Neuroscience
Abstract
Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer’s disease (AD) and related tauopathies. Here, we found that reduced levels of the memory-associated protein KIdney/BRAin (KIBRA) in the brain and increased KIBRA protein levels in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. We next defined a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIBRA protein (CT-KIBRA). We showed that CT-KIBRA restored plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we found that CT-KIBRA stabilized the protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. Thus, our results distinguished KIBRA both as a biomarker of synapse dysfunction and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.
Authors
Grant Kauwe, Kristeen A. Pareja-Navarro, Lei Yao, Jackson H. Chen, Ivy Wong, Rowan Saloner, Helen Cifuentes, Alissa L. Nana, Samah Shah, Yaqiao Li, David Le, Salvatore Spina, Lea T. Grinberg, William W. Seeley, Joel H. Kramer, Todd C. Sacktor, Birgit Schilling, Li Gan, Kaitlin B. Casaletto, Tara E. Tracy
Abstract
Converging studies demonstrate the dysfunction of the dopaminergic neurons following chronic opioid administration. However, the therapeutic strategies targeting opioid-responsive dopaminergic ensembles that contribute to the development of opioid withdrawal remain to be elucidated. Here, we used the neuronal activity-dependent Tet-Off system to label dopaminergic ensembles in response to initial morphine exposure (Mor-Ens) in the ventral tegmental area (VTA). Fiber optic photometry recording and transcriptome analysis revealed downregulated spontaneous activity, dysregulated mitochondrial respiratory, ultrastructure, and oxidoreductase signal pathways after chronic morphine administration in these dopaminergic ensembles. Mitochondrial fragmentation and the decreased mitochondrial fusion gene mitofusin 1 (Mfn1) were found in these ensembles after prolonged opioid withdrawal. Restoration of Mfn1 in the dopaminergic Mor-Ens attenuated excessive oxidative stress and the development of opioid withdrawal. Administration of Mdivi-1, a mitochondrial fission inhibitor, ameliorated the mitochondrial fragmentation and maladaptation of the neuronal plasticity in these Mor-Ens, accompanied by attenuated development of opioid withdrawal after chronic morphine administration, without affecting the analgesic effect of morphine. These findings highlighted the plastic architecture of mitochondria as a potential therapeutic target for opioid analgesic-induced substance use disorders.
Authors
Changyou Jiang, Han Huang, Xiao Yang, Qiumin Le, Xing Liu, Lan Ma, Feifei Wang
Abstract
Spinocerebellar ataxia type 3 (SCA3) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the ataxin-3 (ATXN3) gene. No effective treatment is available for this disorder, other than symptom-directed approaches. Bile acids have shown therapeutic efficacy in neurodegenerative disease models. Here, we pinpointed tauroursodeoxycholic acid (TUDCA) as an efficient therapeutic, improving the motor and neuropathological phenotype of SCA3 nematode and mouse models. Surprisingly, transcriptomic and functional in vivo data showed that TUDCA acts in neuronal tissue through the glucocorticoid receptor (GR), but independently of its canonical receptor, the FXR. TUDCA was predicted to bind to the GR, similarly to corticosteroid molecules. GR levels were decreased in disease-affected brain regions, likely due to increased protein degradation as a consequence of ATXN3 dysfunction, being restored by TUDCA treatment. Analysis of a SCA3 clinical cohort showed intriguing correlations between the peripheral expression of GR and the predicted age at disease onset, in pre-symptomatic subjects, and of FKBP5 expression with disease progression, suggesting this pathway as a potential source of biomarkers for future study. We have established a novel in vivo mechanism for the neuroprotective effects of TUDCA in SCA3, and propose this readily available drug for clinical trials in SCA3 patients.
