A small TAT-TrkB peptide prevents BDNF receptor cleavage and restores synaptic physiology in Alzheimer's disease

Publisher Copyright: Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.In Alzheimer's disease (AD), amyloid β (Aβ)-triggered cleavage of TrkB-FL impairs brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, and synaptic transmission and plasticity. Using cerebrospinal fluid and postmortem human brain samples, we show that TrkB-FL cleavage occurs from the early stages of the disease and increases as a function of pathology severity. To explore the therapeutic potential of this disease mechanism, we designed small TAT-fused peptides and screened their ability to prevent TrkB-FL receptor cleavage. Among these, a TAT-TrkB peptide with a lysine-lysine linker prevented TrkB-FL cleavage both in vitro and in vivo and rescued synaptic deficits induced by oligomeric Aβ in hippocampal slices. Furthermore, this TAT-TrkB peptide improved the cognitive performance, ameliorated synaptic plasticity deficits and prevented Tau pathology progression in vivo in the 5XFAD mouse model of AD. No evidence of liver or kidney toxicity was found. We provide proof-of-concept evidence for the efficacy and safety of this therapeutic strategy and anticipate that this TAT-TrkB peptide has the potential to be a disease-modifying drug that can prevent and/or reverse cognitive deficits in patients with AD.publishersversionpublishe

Hippocampal GABAergic transmission: a new target for adenosine control of excitability

© 2016 International Society for NeurochemistryPhysiological network functioning in the hippocampus is dependent on a balance between glutamatergic cell excitability and the activity of diverse local circuit neurons that release the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Tuners of neuronal communication such as adenosine, an endogenous modulator of synapses, control hippocampal network operations by regulating excitability. Evidence has been recently accumulating on the influence of adenosine on different aspects of GABAergic transmission to shape hippocampal function. This review addresses how adenosine, through its high-affinity A1 (A1 R) and A2A receptors (A2A R), interferes with different GABA-mediated forms of inhibition in the hippocampus to regulate neuronal excitability. Adenosine-mediated modulation of phasic/tonic inhibitory transmission, of GABA transport mechanisms and its interference with other modulatory systems are discussed together with the putative implications for neuronal function in physiological and pathological conditions. This article is part of a mini review series: 'Synaptic Function and Dysfunction in Brain Diseases'.The authors work has been supported by Fundação para a Ciência e Tecnologia (FCT) Portugal (PTDC/DTP-FTO/3346/2014), European Union (SynaNet H2020) twinning action; DM Rombo is in receipt of IMM/BI/43-2016 research fellowship.info:eu-repo/semantics/publishedVersio

Ex vivo model of epilepsy in organotypic slices—a new tool for drug screening

Abstract Background Epilepsy is a prevalent neurological disorder worldwide. It is characterized by an enduring predisposition to generate seizures and its development is accompanied by alterations in many cellular processes. Organotypic slice cultures represent a multicellular environment with the potential to assess biological mechanisms, and they are used as a starting point for refining molecules for in vivo studies. Here, we investigated organotypic slice cultures as a model of epilepsy. Methods We assessed, by electrophysiological recordings, the spontaneous activity of organotypic slices maintained under different culture protocols. Moreover, we evaluated, through molecular-based approaches, neurogenesis, neuronal death, gliosis, expression of proinflammatory cytokines, and activation of NLRP3 inflammasome (nucleotide-binding, leucine-rich repeat, pyrin domain) as biomarkers of neuroinflammation. Results We demonstrated that organotypic slices, maintained under a serum deprivation culture protocol, develop epileptic-like activity. Furthermore, throughout a comparative study with slices that do not depict any epileptiform activity, slices with epileptiform activity were found to display significant differences in terms of inflammation-related features, such as (1) increased neuronal death, with higher incidence in CA1 pyramidal neurons of the hippocampus; (2) activation of astrocytes and microglia, assessed through western blot and immunohistochemistry; (3) upregulation of proinflammatory cytokines, specifically interleukin-1β (IL-1β), interleukin-6, and tumor necrosis factor α, revealed by qPCR; and (4) enhanced expression of NLRP3, assessed by western blot, together with increased NLRP3 activation, showed by IL-1β quantification. Conclusions Thus, organotypic slice cultures gradually deprived of serum mimic the epileptic-like activity, as well as the inflammatory events associated with in vivo epilepsy. This system can be considered a new tool to explore the interplay between neuroinflammation and epilepsy and to screen potential drug candidates, within the inflammatory cascades, to reduce/halt epileptogenesis

