bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2023‒08‒13
thirteen papers selected by
Verena Kohler
  1. Caspase 3 exhibits a yeast metacaspase proteostasis function that protects mitochondria from toxic TDP43 aggregates.
  2. Implications of In Vitro Multi-Serine Phosphorylation of Alpha-Synuclein in Aggregation and Cytotoxicity.
  3. α-Synuclein Aggregation Is Triggered by Oligomeric Amyloid-β 42 via Heterogeneous Primary Nucleation.
  4. L116 Deletion in CSPα Promotes α-Synuclein Aggregation and Neurodegeneration.
  5. GV-971 attenuates α-Synuclein aggregation and related pathology.
  6. Hematoxylin modulates tau-RD protein fibrillization and ameliorates Alzheimer's disease-like symptoms in a yeast model.
  7. Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis.
  8. Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases.
  9. Acetylated α-Tubulin and α-Synuclein: Physiological Interplay and Contribution to α-Synuclein Oligomerization.
  10. A Hairpin Motif in the Amyloid-β Peptide Is Important for Formation of Disease-Related Oligomers.
  11. Intracellular spatially-targeted chemical chaperones increase native state stability of mutant SOD1 barrel.
  12. Expanded polyQ aggregates interact with sarco-endoplasmic reticulum calcium ATPase and Drosophila inhibitor of apoptosis protein1 to regulate polyQ mediated neurodegeneration in Drosophila.
  13. Small molecule inhibitor of tau self-association in a mouse model of tauopathy: A preventive study in P301L tau JNPL3 mice.
  1. Microb Cell. 2023 Aug 07. 10(8): 157-169
    Caspase 3 exhibits a yeast metacaspase proteostasis function that protects mitochondria from toxic TDP43 aggregates.
    Steve Brunette, Anupam Sharma, Ryan Bell, Lawrence Puente, Lynn A Megeney.
      Caspase 3 activation is a hallmark of cell death and there is a strong correlation between elevated protease activity and evolving pathology in neurodegenerative disease, such as amyotrophic lateral sclerosis (ALS). At the cellular level, ALS is characterized by protein aggregates and inclusions, comprising the RNA binding protein TDP-43, which are hypothesized to trigger pathogenic activation of caspase 3. However, a growing body of evidence indicates this protease is essential for ensuring cell viability during growth, differentiation and adaptation to stress. Here, we explored whether caspase 3 acts to disperse toxic protein aggregates, a proteostasis activity first ascribed to the distantly related yeast metacaspase ScMCA1. We demonstrate that human caspase 3 can functionally substitute for the ScMCA1 and limit protein aggregation in yeast, including TDP-43 inclusions. Proteomic analysis revealed that disrupting caspase 3 in the same yeast substitution model resulted in detrimental TDP-43/mitochondrial protein associations. Similarly, suppression of caspase 3, in either murine or human skeletal muscle cells, led to accumulation of TDP-43 aggregates and impaired mitochondrial function. These results suggest that caspase 3 is not inherently pathogenic, but may act as a compensatory proteostasis factor, to limit TDP-43 protein inclusions and protect organelle function in aggregation related degenerative disease.
    Keywords:  TDP43; caspase; metacaspase; protein aggregation; proteostasis; yeast
    DOI:  https://doi.org/10.15698/mic2023.08.801
  2. ACS Chem Neurosci. 2023 Aug 10.
    Implications of In Vitro Multi-Serine Phosphorylation of Alpha-Synuclein in Aggregation and Cytotoxicity.
    Minal Chaturvedi, Ritu Raj, Sanjeev Kumar Yadav, Tulika Srivastava, Shweta Devi, Durga Dharmadana, Céline Valéry, Sandeep K Sharma, Dinesh Kumar, Smriti Priya.