Authors
Sara Duarte-Silva, Jorge Diogo Da Silva, Daniela Monteiro-Fernandes, Marta Daniela Costa, Andreia Neves-Carvalho, Mafalda Raposo, Carina Soares-Cunha, Joana S. Correia, Gonçalo Nogueira-Gonçalves, Henrique S. Fernandes, Stéphanie Oliveira, Ana Rita Ferreira-Fernandes, Fernando Rodrigues, Joana Pereira-Sousa, Daniela Vilasboas-Campos, Sara Guerreiro, Jonas Campos, Liliana Meireles-Costa, Cecilia M.P. Rodrigues, Stephanie Cabantous, Sérgio F. Sousa, Manuela Lima, Andreia Teixeira-Castro, Patricia Maciel
Abstract
Early-life seizures (ELS) can cause permanent cognitive deficits and network hyperexcitability, but it is unclear whether ELS induce persistent alterations to specific neuronal populations and if these changes can be targeted to mitigate network dysfunction. We used the targeted recombination of activated populations (TRAP) approach to genetically label neurons activated by kainate-induced ELS in immature mice. The ELS-TRAPed neurons were mainly found in hippocampal CA1, remained uniquely susceptible to reactivation by later-life seizures, and displayed sustained enhancement in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR)-mediated excitatory synaptic transmission and inward rectification. ELS-TRAPed neurons, but not non-TRAPed surrounding neurons, exhibited enduring decreases in Gria2 mRNA, responsible for encoding the GluA2 subunit of the AMPARs. This was paralleled by decreased synaptic GluA2 protein expression and heightened phosphorylated GluA2 at Ser880 in dendrites, indicative of GluA2 internalization. Consistent with increased GluA2-lacking AMPARs, ELS-TRAPed neurons showed premature silent synapse depletion, impaired long-term potentiation, and impaired long-term depression. In vivo post-seizure treatment with IEM-1460, a GluA2-lacking AMPAR inhibitor, markedly mitigated ELS-induced alterations in TRAPed neurons. These findings show that enduring modifications of AMPARs occur in a subpopulation of ELS-activated neurons, contributing to synaptic dysplasticity and network hyperexcitability, but are reversible with early IEM-1460 intervention.
Authors
Bo Xing, Aaron J. Barbour, Joseph Vithayathil, Xiaofan Li, Sierra Dutko, Jessica Fawcett-Patel, Eunjoo Lancaster, Delia M. Talos, Frances E. Jensen
Abstract
The mechanisms behind a lack of efficient fear extinction in some individuals are unclear. Here, by employing a principal components analysis (PCA)-based approach, we differentiated the mice into extinction-resistant and susceptible groups. We identified that elevated synapsin 2a (Syn2a) in the infralimbic cortex (IL) to basolateral amygdala (BLA) circuit disrupted presynaptic orchestration, leading to an excitatory/inhibitory imbalance in the BLA region and causing extinction resistance. Overexpression or silencing of Syn2a levels in IL neurons replicated or alleviated behavioral, electrophysiological, and biochemical phenotypes in resistant mice. We further identified the proline-rich domain H in the C-terminal of Syn2a was indispensable for the interaction with synaptogyrin-3 (Syngr3) and demonstrated that disrupting this interaction restored extinction impairments. Molecular docking revealed ritonavir, an FDA-approved HIV drug, could disrupt Syn2a-Syngr3 binding and rescue fear extinction behavior in Syn2a-elevated mice. In summary, aberrant Syn2a elevation and its interaction with Syngr3 at the presynaptic site were crucial in fear extinction resistance, suggesting a potential therapeutic avenue for related disorders.
Authors
Xi-Ya Shen, Juan Zhang, He-Zhou Huang, Shao-Dan Li, Ling Zhou, Shi-Ping Wu, Cheng Tang, Xian Huang, Zhi-Qiang Liu, Zi-Yuan Guo, Xiang Li, Heng-Ye Man, You-Ming Lu, Ling-Qiang Zhu, Dan Liu
Abstract
Current treatments for neurodegenerative diseases and neural injuries face major challenges, primarily due to the diminished regenerative capacity of neurons in the mammalian central nervous system (CNS) as they mature. Here, we investigated the role of Ezh2, a histone methyltransferase, in regulating mammalian axon regeneration. We found that Ezh2 declined in the mouse nervous system during maturation but was upregulated in adult dorsal root ganglion neurons following peripheral nerve injury to facilitate spontaneous axon regeneration. In addition, overexpression of Ezh2 in retinal ganglion cells in the CNS promoted optic nerve regeneration via both histone methylation-dependent and -independent mechanisms. Further investigation revealed that Ezh2 fostered axon regeneration by orchestrating the transcriptional silencing of genes governing synaptic function and those inhibiting axon regeneration, while concurrently activating various factors that support axon regeneration. Notably, we demonstrated that GABA transporter 2 encoded by Slc6a13 acted downstream of Ezh2 to control axon regeneration. Overall, our study underscores the potential of modulating chromatin accessibility as a promising strategy for promoting CNS axon regeneration.
