Clearing extracellular alpha-synuclein from cerebrospinal fluid: A new therapeutic strategy in parkinson’s disease

This concept article aims to show the rationale of targeting extracellular α-Synuclein (α-Syn) from cerebrospinal fluid (CSF) as a new strategy to remove this protein from the brain in Parkinson’s disease (PD). Misfolding and intracellular aggregation of α-synuclein into Lewy bodies are thought to be crucial in the pathogenesis of PD. Recent research has shown that small amounts of monomeric and oligomeric α-synuclein are released from neuronal cells by exocytosis and that this extracellular alpha-synuclein contributes to neurodegeneration, progressive spreading of alpha-synuclein pathology, and neuroinflammation. In PD, extracellular oligomeric-α-synuclein moves in constant equilibrium between the interstitial fluid (ISF) and the CSF. Thus, we expect that continuous depletion of oligomeric-α-synuclein in the CSF will produce a steady clearance of the protein in the ISF, preventing transmission and deposition in the brain

Increased neurotransmitter release at the neuromuscular junction in a mouse model of polyglutamine disease

In Huntington's disease (HD), the expansion of polyglutamine (polyQ) repeats at the N terminus of the ubiquitous protein huntingtin (htt) leads to neurodegeneration in specific brain areas. Neurons degenerating in HD develop synaptic dysfunctions. However, it is unknown whether mutant htt impacts synaptic function in general. To investigate that, we have focused on the nerve terminals of motor neurons that typically do not degenerate in HD. Here, we have studied synaptic transmission at the neuromuscular junction of transgenic mice expressing a mutant form of htt (R6/1 mice).Wehave found that the size and frequency of miniature endplate potentials are similar in R6/1 and control mice. In contrast, the amplitude of evoked endplate potentials in R6/1 mice is increased compared to controls. Consistent with a presynaptic increase of release probability, synaptic depression under high-frequency stimulation is higher in R6/1 mice. In addition, no changes were detected in the size and dynamics of the recycling synaptic vesicle pool. Moreover, we have found increased amounts of the synaptic vesicle proteins synaptobrevin 1,2/VAMP 1,2 and cysteine string protein-α, and the SNARE protein SNAP-25, concomitant with normal levels of other synaptic vesicle markers. Our results reveal that the transgenic expression of a mutant form of htt leads to an unexpected gain of synaptic function. That phenotype is likely not secondary to neurodegeneration and might be due to a primary deregulation in synaptic protein levels. Our findings could be relevant to understand synaptic toxic effects of proteins with abnormal polyQ repeats. Copyright©2011 the authors.Instituto de Salud Carlos III (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), the Spanish Ministry of Science and Innovation (BFU2007-66008 to R.F-C., SAF2009-08233 to J.J.L., and Juan de la Cierva contracts to J.L.R. and C.T.-Z.), Junta de Andalucía (P07-CVI- 02854, P06-CVI-02392), Comunidad Autónoma de Madrid, Fundación Ramón Areces, and Fondo Europeo de Desarrollo RegionalPeer Reviewe

Increased neurotransmitter release at the neuromuscular junction in a mouse model of polyglutamine disease

In Huntington’s disease (HD), the expansion of polyglutamine (polyQ) repeats at the N terminus of the ubiquitous protein huntingtin (htt) leads to neurodegeneration in specific brain areas. Neurons degenerating in HD develop synaptic dysfunctions. However, it is unknown whether mutant htt impacts synaptic function in general. To investigate that, we have focused on the nerve terminals of motor neurons that typically do not degenerate in HD. Here, we have studied synaptic transmission at the neuromuscular junction of transgenic mice expressing a mutant form of htt (R6/1 mice).Wehave found that the size and frequency of miniature endplate potentials are similar in R6/1 and control mice. In contrast, the amplitude of evoked endplate potentials in R6/1 mice is increased compared to controls. Consistent with a presynaptic increase of release probability, synaptic depression under high-frequency stimulation is higher in R6/1 mice. In addition, no changes were detected in the size and dynamics of the recycling synaptic vesicle pool. Moreover, we have found increased amounts of the synaptic vesicle proteins synaptobrevin 1,2/VAMP 1,2 and cysteine string protein-_, and the SNARE protein SNAP-25, concomitant with normal levels of other synaptic vesicle markers. Our results reveal that the transgenic expression of a mutant form of htt leads to an unexpected gain of synaptic function. That phenotype is likely not secondary to neurodegeneration and might be due to a primary deregulation in synaptic protein levels. Our findings could be relevant to understand synaptic toxic effects of proteins with abnormal polyQ repeats

New, Fully Implantable Device for Selective Clearance of CSF-Target Molecules: Proof of Concept in a Murine Model of Alzheimer’s Disease

[EN] We have previously proposed a radical change in the current strategy to clear pathogenic proteins from the central nervous system (CNS) based on the cerebrospinal fluid (CSF)-sink therapeutic strategy, whereby pathogenic proteins can be removed directly from the CNS via CSF. To this aim, we designed and manufactured an implantable device for selective and continuous apheresis of CSF enabling, in combination with anti-amyloid-beta (Aβ) monoclonal antibodies (mAb), the clearance of Aβ from the CSF. Here, we provide the first proof of concept in the APP/PS1 mouse model of Alzheimer’s disease (AD). Devices were implanted in twenty-four mice (seventeen APP/PS1 and seven Wt) with low rates of complications. We confirmed that the apheresis module is permeable to the Aβ peptide and impermeable to mAb. Moreover, our results showed that continuous clearance of soluble Aβ from the CSF for a few weeks decreases cortical Aβ plaques. Thus, we conclude that this intervention is feasible and may provide important advantages in terms of safety and efficacy.This work was supported by the Instituto de Salud Carlos III, under Grant DTS19-00071 to M.M.-G. and by the Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología (FICYT), under Grant AYUD/2021/57540, to C.T.-Z

A Multiple-Choice Maze-like Spatial Navigation Task for Humans Implemented in a Real-Space, Multipurpose Circular Arena.

