Neuroscience
Abstract
Purine metabolism dysregulation has been implicated in Alzheimer’s disease (AD), but its temporal dynamics and mechanistic links to core pathologies remain unclear. This translational study integrated a longitudinal preclinical AD mouse model and clinical cohort investigations to define the role of purine metabolism in AD progression. In APPswe/PSEN1dE9 (APP/PS1) mice, serum-untargeted metabolomics identified purine metabolism as the most notably altered pathway, with metabolite levels (e.g., adenine, adenosine) shifting dynamically across disease stages alongside increasing amyloid-β (Aβ) burden. In the pathology-defined clinical cohort, targeted analysis revealed that serum uric acid and allantoin were specifically depleted in the Aβ+ cognitively impaired (CI) group and correlated strongly with higher brain Aβ load, increased neuroinflammation, and poorer cognitive scores. Formal mediation analysis elucidated a plausible mechanistic cascade: the association of uric acid/allantoin with cognitive impairment was primarily mediated by Aβ pathology. Two-year longitudinal data further suggest that changes in specific purine metabolites might predict the rate of cognitive decline. Allantoin supplementation reduced Aβ pathology through promoting microglial phagocytosis of Aβ in APP/PS1 mice. Our findings identified purine metabolism as a key hub connecting Aβ pathology, neuroinflammation, and clinical progression in AD.
Authors
Xiaohang Qian, Zhongxuan Wang, Siyue Chen, Yang Xue, Yawen Yang, Peijing Cui, Miao Zhang, Huidong Tang
Abstract
Genome-targeting strategies to address NaV1.7-mediated signaling in nociceptive afferents are of great clinical interest given its high selectivity and persistent analgesic outcomes. In the present work, we analyze concentration-dependent effects of suppressing primary afferent NaV1.7 using the intrathecal delivery of an antisense oligonucleotide (ASO) on pain behaviors and demonstrate that NaV1.7 ASOs are likely to modulate pain traffic by blocking afferent signaling at the dorsal root ganglion (DRG) level. Intrathecal NaV1.7 ASOs induced a concentration-dependent gradient of knockdown in DRGs (lumbar to cervical) of Scn9a mRNA and ATTO488-ProTx-II binding in small DRG neurons, and a suppression of pain behaviors initiated by mechanical compression, inflammation, and the NaV1.7 agonist OD-1. The rostro-caudal reduction in mRNA correlated with ASO distribution, with implications for dose-related analgesic profiles. Marked reduction in DRG NaV1.7 binding was seen after intrathecal delivery of an ASO optimal dose, with high selectivity for small DRG neurons. Changes in sciatic nerve NaV1.7 binding were not detected, indicating a pain traffic modulation likely happening due to a block of afferent signaling at the DRG level.
Authors
Kaue Malange, Julia Borges Paes Lemes, Briana Noble, Yuvicza Anchondo, Carlos E. Morado-Urbina, Saee Jadhav, Saurabh Yadav, Jingrui Ma, Vineet Augustine, Sara A. Dochnal, Chiraag Kambalimath, Marie Duong, Pedro Alvarez, Bethany Fitzsimmons, Curt Mazur, Holly B. Kordasiewicz, Kim Dore, Hien T. Zhao, Tony Yaksh
Abstract
The inflammasome is an innate immune complex responsible for aberrant interleukin-1β (IL-1β) signaling in numerous chronic inflammatory diseases, including gout and Alzheimer’s disease. The inflammasome is composed of several proteins, including the apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). We developed vaccines targeting various regions of ASC using a Qβ virus-like particle (VLP) platform to assess the efficacy of anti-ASC antibodies for inhibiting inflammasome activity. Using a mouse model of gout, we assessed seven vaccines targeting mouse ASC for their ability to reduce inflammasome activation and neutrophil responses. Three vaccines targeting different regions of the ASC protein (pyrin domain, linker region, and the caspase activation and recruitment domain) successfully targeted ASC, reduced IL-1β, and reduced neutrophil activation. Combining these three vaccines into one cocktail vaccine yielded similar efficacy in the gout model with a favorable safety profile. The combined ASC vaccine also reduced inflammasome levels and pathologically phosphorylated tau in a transgenic mouse model of tauopathy and did not significantly impair host immune responses to bacterial or viral infections. Thus, Qβ-VLP vaccines against ASC can neutralize pathological inflammasome activity across multiple inflammatory disease models.