Differential role of the proteasome in the early and late phases of BDNF-induced facilitation of LTP

Copyright © 2015 the authorsThe neurotrophin brain-derived neurotrophic factor (BDNF) mediates activity-dependent long-term changes of synaptic strength in the CNS. The effects of BDNF are partly mediated by stimulation of local translation, with consequent alterations in the synaptic proteome. The ubiquitin-proteasome system (UPS) also plays an important role in protein homeostasis at the synapse by regulating synaptic activity. However, whether BDNF acts on the UPS to mediate the effects on long-term synaptic potentiation (LTP) has not been investigated. In the present study, we show similar and nonadditive effects of BDNF and proteasome inhibition on the early phase of synaptic potentiation (E-LTP) induced by theta-burst stimulation of rat hippocampal CA1 synapses. The effects of BDNF were blocked by the proteasome activator IU1, suggesting that the neurotrophin acts by decreasing proteasome activity. Accordingly, BDNF downregulated the proteasome activity in cultured hippocampal neurons and in hippocampal synaptoneurosomes. Furthermore, BDNF increased the activity of the deubiquitinating enzyme UchL1 in synaptoneurosomes and upregulated free ubiquitin. In contrast to the effects on posttetanic potentiation, proteasome activity was required for BDNF-mediated LTP. These results show a novel role for BDNF in UPS regulation at the synapse, which is likely to act together with the increased translation activity in the regulation of the synaptic proteome during E-LTP.This work was supported by FEDER (QREN) through Programa Mais Centro (Projects CENTRO-07-ST24-FEDER-002002, CENTRO-07-ST24-FEDER-002006, and CENTRO-07-ST24-FEDER-002008), through Programa Operacional Factores de Competitividade- COMPETE and National funds via Fundação para a Ciência e a Tecnologia (Projects Pest-C/SAU/LA0001/2013–2014, PTDC/SAU-NMC/120144/2010, and PTDC/SAU-NMC/0198/2012).info:eu-repo/semantics/publishedVersio

Abdominal splenosis mimicking peritoneal carcinomatosis of ovarian cancer

We present the clinical case of a 53-year-old woman referred for suspicion of recurrence of a mesonephric-like adenocarcinoma of the ovary. Abdominal and pelvic CT revealed multiple round/oval solid nodules with similar density scattered throughout the abdomen and pelvis, the biggest ones appearing in the left hypochondrium; no normal-appearing spleen or ascites were observed. These radiological findings and the absence of significant elevation of CA 125 levels made the radiologists hypothesize that these aspects were related to abdominal splenosis. They asked the patient about previous medical history of splenic injury, which she confirmed, referring it was a consequence of a remote major trauma. A 99mTc-labeled heat-denatured erythrocytes (99mTc-DRBC) scintigraphy/ hybrid SPECT/CT was then performed for definitive diagnosis; it showed spleen remnants as foci of increased radiopharmaceutical uptake in the same locations as the nodules appearing in the CT. This diagnostic work-up was consistent with abdominal splenosis, mimicking peritoneal carcinomatosis of ovarian cancer

Enhanced LTP in aged rats: detrimental or compensatory?

© 2016 Published by Elsevier Ltd.Age-dependent memory deterioration has been well documented and yet an increase in rat hippocampal LTP upon aging has been reported. This poses the question of whether the enhanced LTP is a cause or an attempt to compensate the memory deficits described in aged rats. Hippocampal slices from young, adult and aged Wistar rats were pre-incubated, with an NMDA receptor (NMDAR) antagonist, memantine (1 μM, 4 h), and hippocampal LTP was evaluated. The results show that memantine significantly decreases the larger LTP magnitude recorded in hippocampal slices from aged rats without compromising LTP recorded in slices from young and adult animals. To unveil the impact of in vivo administration of memantine, different doses (1, 5 and 10 mg/kg/day) or saline vehicle solution were intraperitoneally administered, for 15-20 days, to both young and aged animals. Memantine did not significantly affect neither the place learning of young animals, evaluated by Morris Water Maze, nor LTP recorded from hippocampal slices from the same group of animals. However, memantine (5 and 10 mg/kg/day) significantly decreased the large LTP recorded in hippocampal slices from aged animals. Moreover, aged animals treated with memantine (10 mg/kg/day) showed a significantly compromised place learning when compared to aged control animals. Overall, these results suggest that the larger LTP observed in aged animals is a compensatory phenomenon, rather than pathological. The finding that age-dependent blockade of LTP by a NMDAR antagonist leads to learning deficits, implies that the increased LTP observed upon aging may be playing an important role in the learning process.This work was supported by Bial Foundation (Grant 57/12) and the “Educação pela Ciência” Program, GAPIC/Faculty of Medicine of the University of Lisbon (201100015). LVL is an investigator FCT.info:eu-repo/semantics/publishedVersio