Spatial navigation is a key aspect of human behavior and it is still not completely understood. A number of experimental approaches exist, although most of the published data in the last decades have relied on virtual maze on-screen simulation or not-completely freely moving 3D devices. Some interesting recent developments, such as circular mazes, have contributed to analyze critical aspects of freely moving human spatial navigation in real space, although dedicated protocols only allow for simple approaches. Here, we have developed both specifically designed and home-assembled hardware equipment, and a customized protocol for spatial navigation evaluation in freely moving humans in a real space circular arena. The spatial navigation protocol poses an imitation of a real-space multiple-choice path maze with cul-de-sac and instances of non-linear movement. We have compared the results of this system to those of a number of validated, both virtual and real, spatial navigation tests in a group of participants. The system composed by hardware, the test protocol, and dedicated measure analysis designed in our laboratory allows us to evaluate human spatial navigation in a complex maze with a small and portable structure, yielding a highly flexible, adaptable, and versatile access to information about the subjects’ spatial navigation abilities.P.M. was funded by a predoctoral fellowship (FPI) grant, PRE2020/093032, from the Ministerio de Ciencia e Innovación; E.C. was funded by a predoctoral fellowship (FPI) grant, BES-2017/080415, from the Ministerio de Economía y Competitividad; P.T. was funded by a predoctoral fellowship (FPU) grant, 18/00069, from the Ministerio de Universidades. This research received no other external specific funding

A Multiple-Choice Maze-like Spatial Navigation Task for Humans Implemented in a Real-Space, Multipurpose Circular Arena

Spatial navigation is a key aspect of human behavior and it is still not completely understood. A number of experimental approaches exist, although most of the published data in the last decades have relied on virtual maze on-screen simulation or not-completely freely moving 3D devices. Some interesting recent developments, such as circular mazes, have contributed to analyze critical aspects of freely moving human spatial navigation in real space, although dedicated protocols only allow for simple approaches. Here, we have developed both specifically designed and home-assembled hardware equipment, and a customized protocol for spatial navigation evaluation in freely moving humans in a real space circular arena. The spatial navigation protocol poses an imitation of a real-space multiple-choice path maze with cul-de-sac and instances of non-linear movement. We have compared the results of this system to those of a number of validated, both virtual and real, spatial navigation tests in a group of participants. The system composed by hardware, the test protocol, and dedicated measure analysis designed in our laboratory allows us to evaluate human spatial navigation in a complex maze with a small and portable structure, yielding a highly flexible, adaptable, and versatile access to information about the subjects’ spatial navigation abilities

Physical exercise shapes the mouse brain epigenome

[Objective]: To analyze the genome-wide epigenomic and transcriptomic changes induced by long term resistance or endurance training in the hippocampus of wild-type mice.[Methods]: We performed whole-genome bisulfite sequencing (WGBS) and RNA sequencing (RNA-seq) of mice hippocampus after 4 weeks of specific training. In addition, we used a novel object recognition test before and after the intervention to determine whether the exercise led to an improvement in cognitive function.[Results]: Although the majority of DNA methylation changes identified in this study were training-model specific, most were associated with hypomethylation and were enriched in similar histone marks, chromatin states, and transcription factor biding sites. It is worth highlighting the significant association found between the loss of DNA methylation in Tet1 binding sites and gene expression changes, indicating the importance of these epigenomic changes in transcriptional regulation. However, endurance and resistance training activate different gene pathways, those being associated with neuroplasticity in the case of endurance exercise, and interferon response pathways in the case of resistance exercise, which also appears to be associated with improved learning and memory functions.[Conclusions]: Our results help both understand the molecular mechanisms by which different exercise models exert beneficial effects for brain health and provide new potential therapeutic targets for future research.This work was supported by the Spanish Association Against Cancer (PROYE18061FERN to M.F.F.), the Asturias Government (PCTI) co-funding 2018-2022/FEDER (IDI/2018/146 to M.F.F.), the Fundación General CSIC (0348_CIE_6_E to M.F.F.), the Health Institute Carlos III (Plan Nacional de I+D+I) co-funding FEDER (PI18/01527 to M.F.F and A.F.F.), the MINECO (DEP2015-69980-P to B.F.G.), and the Fundación Tatiana Pérez de Guzmán el Bueno (“Ayudas a Proyectos de Investigación en Neurociencia-2020” to C.T.Z and E.I.G.). R.G.U. is supported by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER). J.R.T. is supported by a Juan de la Cierva fellowship from the Spanish Ministry of Science and Innovation MCIN/AEI /10.13039/501100011033 (IJC2018-036825-I). R.F.P. is supported by the Severo Ochoa program (BP17-114). P.P.H. is supported by Ayudas para la realización de Tesis Doctorales. Modalidad A fellowship from the University of Oviedo (PAPI-20-PF-19). We also acknowledge support from the IUOPA-ISPA-FINBA (the IUOPA is supported by the Obra Social Cajastur-Liberbank, Spain).Peer reviewe