some common pathophysiological features. In fact, β-secretase (BACE1) and acetylcholinesterase (AChE), two enzymes involved in both conditions, have been considered promising targets for both pathologies. In this regard, due to the multifactorial origin of these diseases, current research efforts are focusing on the development of multi-target drugs as a very promising option to derive effective treatments for both conditions. In the present study, we evaluated the effect of rhein-huprine hybrid (RHE-HUP), a synthesized BACE1 and AChE inhibitor, both considered key factors not only in AD but also in metabolic pathologies. Thus, the aim of this study is to evaluate the effects of this compound in APP/PS1 female mice, a well-established familial AD mouse model, challenged by high-fat diet (HFD) consumption to concomitantly simulate a T2DM-like condition. Results: Intraperitoneal treatment with RHE-HUP in APP/PS1 mice for 4 weeks reduced the main hallmarks of AD, including Tau hyperphosphorylation, Aβ42 peptide levels and plaque formation. Moreover, we found a decreased inflammatory response together with an increase in different synaptic proteins, such as drebrin 1 (DBN1) or synaptophysin, and in neurotrophic factors, especially in BDNF levels, correlated with a recovery in the number of dendritic spines, which resulted in memory improvement. Notably, the improvement observed in this model can be attributed directly to a protein regulation at central level, since no peripheral modification of those alterations induced by HFD consumption was observed. Conclusions: Our results suggest that RHE-HUP could be a new candidate for the treatment of AD, even for individuals with high risk due to peripheral metabolic disturbances, given its multi-target profile which allows for the improvement of some of the most important hallmarks of the disease

Somatic signature of brain-specific single nucleotide variations in sporadic alzheimer's disease

© 2014 IOS Press and the authors. All rights reserved. Background: Although genome-wide association studies have shown that genetic factors increase the risk of suffering late-onset, sporadic Alzheimer's disease (SAD), the molecular mechanisms responsible remain largely unknown. Objective: The aim of the study was to investigate the presence of somatic, brain-specific single nucleotide variations (SNV) in the hippocampus of SAD samples. Methods: By using bioinformatic tools, we compared whole exome sequences in paired blood and hippocampal genomic DNAs from 17 SAD patients and from 2 controls and 2 vascular dementia patients. Results: We found a remarkable number of SNVs in SAD brains (~575 per patient) that were not detected in blood. Loci with hippocampus-specific (hs)-SNVs were common to several patients, with 38 genes being present in 6 or more patients out of the 17. While some of these SNVs were in genes previously related to SAD (e.g., CSMD1, LRP2), most hs-SNVs occurred in loci previously unrelated to SAD. The most frequent genes with hs-SNVs were associated with neurotransmission, DNA metabolism, neuronal transport, and muscular function. Interestingly, 19 recurrent hs-SNVs were common to 3 SAD patients. Repetitive loci or hs-SNVs were underrepresented in the hippocampus of control or vascular dementia donors, or in the cerebellum of SAD patients. Conclusion: Our data suggest that adult blood and brain have different DNA genomic variations, and that somatic genetic mosaicism and brain-specific genome reshaping may contribute to SAD pathogenesis and cognitive differences between individuals.BBVA Foundation and MICINN-MINECO. We also like to thank the support of the Reina Sofia Foundation, the CIEN Foundation, CIBERNED (ISCIII

A novel rhein-huprine hybrid ameliorates disease-modifying properties in preclinical mice model of Alzheimer's disease exacerbated with high fat diet