Authors
Xue-Wei Wang, Shu-Guang Yang, Ming-Wen Hu, Rui-Ying Wang, Chi Zhang, Anish R. Kosanam, Arinze J. Ochuba, Jing-Jing Jiang, Ximei Luo, Yun Guan, Jiang Qian, Chang-Mei Liu, Feng-Quan Zhou
Abstract
Blood–brain barrier (BBB) disruption is a serious pathological consequence of traumatic brain injury (TBI), for which there are limited therapeutic strategies. Tissue inhibitor of metalloproteinase-2 (TIMP2), a molecule with dual functions of inhibiting matrix metalloproteinase (MMP) activity and displaying cytokine-like activity through receptor binding, has been reported to inhibit VEGF-induced vascular hyperpermeability. Here, we investigate the ability of TIMP2 to ameliorate BBB disruption in TBI and the underlying molecular mechanisms. Both TIMP2 and AlaTIMP2, a TIMP2 mutant without MMP-inhibiting activity, attenuated neurological deficits and BBB leakage in TBI mice, as well as inhibited junctional protein degradation and translocation to reduce paracellular permeability in HBMECs exposed to hypoxic plus inflammatory insult. Mechanistic studies revealed that TIMP2 interacted with integrin α3β1 on endothelial cells (ECs), inhibiting Src activation-dependent VE-Cadherin phosphorylation, VE-Cadherin/catenin complex destabilization and subsequent VE-Cadherin internalization. Notably, localization of VE-Cadherin on the membrane was critical for TIMP2-mediated EC barrier integrity. Furthermore, TIMP2-mediated increased membrane localization of VE-Cadherin enhanced the level of active Rac1, thereby inhibiting stress fiber formation. Together, our studies have identified an MMP-independent mechanism by which TIMP2 regulates EC barrier integrity after TBI. TIMP2 may be a therapeutic agent for TBI and other neurological disorders involving BBB breakdown.
Authors
Jingshu Tang, Yuying Kang, Yujun Zhou, Nianying Shang, Xinnan Li, Hongyue Wang, Jiaqi Lan, Shuai Wang, Lei Wu, Ying Peng
Abstract
Vascular aging impacts multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, along with molecular read-outs, remain vastly incomplete. Here we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels. To clarify the consequences of Notch3 loss in the brain vasculature, we used single-cell transcriptomics and uncovered that Notch3 inactivation alters regulation of calcium, contractile function, and promotes a notable increase in extracellular matrix. These alterations adversely impact vascular reactivity, manifesting as dilation, tortuosity, microaneurysms, and decreased cerebral blood flow, as observed by MRI. Combined, these vascular impairments hinder glymphatic flow and result in buildup of glycosaminoglycans within the brain parenchyma. Remarkably, this phenomenon mirrors a key pathological feature found in brains of CADASIL patients – a hereditary vascular dementia associated with NOTCH3 missense mutations. Additionally, single-cell RNA sequencing of the neuronal compartment in aging Notch3 null mice has unveiled patterns reminiscent of those observed in neurodegenerative diseases. These findings offer direct evidence that age-related NOTCH3 deficiencies trigger a progressive decline in vascular function, subsequently affecting glymphatic flow and culminating in neurodegeneration.