Authors
Jonathan Hulse, Zachary Villaseñor, Samuel Kress, Kathryn Sánchez, Julianne Peabody, Kimberly A. Morrissey, Alan McNolty, Benjamin Lantz, Laura Gonzalez Bosc, Judy L. Cannon, Seth Daly, Bryce Chackerian, Kiran Bhaskar
Abstract
Defective synaptic transmission is a prominent pathology that underlies cognitive deficits in Alzheimer’s disease (AD), highlighting the need to elucidate molecular mechanisms of synaptic failure. Vacuolar H+-ATPase (V-ATPase), a proton-pumping enzyme, is essential for synaptic vesicle acidification and neurotransmitter loading. However, whether SV-associated V-ATPase is vulnerable to AD remains unclear. Here, using SV-rich fractions from postmortem brain tissues, we identified SV-associated V-ATPase deficits, including decreased enzymatic activity, impaired complex assembly, and altered expression of its key subunits in AD. SV-associated V-ATPase dysfunction was further associated with pathological and clinical characteristics of AD. Genetic downregulation of the V-ATPase V1D subunit, a component reduced in AD brains, disrupted V-ATPase proton transport and impaired SV acidification. Further experiments using 5×FAD mice, which exhibited AD-like SV-associated V-ATPase deficits, demonstrated the deleterious impact of V-ATPase dysfunction on SV acidification and synaptic transmission including presynaptic neurotransmitter release. In addition, ex vivo studies identified amyloid β–induced oxidative stress as a driver of V1D loss and V-ATPase disassembly, linking AD pathology to SV-associated V-ATPase dysfunction. These findings indicate that SV-associated V-ATPase dysfunction contributes to synaptic failure and cognitive deficits in AD. Therapeutic avenues to mitigate V-ATPase dysfunction have the potential to attenuate synaptic failure for the management of AD.
Authors
Yanting Chen, Khloud Ashraf Farouk Emam, Shuwen Yue, Jing Tian, Tienju Wang, Albert Park, Shalini Mishra, Gagan Deep, Zi-Jun Wang, Heng Du, Lan Guo
Abstract
The hypothesized cellular and molecular mechanisms underlying dystonia are broad and include mutations that perturb Ca2+ signaling, including those affecting voltage gated calcium channels (VGCC). In mice, pharmacological activation of neuronal L-type VGCCs induces dystonia in a dose dependent manner. Here we demonstrate that mice expressing a gain-of-function mutation in the L-type VGCC CaV1.2, associated with Timothy syndrome (TS), exhibit motor dysfunction consistent with dystonia. Although CaV1.2 is broadly expressed throughout peripheral tissues and across the brain, we establish that the dystonia-like behavior is driven by neuronal expression of the mutant calcium channel and observe an associated potential excitatory/inhibitory (E/I) imbalance. Because patients with TS have profound metabolic dysregulation, which is associated with some dystonias, we measured changes in circulating metabolites. The dystonia-like events are sensitive to perturbations in pyruvate metabolism, reminiscent of a subset of dystonias associated with pyruvate dysregulation. Our study provides insight into the potential convergence of previously established causes of dystonia, calcium signaling and metabolic homeostasis.
Authors
Patrick Towers, Hong-Gang Wang, Maiko Matsui, Geoffrey S. Pitt
Abstract
The hypothalamic-pituitary-adrenal (HPA) axis integrates central neural processing and responses to stress with endocrine and metabolic responses. We utilized a monoclonal antibody binding corticotrophin-releasing factor (anti-CRF) to achieve durable HPA axis modulation. In mice, anti-CRF treatment decreased plasma corticosterone, food-intake, body weight and fat mass, but preserved lean mass and improved metabolic parameters including insulin sensitization. These body composition effects were observed in middle aged mice on normal chow or high fat diet, aged mice, and Mc4r-/- and ob/ob mice. Single-dose studies demonstrated impacts on weight gain and body composition lasting beyond the period of pharmacological target engagement. Multi-organ transcriptomic and proteomic analyses revealed organ-specific effects of anti-CRF and are consistent with altered glucocorticoid receptor (GR) signaling as a mediator of the observed phenotypes. These studies support anti-CRF-mediated HPA-axis modulation as a metabolic and anti-obesity therapeutic approach distinct from incretins.
