SER-214 / Serina Therap - LARVOL DELTA

A Study of Weekly Subcutaneous Injections of SER-214 in Subjects With Parkinson's Disease (PD), to Determine the Safety, Tolerability and Pharmacokinetic (PK) Profile of SER-214 (clinicaltrials.gov) - P1 | N=20 | Active, not recruiting | Sponsor: Serina Therapeutics | Trial completion date: Dec 2022 ➔ Dec 2023 | Trial primary completion date: Dec 2022 ➔ Dec 2023

Trial completion date • Trial primary completion date • CNS Disorders • Movement Disorders • Parkinson's Disease

A Study of Weekly Subcutaneous Injections of SER-214 in Subjects With Parkinson's Disease (PD), to Determine the Safety, Tolerability and Pharmacokinetic (PK) Profile of SER-214 (clinicaltrials.gov) - P1 | N=20 | Active, not recruiting | Sponsor: Serina Therapeutics | Trial completion date: Dec 2021 ➔ Dec 2022 | Trial primary completion date: Dec 2020 ➔ Dec 2022

Trial completion date • Trial primary completion date • CNS Disorders • Movement Disorders • Parkinson's Disease

High-fat diet-induced activation of SGK1 promotes Alzheimer's disease-associated tau pathology. (PubMed, Hum Mol Genet) - "Here, we reported that serum/glucocorticoid-regulated kinase1 (SGK1) is activated by administering a chronic high-fat diet (HFD), which increases the risk of T2DM, and thus promotes Tau pathology via the phosphorylation of tau at Ser214 and the activation of a key tau kinase, namely, GSK-3ß, forming SGK1-GSK-3ß-tau complex...Upregulation and activation of SGK1, SGK1-GSK-3ß-tau complex were also observed in the hippocampi of ad cases. Our results suggest that SGK1 is a key modifier of tau pathology in ad, linking ad to corticosteroid effects and T2DM."

Journal • Alzheimer's Disease • CNS Disorders • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • SGK1

Protein kinase G phosphorylates the Alzheimer's disease-associated tau protein at distinct Ser/Thr sites. (PubMed, Biofactors) - "Here, for the first time, we demonstrate that the cGMP-dependent protein kinase G (PKG) phosphorylates tau in both in vitro and in vivo models. More intriguingly, we provide evidence that PKG phosphorylates tau at Ser214 but not at Ser202, a condition that could reduce the pathological aggregation of the protein shifting tau from a pro-aggregant to a neuroprotective anti-aggregant conformation."

Journal • Alzheimer's Disease • CNS Disorders

[VIRTUAL] PKG PHOSPHORYLATES TAU PROTEIN AT DISTINCT SER/THR SITES (ADPD 2021) - "Among such kinases, the cAMP-dependent protein kinase A (PKA) phosphorylates tau at Ser214, an event that exerts a protective effect against the assembly of tau into paired helical filaments... The cGMP enhancer vardenafil was used in different model systems: neuro N2a cells, rat hippocampal slices and adult male C57BL/6 mice... Our results indicate the existence of a PKG-mediated mechanism that might shift tau from a pro-aggregant to an anti-aggregant conformation, which has been reported to exert neuroprotective functions."

Assessing the therapeutic potential of Graptopetalum paraguayense on Alzheimer's disease using patient iPSC-derived neurons. (PubMed, Sci Rep) - "We found that administration of a GP extract caused a significantly reduction in the AD-associated phenotypes of the iNs, including decreased levels of extracellular Aβ40 and Aβ42, as well as reduced Tau protein phosphorylation at positions Ser214 and Ser396...These findings provide valuable information that suggests moving extracts of GP toward drug development, either for treating AD or as a health supplement to prevent AD. Furthermore, our human iN-based platform promises to be a useful strategy when it is used for AD drug discovery."

Clinical • Journal • Alzheimer's Disease • CNS Disorders • Dementia

A Study of Weekly Subcutaneous Injections of SER-214 in Subjects With Parkinson's Disease (PD), to Determine the Safety, Tolerability and Pharmacokinetic (PK) Profile of SER-214 (clinicaltrials.gov) - P1; N=20; Active, not recruiting; Sponsor: Serina Therapeutics; Trial completion date: Dec 2020 ➔ Dec 2021; Trial primary completion date: Dec 2019 ➔ Dec 2020

Clinical • Trial completion date • Trial primary completion date • CNS Disorders • Movement Disorders • Parkinson's Disease

Rictor promotes cell migration and actin polymerization through regulating ABLIM1 phosphorylation in Hepatocellular Carcinoma. (PubMed, Int J Biol Sci) - "We generated ABLIM1 knockout cell lines of HCC, in which dominant negative mutations of Ser 214 and Ser 431 residues inhibited the ABLIM1-mediated actin polymerization and the MKL1 signaling pathway. Overall, ABLIM1 phosphorylation induced by Rictor plays an important role in controlling actin polymerization in HCC cells."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor

Rv3091, An Extracellular Patatin-Like Phospholipase in Mycobacterium tuberculosis, Prolongs Intracellular Survival of Recombinant Mycolicibacterium smegmatis by Mediating Phagosomal Escape. (PubMed, Front Microbiol) - "We confirm the putative active site residues, namely, Ser214 and Asp407, using site directed mutagenesis...Moreover, Rv3091 significantly increased the survival of M. smegmatis and aggravated lesions in C57BL/6 J murine lungs in vivo. Taken together, our results indicate that Rv3091 as an extracellular PLP that is critical to the pathogenicity of mycobacterium as it allows mycobacterium to utilize phospholipids for its growth and provides resistance to phagosome killing, resulting in its enhanced intracellular survival."