Alzheimer's disease (AD) is characterized by a polyetiological origin. Despite the global burden of AD and the advances made in AD drug research and development, the cure of the disease remains elusive, since any developed drug has demonstrated effectiveness to cure AD. Strikingly, an increasing number of studies indicate a linkage between AD and type 2 diabetes mellitus (T2DM), as both diseases share some common pathophysiological features. In fact, β-secretase (BACE1) and acetylcholinesterase (AChE), two enzymes involved in both conditions, have been considered promising targets for both pathologies. In this regard, due to the multifactorial origin of these diseases, current research efforts are focusing on the development of multi-target drugs as a very promising option to derive effective treatments for both conditions. In the present study, we evaluated the effect of rhein-huprine hybrid (RHE-HUP), a synthesized BACE1 and AChE inhibitor, both considered key factors not only in AD but also in metabolic pathologies. Thus, the aim of this study is to evaluate the effects of this compound in APP/PS1 female mice, a well-established familial AD mouse model, challenged by high-fat diet (HFD) consumption to concomitantly simulate a T2DM-like condition.This work was supported by the Spanish Ministry of Science and Innovation (SAF2017-84283-R, PID2020-118127RB-I00, PID2021-122473OA-I00, PID2021-122187NB-C32, PID2021-123462OB-I00), the Fondo de Investigación Sanitaria (PI19/00854) and co founded by the Fondo Europeo de Desarrollo Regional (FEDER), theCentre for Network Biomedical Research on Neurodegenerative Diseases CB06/05/0024) and the Generalitat de Catalunya (2014SGR‑525). This research was partially funded by PRIME/H2020-SC1-BHC-2018–2020, Ref: 847879) and Programa Estatal de Fomento de la investigación Científica y Técnica de Excelencia Maria de Maeztu (CEX2021-001159-M), Universidad de Barcelona, UBNEURO Instituto de neurociencias. AC is a recipient of the Instituto de Salud Calos III Sara Borrell fellowship (grant CD22/00125). ESL is supported by the Requalification of the Spanish University System Program. JO and ME are Serra Húnter fellows.Peer reviewe

Paper de la molècula d'adhesió neuronal Ncam2 en desenvolupament i plasticitat neuronal

[cat] La correcta migració, la polarització neuronal i el manteniment de l'estructura neuronal són claus per l'òptim funcionament del cervell. Existeix un reconeixement molecular que permet la formació de les connexions neuronals. El manteniment d'aquestes connexions són claus en cervell adult. A més a més, la pèrdua progressiva d'aquestes donen lloc a processos neurodegeneratius. Les molècules d'adhesió cel·lulars realitzen diferents funcions essencials durant el desenvolupament i en la plasticitat neuronal. Estan involucrades en la migració ,creixement neurític, sinaptogènesi i plasticitat. Aquesta tesi es focalitza en l'estudi de les funcions que realitza una d'aquestes molècules d'adhesió, la molècula d'adhesió cel·lular neuronal 2 (neural cell adhesion molecule 2, Ncam2). Ncam2 és una glicoproteïna de la família de les Ncam. En concret, el gen Ncam2 és paràleg amb Ncam1 i presenta el mateix domini extracel·lular que Ncam1. Ncam2 presenta dues isoformes degut a un empalmament alternatiu que genera la isoforma Ncam2.1 i la isoforma Ncam2.2. En mamífers, Ncam2 s'expressa en diferents teixits del cos i el teixit on és més abundant és el cervell. Ncam2 s'expressa en diferents regions del cervell però la seva funció ha estat extensament estudiada en el bulb olfactori, on s'ha vist que participa en la formació i el manteniments de les connexions en el glomèrul. En concret, participa en la fasciculació dels axons i el creixement neurític. A més a més, en cultius de neurones corticals Ncam2 participa en la formació de fil·lopodis i la ramificació de les neurites. Tot i l'expressió en hipocamp i còrtex, la funció de Ncam2 no és coneixia en aquests teixits. En aquest sentit, al llarg de la tesi hem modulat l'expressió en diferents experiments in vitro i in vivo per determinar la funció de Ncam2 en el desenvolupament, morfogènesi neuronal i plasticitat adulta. En desenvolupament hem observat que Ncam2 s'expressa en les neurones que migren radialment i la seva expressió és necessària pel correcte posicionament en el còrtex. A més a més, l'expressió de Ncam2 en hipocamp és necessària per la morfogènesi neuronal degut a que participa en els processos de polarització, creixement dendrític i ramificació axonal. En hipocamp adult, Ncam2 controla la plasticitat neuronal i la neurogènesi adulta. En concret, Ncam2 controla la densitat d'espines de les neurones piramidals de CA1 i les neurones granulars del gir dentat. A més a més, també modula la densitat de contactes que formen les fibres molsoses a la CA3. A nivell de neurogènesi adulta, els nostres resultats indiquen que Ncam2 controla la diferenciació neuronal de les neurones generades en el gir dentat. A nivell de senyalització, els nostres resultats indiquen que Ncam2 interacciona amb diferents molècules que controlen les dinàmiques del citoesquelet d'actina i microtúbuls, la senyalització de calci, la transcripció genètica i el tràfic cel·lular. Aquestes dades obren la via d'estudi dels mecanismes que vehiculen les funcions de Ncam2. Les nostres dades posen de manifest diferents funcions que realitza Ncam2 en el cervell. En cap sentit, les interaccions i funcions descrites semblen exclusives de Ncam2 sinó que són processos en que hi ha un solapament funcional de moltes proteïnes d'adhesió, fet que confereix robustesa als processos de formació, manteniment i remodelació de les estructures neuronals. En concret, Ncam2 formaria part del conjunt de molècules que permeten la identitat molecular de les neurones. Una identitat clau perquè permet la formació i el manteniment de circuits neuronals específics.[eng] The proper migration, neuronal polarity and long-term maintenance of neurons are crucial for correct brain functioning, with special relevance for the connectivity orchestration during development and learning processes. Furthermore, changes in these processes are one of the keys features in neurodegenerative diseases. Cell Adhesion Molecules (CAMs) play an important role during brain development and brain plasticity processes, being involved in neurite outgrowth, synaptogenesis and synaptic plasticity. Neural cell adhesion molecule 2 (Ncam2) is a CAM family member homologous to Ncam1 with a similar ectodomain. Ncam2 has two different isoforms generated by alternative splicing known as Ncam2.1 (transmembrane isoform) and Ncam2.2 (glycosylphosphatidylinositol (GPI) anchored isoform). In mammals, NCAM2 is expressed predominantly in brain, and its expression pattern demonstrates a putative important role of this protein in both embryonic and adult brain function. NCAM2 role has been extensively investigated in the olfactory system where it plays an important role in axonal fasciculation and neurite outgrowth. Recently, different studies have revealed that Ncam2 also participates in the formation of filopodia and in neurite branching of cortical mouse neurons. Nevertheless its function in hippocampal development and adult plasticity remains largely unknown. We used different cell biology and molecular approaches, including loos-of- and gain-of-function models, to determine the role of Ncam2 in the development of the brain and adult plasticity. Our data show that Ncam2 is expressed in migrating neurons and that it is necessary for their correct position in the cortex. Moreover, Ncam2 is also expressed in the hippocampus and it is essential for the appropriate neuronal polarity. Ncam2 plays a role in neurite outgrowth, axonal branching and dendrite formation by modulating cytoskeletal dynamics. In adult hippocampus, our data show that Ncam2 contributes in synaptic plasticity and adult neurogenesis. Ncam2 modulates the spine density of pyramidal neurons in CA1 and granule cells in dentate gyrus. Furthermore, Ncam2 controls the mossy fibber contacts in CA3. Regarding to the adult neurogenesis, gain-of function of Ncam2 changes the neuronal differentiation of the new neurons. Our experiments indicate that Ncam2 interacts with a diversity of proteins including cytoskeletal components associated to the microtubule and actin networks, thus pointing to hypothetical mechanistic insights to be explored. Taken together, our results indicate that Ncam2 is an important molecule for the development, specification and connectivity of brain formation and adult plasticity