Authors
Zachary A. Krumm, Tariful Islam, Caroline M. Watson, Yong Ran, Yona Levites, Hunter S. Futch, Luming Yin, Edgardo Rodriguez-Lebron, Xuefei Liu, Kazi Farhana Afroz, Ariella Goloborodsky, Thomas B. Ladd, Kristy D. Dillon, Danny Ryu, Jennifer L. Bizon, Jada Lewis, Karen A. Scott, Annette de Kloet, Nicholas T. Seyfried, Eric G. Krause, Karen N. McFarland, Todd E. Golde
Serine palmitoyltransferase (SPT) inhibition in SPTSSA-related complex hereditary spastic paraplegia
Abstract
Defective feedback inhibition of serine palmitoyltransferase (SPT) caused by pathogenic SPTSSA variants underlies childhood-onset complex hereditary spastic paraplegia, yet the developmental timing and therapeutic reversibility of sphingolipid dysregulation remain unclear. We generated a knock-in mouse carrying the disease-associated SptssaT51I variant and show that heterozygous animals exhibit preserved intrinsic SPT activity but impaired ORMDL-mediated regulation, leading to sustained elevation of bioactive sphingolipid intermediates that peak during postnatal myelination. Although gross myelin formation was initially maintained, excess sphingolipid flux rendered oligodendrocytes and neurons selectively vulnerable. Dietary L-serine, which augments SPT substrate availability, amplified sphingolipid accumulation in mutant but not wild-type mice, unmasking progressive spasticity, axonal injury, myelin ultrastructural defects, and, when administered during early postnatal development, severe pulmonary pathology likely responsible for lethality. Pharmacologic SPT inhibition with myriocin normalized sphingolipid synthesis, prevented serine-induced lethality, and reversed neurological and metabolic abnormalities. Translating these findings, treatment of a child with SPTSSA-T51I–associated complex hereditary spastic paraplegia using the FDA approved SPT inhibitor D-Cycloserine resulted in sustained improvement in spasticity, reduced baclofen requirement, and decreased plasma levels of neurofilament light chain (NFL). These data define dysregulated sphingolipid biosynthesis as a developmentally and metabolically sensitive driver of neurodegeneration and suggest SPT inhibition as a mechanistically grounded therapeutic strategy.
Authors
Yi Gong, Robert Thompson, Ashley M. Glover, Kenneth Gable, Sita D. Gupta, Natalie Golovanov, Julie Tassinari, Nathan Casey, Brian D. Wishart, Elise L. Townsend, April Qian, Martin Selig, Armen Yerevanian, Teresa M. Dunn, Florian Eichler
Abstract
Premature infants often require supplemental oxygen therapy, a major risk factor for bronchopulmonary dysplasia and subsequent neurodevelopmental impairment. To determine how neonatal hyperoxia affects prefrontal cortex (PFC) development, we exposed neonatal mice to 85% oxygen (O₂) from postnatal day (P)1–P14 and performed integrated single-nucleus transcriptomic and chromatin accessibility profiling with in vivo and in vitro validation. Hyperoxia induced sex-dependent cellular remodeling, reducing L4/5 intratelencephalic projecting glutamatergic neurons in females and mature oligodendrocytes in males. Across both sexes, hyperoxia suppressed oligodendrocyte maturation, with decreased expression of the myelination genes proteolipid protein 1 (Plp1) and myelin basic protein (Mbp), altered chromatin accessibility, and increased oligodendrocyte transcription factor 2 (OLIG2) protein expression. Regulatory responses were sex specific, with tumor protein p53 (TP53)-regulated metabolic disruption and lysine demethylase 3A (Kdm3a) induction in females, and Netrin-1 signaling in males. Hyperoxia impaired oligodendrocyte progenitor cell (OPC) proliferation and differentiation. These abnormalities were recapitulated in postmortem PFC tissue from infants with BPD and human induced pluripotent stem cell (iPSC)-derived OPCs. These findings show that neonatal hyperoxia disrupts PFC development through sex-dependent effects on neuronal and oligodendrocyte lineages while converging on impaired myelination, highlighting oligodendrocyte dysfunction as a clinically relevant consequence of neonatal oxygen exposure.