Role of adenosine in epilepsy and seizures

© Mary Ann Liebert, Inc.Adenosine is an endogenous anticonvulsant and neuroprotectant of the brain. Seizure activity produces large quantities of adenosine, and it is this seizure-induced adenosine surge that normally stops a seizure. However, within the context of epilepsy, adenosine plays a wide spectrum of different roles. It not only controls seizures (ictogenesis), but also plays a major role in processes that turn a normal brain into an epileptic brain (epileptogenesis). It is involved in the control of abnormal synaptic plasticity and neurodegeneration and plays a major role in the expression of comorbid symptoms and complications of epilepsy, such as sudden unexpected death in epilepsy (SUDEP). Given the important role of adenosine in epilepsy, therapeutic strategies are in development with the goal to utilize adenosine augmentation not only for the suppression of seizures but also for disease modification and epilepsy prevention, as well as strategies to block adenosine A2A receptor overfunction associated with neurodegeneration. This review provides a comprehensive overview of the role of adenosine in epilepsy.The authors acknowledge grant support from the National Institutes of Health to D.B. (NINDS: NS103740, NS065957); support to A.M.S. by LISBOA-01-0145-FEDER-007391, project cofunded by Fundo Europeu Para o Desenvolvimento Regional through POR Lisboa 2020 (Programa Operacional Regional de Lisboa) from PORTUGAL 2020 and Fundação para a Ciência e Tecnologia (FCT), by an FCT project (PTDC/MED-FAR/30933/2017) and by Twinning action (SynaNet) from the EU H2020 programme (project number: 692340); and support to R.A.C. and A.R.T. by Fundacion LaCaixa (LCF/PR/HP17/52190001), Centro 2020 (CENTRO-01-0145-FEDER-000008: BrainHealth 2020 and CENTRO-01-0246-FEDER-000010) and FCT (POCI-01-0145-FEDER-03127).info:eu-repo/semantics/publishedVersio

Extracellular Alpha-Synuclein Oligomers Modulate Synaptic Transmission and Impair LTP Via NMDA-Receptor Activation

Parkinson’s disease (PD) is the most common representative of a group of disorders known as synucleinopathies, in which misfolding and aggregation of -synuclein (a-syn) in various brain regions is themajorpathological hallmark. Indeed, themotorsymptomsinPDare causedby a heterogeneous degeneration of brain neurons not only in substantia nigra pars compacta but also in other extrastriatal areas of the brain. In addition to the well known motor dysfunction in PD patients, cognitive deficits and memory impairment are also an important part of the disorder, probably due to disruption of synaptic transmission and plasticity in extrastriatal areas, including the hippocampus. Here, we investigated the impact of a-syn aggregation onAMPAandNMDAreceptor-mediated rat hippocampal (CA3-CA1) synaptic transmission and long-term potentiation (LTP), the neurophysiological basis for learning and memory. Our data show that prolonged exposure to a-syn oligomers, but not monomers or fibrils, increases basal synaptic transmission through NMDA receptor activation, triggering enhanced contribution of calcium-permeable AMPA receptors. Slices treated with a-syn oligomers were unable to respond with further potentiation to theta-burst stimulation, leading to impaired LTP. Prior delivery of a low-frequency train reinstated the ability to express LTP, implying that exposuretoa-synoligomersdrivestheincreaseofglutamatergicsynaptictransmission,preventingfurtherpotentiationbyphysiologicalstimuli. Our novel findings provide mechanistic insight on how a-syn oligomers may trigger neuronal dysfunction and toxicity in PD and other synucleinopathies