      Post-translational modifications guide the functional diversity and identity of proteins. Phosphorylation is one such post-translational modification that has been reported in pathological proteins related to various neurodegenerative disorders such as α-synuclein (α-syn) phosphorylation in Parkinson's disease and other synucleinopathies. In α-syn, the phosphorylation has mostly been observed at S129; however, the occurrence of other serine modifications at S9, S42, and S87 is partially explored. In pathogenic conditions, where α-syn is phosphorylated by complex kinase pathways, multi-site modifications may happen and alter the mechanism of α-syn aggregation. Here, using Polo-like kinase 2 and G-protein coupled receptor kinase 4, the in vitro phosphorylation of α-syn was performed, which revealed multi-serine phosphorylation. Mass spectrometry with customized proteolytic digestion showed prominent phosphorylation at S129 and modifications at S87 and S42 with PLK2 and S87 with GRK4. The phosphorylation at the identified serine residues was further validated with NMR and western blotting. Multi-serine phosphorylation aggravates the aggregation potential of monomeric α-syn, seeding capacity, and cytotoxicity in the SH-SY5Y cell line. This study proposes evidence for in vitro multi-site phosphorylation and its significance in α-syn aggregation, toxicity, and related pathogenesis.
    Keywords:  Parkinson’s disease; alpha-synuclein; phosphorylation; post-translational modifications; protein aggregation; protein misfolding
    DOI:  https://doi.org/10.1021/acschemneuro.3c00234
  3. J Am Chem Soc. 2023 Aug 09.
    α-Synuclein Aggregation Is Triggered by Oligomeric Amyloid-β 42 via Heterogeneous Primary Nucleation.
    Devkee M Vadukul, Marcell Papp, Rebecca J Thrush, Jielei Wang, Yiyun Jin, Paolo Arosio, Francesco A Aprile.
      An increasing number of cases where amyloids of different proteins are found in the same patient are being reported. This observation complicates diagnosis and clinical intervention. Amyloids of the amyloid-β peptide or the protein α-synuclein are traditionally considered hallmarks of Alzheimer's and Parkinson's diseases, respectively. However, the co-occurrence of amyloids of these proteins has also been reported in patients diagnosed with either disease. Here, we show that soluble species containing amyloid-β can induce the aggregation of α-synuclein. Fibrils formed under these conditions are solely composed of α-synuclein to which amyloid-β can be found associated but not as part of the core of the fibrils. Importantly, by global kinetic analysis, we found that the aggregation of α-synuclein under these conditions occurs via heterogeneous primary nucleation, triggered by soluble aggregates containing amyloid-β.
    DOI:  https://doi.org/10.1021/jacs.3c03212
  4. Mol Neurobiol. 2023 Aug 11.
    L116 Deletion in CSPα Promotes α-Synuclein Aggregation and Neurodegeneration.
    Tao Guo, Jing Xiong, Hongyan Feng, Lihong Bu, Tingting Xiao, Lingyan Zhou, Juanfeng He, Min Deng, Yan Liu, Zhaohui Zhang, Zhentao Zhang.
      Parkinsonism is a clinical syndrome that is caused by Parkinson's disease (PD) and other neurodegenerative diseases. Here, we report a patient who exhibited progressive parkinsonism, epilepsy, and cognitive impairment and was diagnosed with adult-onset neuronal ceroid lipofuscinoses (ANCLs). The patient carries a mutation (p.Leu116 del) in the DNAJC5 gene that encodes cysteine string protein (CSPα). Since the patient shows typical parkinsonism and loss of dopamine transporter in the striatum, we investigated the effect of wild-type and L116del mutant CSPα on the aggregation of α-synuclein (α-syn) and neurotoxicity in vitro. Overexpression of wild-type CSPα attenuated the phosphorylation, ubiquitination, and aggregation of α-syn induced by α-syn fibrils. Moreover, wild-type CSPα inhibits oxidative stress and cell apoptosis and rescues inefficient SNARE complex formation induced by α-syn fibrils in SH-SY5Y cells. However, these protective effects of CSPα were abolished by the L116del mutation. Collectively, these results indicate that L116 deletion in CSPα promotes α-syn pathology and neurotoxicity. Boosting CSPα may be therapeutically useful for treating synucleinopathies.
    Keywords:  DNAJC5; Neuronal ceroid lipofuscinoses; Parkinsonism; SNARE; α-Synuclein
    DOI:  https://doi.org/10.1007/s12035-023-03552-z
  5. CNS Neurosci Ther. 2023 Aug 10.
    GV-971 attenuates α-Synuclein aggregation and related pathology.
    Zhenwei Yu, Ying Yang, Robin Barry Chan, Min Shi, Tessandra Stewart, Yang Huang, Zongran Liu, Guoyu Lan, Lifu Sheng, Chen Tian, Dishun Yang, Jing Zhang.