The Hidden Side of NCAM Family: NCAM2, a Key Cytoskeleton Organization Molecule Regulating Multiple Neural Functions

Although it has been over 20 years since Neural Cell Adhesion Molecule 2 (NCAM2) was identified as the second member of the NCAM family with a high expression in the nervous system, the knowledge of NCAM2 is still eclipsed by NCAM1. The first studies with NCAM2 focused on the olfactory bulb, where this protein has a key role in axonal projection and axonal/dendritic compartmentalization. In contrast to NCAM1, NCAM2’s functions and partners in the brain during development and adulthood have remained largely unknown until not long ago. Recent studies have revealed the importance of NCAM2 in nervous system development. NCAM2 governs neuronal morphogenesis and axodendritic architecture, and controls important neuron-specific processes such as neuronal differentiation, synaptogenesis and memory formation. In the adult brain, NCAM2 is highly expressed in dendritic spines, and it regulates synaptic plasticity and learning processes. NCAM2’s functions are related to its ability to adapt to the external inputs of the cell and to modify the cytoskeleton accordingly. Different studies show that NCAM2 interacts with proteins involved in cytoskeleton stability and proteins that regulate calcium influx, which could also modify the cytoskeleton. In this review, we examine the evidence that points to NCAM2 as a crucial cytoskeleton regulation protein during brain development and adulthood. This key function of NCAM2 may offer promising new therapeutic approaches for the treatment of neurodevelopmental diseases and neurodegenerative disorders