Authors
Xingrao Ke, Wei Yu, Carl F. Schreck, Joseph M. Varberg, Melissa A. Gener, Daniel A. Louiselle, Sheng Xia, Sherry M. Mabry, Heather L. Menden, Venkatesh Sampath, Robert H. Lane, Kaela M. Varberg
Abstract
Congenital and early-life Zika virus (ZIKV) infection can result in neurologic deficits. Precise mechanisms of injury, especially in the more subtle presentation of postnatal infection, are not fully elucidated. Here, we defined the effects of ZIKV on the developing brain using single cell transcriptomics, histopathology and design-based stereology, diffusion MRI, and neurobehavioral assessments in infant rhesus macaques. ZIKV upregulated interferon-stimulated genes in activated microglia and cell death pathways in neurons and downregulated metabolism and differentiation genes in mature oligodendrocytes. Abnormal micro-organization of the corpus collosum and limbic white matter tracts was seen on diffusion weighted imaging. A curated gene set associated with autism spectrum disorder risk was negatively enriched in inhibitory and excitatory neurons from ZIKV-infected infants, with increased emotional reactivity already evident two weeks following infection. From single cells to organism-level behaviors, these results define the pathways and processes disrupted by early-life ZIKV infection.
Authors
Venkata-Viswanadh Edara, Sienna Freeman, Maureen Sampson, Kathryn M. Moore, Rebecca Richardson, Nils Schoof, Divine Burgess, Michelle J. Lee, Gregory K. Tharp, Roza Vlasova, Shane Taylor, Ariana Hodjatzadeh, Yihana P. Melendez-Alejandro, Samia M. Abdallah, Esther W. Ndungu, Ava K. Mascarenhas, Chao-Hsiung Hsu, Tsang-Wei Tu, Martin Styner, Mehul S. Suthar, Mar M. Sanchez, Steven E. Bosinger, Mark W. Burke, Steven A. Sloan, Jessica Raper, Ann Chahroudi
Mitochonic acid 5 alleviates amyotrophic lateral sclerosis phenotypes via mitochondrial augmentation
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that urgently requires effective treatment. Mitochondrial dysfunction underlies ALS pathology and represents a potential therapeutic target. Here, we demonstrated the therapeutic potential of mitochonic acid 5 (MA-5), a novel mitochondria-targeted compound that ameliorated ALS phenotypes by enhancing mitochondrial function. In a Drosophila ALS model expressing a mutant human SOD1 (G85R), MA-5 significantly improved locomotor activity, with a trend toward restoration of mitochondrial integrity. In skin fibroblasts derived from ALS patients and motor neurons derived from induced pluripotent stem cells, MA-5 restored ATP production and increased mitochondrial motility. Multiomics analyses suggested that MA-5 modulated mitochondria-linked gene expression and downregulated the glycerophosphate shuttle, contributing to mitochondrial reactive oxygen species production. Transcriptomic analysis identified C7orf31 as a potential marker for monitoring the therapeutic effects of MA-5 and diagnosing ALS subtypes. These findings support MA-5 as a promising therapeutic candidate for ALS and propose C7orf31 as a potential biomarker for treatment monitoring and for disease subtyping.
Authors
Yoshitsugu Oikawa, Yuhan Luo, Naoki Suzuki, Tomoko Kasahara, Yoshiyasu Tongu, Yuki Yoshida, Tsukasa Tominari, Shogo Tanabe, Yoshiko Suto, Hitomi Kashiwagi, Saki Saito, Kensuke Ikeda, Chitose Suzuki, Arata Kuranaga, Tetsuya Akiyama, Satoru Morimoto, Yoshitsugu Aoki, Rieko Muramatsu, Tomoyoshi Soga, Masashi Aoki, Hideyuki Okano, Tetsuhiro Tanaka, Takaaki Abe, Erina Kuranaga, Takafumi Toyohara
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