      RATIONALE: Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), share a distinct pathological feature, that is, a widespread accumulation of α-synuclein (α-syn) in the brain. There is a significant clinical unmet need for disease-modifying treatments for synucleinopathies. Recently, a seaweed-derived mixture of oligosaccharides sodium oligomannate, GV-971, was approved for Phase 2 clinical trials for PD. This study aimed to further evaluate the therapeutic effects of GV-971 on synucleinopathies using cellular and animal models and explore its associated molecular mechanisms.METHODS: α-Syn aggregation was assessed, in vitro and ex vivo, by ThT assay. A dopaminergic neuron cell line, Prnp-SNCAA53T mice, and brain slices from PD and DLB patients were used to determine the efficacy of GV-971 in ameliorating α-syn pathology. Measurements of motor functions, including pole, cylinder, and rotarod tests, were conducted on Prnp-SNCAA53T mice 4 weeks after intragastric administration of GV-971 (200 mg day-1  kg-1 ).
    RESULTS: GV-971 effectively prevented α-syn aggregation and even disassembled pre-aggregated α-syn fibrils, in vitro and ex vivo. In addition, GV-971 was able to rescue α-syn-induced neuronal damage and reduced release of extracellular vesicles (EVs), likely via modulating Alix expression. In the Prnp-SNCAA53T mouse model, when treated at the age of 5 months, GV-971 significantly decreased α-syn deposition in the cortex, midbrain, and cerebellum regions, along with ameliorating the motor dysfunctions.
    CONCLUSIONS: Our results indicate that GV-971, when administered at a relatively early stage of the disease process, significantly reduced α-syn accumulation and aggregation in Prnp-SNCAA53T mice. Furthermore, GV-971 corrected α-syn-induced inhibition of EVs release in neurons, contributing to neuronal protection. Future studies are needed to further assess GV-971 as a promising disease-modifying therapy for PD and other synucleinopathies.
    Keywords:  GV-971; Synucleinopathy; extracellular vesicle; α-Synuclein aggregation
    DOI:  https://doi.org/10.1111/cns.14393
  6. Int J Biol Macromol. 2023 Aug 04. pii: S0141-8130(23)03036-2. [Epub ahead of print]250 126140
    Hematoxylin modulates tau-RD protein fibrillization and ameliorates Alzheimer's disease-like symptoms in a yeast model.
    Huan-Huan Yin, Yin-Lei Han, Xiao Yan, Yi-Xin Guan.
      Alzheimer's disease (AD) is one of the most serious neurodegenerative diseases with no effective treatment options available. The formation of insoluble amyloid fibrils of the hyperphosphorylated tau protein is intimately associated with AD, hence the tau protein has been a key target for AD drug development. In this work, hematoxylin was discovered as a dual functional compound, that is, acting in the inhibition of repeat domain of tau (tau-RD) protein fibrillogenesis and remodeling of pre-formed tau-RD fibrils in vitro. Meanwhile, hematoxylin was able to reduce the accumulation of tau-RD aggregates in Saccharomyces cerevisiae. Experimental and computational studies indicated that hematoxylin directly interacts with tau-RD protein through hydrophobic forces, hydrogen bonds, π-cation interactions, and π-π stackings. In addition, cellular viability assays showed that hematoxylin greatly reduced cytotoxicity induced by tau-RD aggregates. In summary, hematoxylin might be a promising candidate for further development as a potential therapeutic drug for AD patients.
    Keywords:  Aggregation; Alzheimer's disease; Disaggregation; Hematoxylin; Molecular dynamics simulation; Tau protein
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.126140
  7. Int J Mol Sci. 2023 Jul 29. pii: 12176. [Epub ahead of print]24(15):
    Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis.
    Hiroyuki Yabata, Yuichi Riku, Hiroaki Miyahara, Akio Akagi, Jun Sone, Makoto Urushitani, Mari Yoshida, Yasushi Iwasaki.