Authors
Milagros C. Romay, Russell H. Knutsen, Feiyang Ma, Ana Mompeón, Gloria E. Hernandez, Jocelynda Salvador, Snezana Mirkov, Ayush Batra, David P. Sullivan, Daniele Procissi, Samuel Buchanan, Elise Kronquist, Elisa A. Ferrante, William A. Muller, Jordain Walshon, Alicia Steffens, Kathleen McCortney, Craig Horbinski, Elisabeth Tournier‑Lasserve, Adam M. Sonabend, Farzaneh A. Sorond, MichaelM. Wang, Manfred Boehm, Beth A. Kozel, M. Luisa Iruela-Arispe
Abstract
Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β plaques, aggregation of hyperphosphorylated tau (pTau), and microglia activation. Galectin-3 (Gal3) is a β-galactoside-binding protein that has been implicated in amyloid pathology. Its role in tauopathy remains enigmatic. Here, we showed that Gal3 was upregulated in the microglia of humans and mice with tauopathy. pTau triggered the release of Gal3 from human induced pluripotent stem cell-derived microglia (iMGL) in both its free and extracellular vesicular (EV)-associated forms. Both forms of Gal3 increased the accumulation of pathogenic tau in recipient cells. Binding of Gal3 to pTau greatly enhanced tau fibrillation. Besides Gal3, pTau was sorted into EVs for transmission. Moreover, pTau markedly enhanced the numbers of EVs released by iMGL in a Gal3-dependent manner, suggesting a role of Gal3 in EVs biogenesis. Single-cell RNA-seq analysis of the hippocampus of a mouse model of tauopathy (THY-Tau22) revealed a group of pathogenic tau-evoked, Gal3-associated microglia (GAM) with altered cellular machineries implicated in neurodegeneration, including enhanced immune and inflammatory responses. Genetic removal of Gal3 in THY-Tau22 mice suppressed microglia activation, reduced the level of pTau and synaptic loss in neurons, and rescued the memory impairment. Collectively, Gal3 is a potential therapeutic target for tauopathy.
Authors
Jian Jing Siew, Hui-Mei Chen, Feng-Lan Chiu, Chia-Wei Lee, Yao-Ming Chang, Hung-Lin Chen, Thi Ngoc Anh Nguyen, Hung-Ting Liao, Mengyu Liu, Hsiao-Tien Hagar, Yung-Chen Sun, Hsing-Lin Lai, Min-Hao Kuo, David Blum, Luc Buée, Lee-Way Jin, Shih-Yu Chen, Tai-Ming Ko, Jie-rong Huang, Hung-Chih Kuo, Fu-Tong Liu, Yijuang Chern
Abstract
Skull development coincides with the onset of cerebrospinal fluid (CSF) circulation, brain-CSF perfusion, and meningeal lymphangiogenesis, processes essential for brain waste clearance. How these processes are affected by craniofacial disorders such as craniosynostosis are poorly understood. We report that raised intracranial pressure and diminished CSF flow in craniosynostosis mouse models associates with pathological changes to meningeal lymphatic vessels that affect their sprouting, expansion, and long-term maintenance. We also show that craniosynostosis affects CSF circulatory pathways and perfusion into the brain. Further, craniosynostosis exacerbates amyloid pathology and plaque buildup in Twist1+/-:5xFAD transgenic Alzheimer’s disease models. Treating craniosynostosis mice with Yoda1, a small molecule agonist for Piezo1, reduces intracranial pressure and improves CSF flow, in addition to restoring meningeal lymphangiogenesis, drainage to the deep cervical lymph nodes, and brain-CSF perfusion. Leveraging these findings, we show Yoda1 treatments in aged mice with reduced CSF flow and turnover improve lymphatic networks, drainage, and brain-CSF perfusion. Our results suggest CSF provides mechanical force to facilitate meningeal lymphatic growth and maintenance. Additionally, applying Yoda1 agonist in conditions with raised intracranial pressure and/or diminished CSF flow, as seen in craniosynostosis or with ageing, is a possible therapeutic option to help restore meningeal lymphatic networks and brain-CSF perfusion.
Authors
Matt J. Matrongolo, Phillip S. Ang, Junbing Wu, Aditya Jain, Joshua K. Thackray, Akash G. Reddy, Chi Chang Sung, Gaetan Barbet, Young-Kwon Hong, Max A. Tischfield
Copyright © 2024 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)