      The transactive response DNA-binding protein of 43 kDa (TDP-43) is a pathological protein of amyotrophic lateral sclerosis (ALS). TDP-43 pathology is characterized by a combination of the cytoplasmic aggregation and nuclear clearance of this protein. However, the mechanisms underlying TDP-43 pathology have not been fully clarified. The aim of this study was to evaluate the relationships between the expression level of nuclear TDP-43 and the pathological properties of cytoplasmic aggregates in autopsied ALS cases. We included 22 consecutively autopsied cases with sporadic TDP-43-related ALS. The motor neuron systems were neuropathologically assessed. We identified 790 neurons with cytoplasmic TDP-43 inclusions from the lower motor neuron system of included cases. Nuclear TDP-43 disappeared in 84% (n = 660) and expressed in 16% (n = 130) of neurons with cytoplasmic inclusions; the former was defined as TDP-43 cytoplasmic immunoreactivity (c-ir), and the latter was defined as nuclear and cytoplasmic immunoreactivity (n/c-ir). Morphologically, diffuse cytoplasmic inclusions were significantly more prevalent in TDP-43 n/c-ir neurons than in c-ir neurons, while skein-like and round inclusions were less prevalent in n/c-ir neurons. The cytoplasmic inclusions of TDP-43 n/c-ir neurons were phosphorylated but poorly ubiquitylated when compared with those of c-ir neurons. TDP-43 n/c-ir neurons became less dominant than the c-ir neurons among cases with a prolonged disease duration. The expression level of nuclear TDP-43 was significantly lower in n/c-ir neurons than in normal neurons without cytoplasmic inclusions. Our results indicate that the maturation of cytoplasmic TDP-43 inclusions correlates with the depletion of nuclear TDP-43 in each affected neuron. This finding supports the view that an imbalance between nuclear and cytoplasmic TDP-43 may be an essential pathway to TDP-43 pathology.
    Keywords:  ALS; FTLD; TDP-43; and ubiquitin; autopsy; mislocalization; motor neuron; spinal cord
    DOI:  https://doi.org/10.3390/ijms241512176
  8. Mol Neurodegener. 2023 08 07. 18(1): 52
    Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases.
    Siwei Chu, Xinyi Xie, Carla Payan, Ursula Stochaj.
      The AAA+ ATPase valosin containing protein (VCP) is essential for cell and organ homeostasis, especially in cells of the nervous system. As part of a large network, VCP collaborates with many cofactors to ensure proteostasis under normal, stress, and disease conditions. A large number of mutations have revealed the importance of VCP for human health. In particular, VCP facilitates the dismantling of protein aggregates and the removal of dysfunctional organelles. These are critical events to prevent malfunction of the brain and other parts of the nervous system. In line with this idea, VCP mutants are linked to the onset and progression of neurodegeneration and other diseases. The intricate molecular mechanisms that connect VCP mutations to distinct brain pathologies continue to be uncovered. Emerging evidence supports the model that VCP controls cellular functions on multiple levels and in a cell type specific fashion. Accordingly, VCP mutants derail cellular homeostasis through several mechanisms that can instigate disease. Our review focuses on the association between VCP malfunction and neurodegeneration. We discuss the latest insights in the field, emphasize open questions, and speculate on the potential of VCP as a drug target for some of the most devastating forms of neurodegeneration.
    Keywords:  Chaperone networks; Inclusion bodies; Neurodegeneration; Proteostasis; Stress granules; Valosin containing protein
    DOI:  https://doi.org/10.1186/s13024-023-00639-y
  9. Int J Mol Sci. 2023 Jul 31. pii: 12287. [Epub ahead of print]24(15):
    Acetylated α-Tubulin and α-Synuclein: Physiological Interplay and Contribution to α-Synuclein Oligomerization.
    Alessandra Maria Calogero, Milo Jarno Basellini, Huseyin Berkcan Isilgan, Francesca Longhena, Arianna Bellucci, Samanta Mazzetti, Chiara Rolando, Gianni Pezzoli, Graziella Cappelletti.
      Emerging evidence supports that altered α-tubulin acetylation occurs in Parkinson's disease (PD), a neurodegenerative disorder characterized by the deposition of α-synuclein fibrillary aggregates within Lewy bodies and nigrostriatal neuron degeneration. Nevertheless, studies addressing the interplay between α-tubulin acetylation and α-synuclein are lacking. Here, we investigated the relationship between α-synuclein and microtubules in primary midbrain murine neurons and the substantia nigra of post-mortem human brains. Taking advantage of immunofluorescence and Proximity Ligation Assay (PLA), a method allowing us to visualize protein-protein interactions in situ, combined with confocal and super-resolution microscopy, we found that α-synuclein and acetylated α-tubulin colocalized and were in close proximity. Next, we employed an α-synuclein overexpressing cellular model and tested the role of α-tubulin acetylation in α-synuclein oligomer formation. We used the α-tubulin deacetylase HDAC6 inhibitor Tubacin to modulate α-tubulin acetylation, and we evaluated the presence of α-synuclein oligomers by PLA. We found that the increase in acetylated α-tubulin significantly induced α-synuclein oligomerization. In conclusion, we unraveled the link between acetylated α-tubulin and α-synuclein and demonstrated that α-tubulin acetylation could trigger the early step of α-synuclein aggregation. These data suggest that the proper regulation of α-tubulin acetylation might be considered a therapeutic strategy to take on PD.
    Keywords:  Parkinson’s disease; Proximity Ligation Assay; Tubacin; acetylated α-tubulin; neurodegeneration; oligomers; α-synuclein
    DOI:  https://doi.org/10.3390/ijms241512287
  10. J Am Chem Soc. 2023 Aug 09.
    A Hairpin Motif in the Amyloid-β Peptide Is Important for Formation of Disease-Related Oligomers.
    Mohammed Khaled, Isabel Rönnbäck, Leopold L Ilag, Astrid Gräslund, Birgit Strodel, Nicklas Österlund.
      The amyloid-β (Aβ) peptide is associated with the development of Alzheimer's disease and is known to form highly neurotoxic prefibrillar oligomeric aggregates, which are difficult to study due to their transient, low-abundance, and heterogeneous nature. To obtain high-resolution information about oligomer structure and dynamics as well as relative populations of assembly states, we here employ a combination of native ion mobility mass spectrometry and molecular dynamics simulations. We find that the formation of Aβ oligomers is dependent on the presence of a specific β-hairpin motif in the peptide sequence. Oligomers initially grow spherically but start to form extended linear aggregates at oligomeric states larger than those of the tetramer. The population of the extended oligomers could be notably increased by introducing an intramolecular disulfide bond, which prearranges the peptide in the hairpin conformation, thereby promoting oligomeric structures but preventing conversion into mature fibrils. Conversely, truncating one of the β-strand-forming segments of Aβ decreased the hairpin propensity of the peptide and thus decreased the oligomer population, removed the formation of extended oligomers entirely, and decreased the aggregation propensity of the peptide. We thus propose that the observed extended oligomer state is related to the formation of an antiparallel sheet state, which then nucleates into the amyloid state. These studies provide increased mechanistic understanding of the earliest steps in Aβ aggregation and suggest that inhibition of Aβ folding into the hairpin conformation could be a viable strategy for reducing the amount of toxic oligomers.
    DOI:  https://doi.org/10.1021/jacs.3c03980
  11. Biol Chem. 2023 Aug 09.
    Intracellular spatially-targeted chemical chaperones increase native state stability of mutant SOD1 barrel.
    Sara S Ribeiro, David Gnutt, Salome Azoulay-Ginsburg, Zamira Fetahaj, Ella Spurlock, Felix Lindner, Damon Kuz, Yfat Cohen-Erez, Hanna Rapaport, Adrian Israelson, Arie-Lev Gruzman, Simon Ebbinghaus.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder with currently no cure. Central to the cellular dysfunction associated with this fatal proteinopathy is the accumulation of unfolded/misfolded superoxide dismutase 1 (SOD1) in various subcellular locations. The molecular mechanism driving the formation of SOD1 aggregates is not fully understood but numerous studies suggest that aberrant aggregation escalates with folding instability of mutant apoSOD1. Recent advances on combining organelle-targeting therapies with the anti-aggregation capacity of chemical chaperones have successfully reduce the subcellular load of misfolded/aggregated SOD1 as well as their downstream anomalous cellular processes at low concentrations (micromolar range). Nevertheless, if such local aggregate reduction directly correlates with increased folding stability remains to be explored. To fill this gap, we synthesized and tested here the effect of 9 ER-, mitochondria- and lysosome-targeted chemical chaperones on the folding stability of truncated monomeric SOD1 (SOD1bar) mutants directed to those organelles. We found that compound ER-15 specifically increased the native state stability of ER-SOD1bar-A4V, while scaffold compound FDA-approved 4-phenylbutyric acid (PBA) decreased it. Furthermore, our results suggested that ER15 mechanism of action is distinct from that of PBA, opening new therapeutic perspectives of this novel chemical chaperone on ALS treatment.
    Keywords:  SOD1; chemical chaperones; organelle-targeting therapy; osmolytes; protein folding and aggregation; targeted drugs
    DOI:  https://doi.org/10.1515/hsz-2023-0198
  12. Mol Cell Neurosci. 2023 Aug 09. pii: S1044-7431(23)00080-5. [Epub ahead of print] 103886
    Expanded polyQ aggregates interact with sarco-endoplasmic reticulum calcium ATPase and Drosophila inhibitor of apoptosis protein1 to regulate polyQ mediated neurodegeneration in Drosophila.
    Chandan Kumar Maurya, Madhu G Tapadia.
      Polyglutamine (polyQ) induced neurodegeneration is one of the leading causes of progressive neurodegenerative disorders characterized clinically by deteriorating movement defects, psychiatric disability, and dementia. Calcium [Ca2+] homeostasis, which is essential for the functioning of neuronal cells, is disrupted under these pathological conditions. In this paper, we simulated Huntington's disease phenotype in the neuronal cells of the Drosophila eye and identified [Ca2+] pump, sarco-endoplasmic reticulum calcium ATPase (SERCA), as one of the genetic modifiers of the neurodegenerative phenotype. This paper shows genetic and molecular interaction between polyglutamine (polyQ) aggregates, SERCA and DIAP1. We present evidence that polyQ aggregates interact with SERCA and alter its dynamics, resulting in a decrease in cytosolic [Ca2+] and an increase in ER [Ca2+], and thus toxicity. Downregulating SERCA lowers the enhanced calcium levels in the ER and rescues, morphological and functional defects caused due to expanded polyQ repeats. Cell proliferation markers such as Yorkie (Yki), Scalloped (Sd), and phosphatidylinositol 3 kinases/protein kinase B (PI3K/Akt), also respond to varying levels of calcium due to genetic manipulations, adding to the amelioration of degeneration. These results imply that neurodegeneration due to expanded polyQ repeats is sensitive to SERCA activity, and its manipulation can be an important step toward its therapeutic measures.
    Keywords:  Calcium; Drosophila; Eye disc; Neurodegeneration; PolyQ; SERCA
    DOI:  https://doi.org/10.1016/j.mcn.2023.103886
  13. PLoS One. 2023 ;18(8): e0286523
    Small molecule inhibitor of tau self-association in a mouse model of tauopathy: A preventive study in P301L tau JNPL3 mice.
    Eliot J Davidowitz, Patricia Lopez, Heidy Jimenez, Leslie Adrien, Peter Davies, James G Moe.
      Advances in tau biology and the difficulties of amyloid-directed immunotherapeutics have heightened interest in tau as a target for small molecule drug discovery for neurodegenerative diseases. Here, we evaluated OLX-07010, a small molecule inhibitor of tau self-association, for the prevention of tau aggregation. The primary endpoint of the study was statistically significant reduction of insoluble tau aggregates in treated JNPL3 mice compared with Vehicle-control mice. Secondary endpoints were dose-dependent reduction of insoluble tau aggregates, reduction of phosphorylated tau, and reduction of soluble tau. This study was performed in JNPL3 mice, which are representative of inherited forms of 4-repeat tauopathies with the P301L tau mutation (e.g., progressive supranuclear palsy and frontotemporal dementia). The P301L mutation makes tau prone to aggregation; therefore, JNPL3 mice present a more challenging target than mouse models of human tau without mutations. JNPL3 mice were treated from 3 to 7 months of age with Vehicle, 30 mg/kg compound dose, or 40 mg/kg compound dose. Biochemical methods were used to evaluate self-associated tau, insoluble tau aggregates, total tau, and phosphorylated tau in the hindbrain, cortex, and hippocampus. The Vehicle group had higher levels of insoluble tau in the hindbrain than the Baseline group; treatment with 40 mg/kg compound dose prevented this increase. In the cortex, the levels of insoluble tau were similar in the Baseline and Vehicle groups, indicating that the pathological phenotype of these mice was beginning to emerge at the study endpoint and that there was a delay in the development of the phenotype of the model as originally characterized. No drug-related adverse effects were observed during the 4-month treatment period.
    DOI:  https://doi.org/10.1371/journal.pone.0286523
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