Journal • Infectious Disease • Tuberculosis

[VIRTUAL] History of Seizures in Alzheimer’s Disease Patients is Associated with Elevations in mTOR Activity and Neuropathology (ANA 2020) - "Seizures were also associated with a significant increase in tau hyperphosphorylation on [Thr212, Ser214] (AT100) (p<0.01). Our study indicates that seizures may exacerbate neuropathology of AD through tau hyperphosphorylation and suggests that AD patients should be evaluated for seizures and treated accordingly. Additionally, rapamycin may be a potential therapeutic target in patients with AD and seizures as mTOR is involved in both epileptogenesis and AD neuropathology."

Clinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Epilepsy

[VIRTUAL] No frank biochemical evidence of proteinopathy in the cerebellar cortex of patients with essential tremor (MDS Congress 2020) - " No statistically significant changes were detected in the cerebellar concentrations of total tau (mAbs: tau-13 and tau-5), phosphorylated tau (Ser396/404 and Thr212/Ser214, mAbs AD2 and AT100), TDP-43 (full length 2E2-D3 mAbs and C-terminal segment pAbs), phospho-TDP-43 (Ser409/410 pAbs), FUS (pAbs ), α-syn and phospho-α-syn (Ser129, mAbs MJF-R1 and MJF-R13) between each of the groups studied... The present data does not support the hypothesis that the pathogenesis of ET is associated with the frank development of classical forms of the proteinopathies in the cerebellar cortex."

Clinical • CNS Disorders • Essential Tremor • Proteinopathy • TARDBP

Phospho-Tau Changes in the Human CA1 During Alzheimer's Disease Progression. (PubMed, J Alzheimers Dis) - "Here, by using the antibodies AT100 (recognizes tau protein phosphorylated at Thr212 and Ser214 in the proline-rich region) and pS396 (recognizes tau protein phosphorylated at serine residue 396 in the C-terminal region), we examined phospho-tau immunostaining in neurons from the hippocampal CA1 region of 21 human cases with tau pathology ranging from Braak stage I to VI...Our findings also suggest a conformational modification in tau protein that may cause the disappearance of the AT100 epitope in the late stages of tau pathology, which may play a role in the toxic tangle aggregation. Thus, this study provides new insights underlying the stages for the formation of neurofibrillary tangles in Alzheimer's disease."

Journal • Alzheimer's Disease • CNS Disorders

Flavonoids from Stem and Leaf of Scutellaria Baicalonsis Georgi Inhibit the Phosphorylation on Multi-sites of Tau Protein Induced by Okadaic Acid and the Regulative Mechanism of Protein Kinases in Rats. (PubMed, Comb Chem High Throughput Screen) - "The results demonstrated that SSF could inhibit the hyperphosphorylation of tau in rats' cerebral cortex and hippocampus induced by microinjection of OA, which may be related to the activities of protein kinase CDK5, PKA, and GSK3β."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders

Synthesis of CC, CN coupled novel substituted dibutyl benzothiazepinone derivatives and evaluation of their thrombin inhibitory activity. (PubMed, Bioorg Chem) - "Molecular docking studies suggested that the benzothiazepinones evaluated here consistently display hydrogen bonding with Ser214 of thrombin, which is similar to that of the co-crystallized ligand (1-(2R)-2-amino-3-phenyl-propanoyl-N-(2,5dichlorophenyl)methylpyrrolidine-2-carboxamide). DCT displayed additional hydrogen bonding to Ser195 and π-π interactions between its methoxyphenyl groups and Trp60, thereby providing a structural rationale for the observed biological effect."

Journal • Cardiovascular • Thrombosis

[VIRTUAL] The role of ABI3 in human induced pluripotent stem cell-derived microglia (AAIC 2020) - "In conclusion, ABI3 deficiency in microglia significantly impaired phagocytosis and ADP-induced migration but did not have an effect on AD-like pathology in co-culture with diseased iPS-derived neurons."

Alzheimer's Disease • CNS Disorders • SLC2A1

Germ cell arrest associated with aSETX mutation in ataxia oculomotor apraxia type 2. (PubMed, Reprod Biomed Online) - "In accordance with the murine phenotype, testis histology revealed disrupted seminiferous tubules with spermatogonia and primary spermatocytes, but absent spermatids. Collectively, these data support an essential role of senataxin in human spermatogenesis, and provide a compelling case that men with AOA2 should be counselled at diagnosis about the possibility of infertility."

Journal • Gene Therapies • Infertility • Movement Disorders • Pain • Sexual Disorders

Effect of tau-pathology on charged multivesicular body protein 2b (CHMP2B). (PubMed, Brain Res) - "57% of neurons with GVD displayed GVD-granules double-labeled for CHMP2B and the GVD-marker casein kinase 1δ in 24 months-old tau-transgenic mice and 5.7% of neurons with tau hyper-phosphorylated at Thr212 and Ser214 (immunoreactive with antibody AT100) displayed CHMP2B-positive GVD-granules, in human hippocampi it was 100% and 46% respectively...The results suggest dysregulation of CHMP2B together with tau-pathology and possibly a disturbance of the regulation of vesicular compartments. The absence of combined Aβ- and tau-associated pathology in the transgenic mice may account for the difference in CHMP2B-immunoreactivity between the transgenic mice and human hippocampus."

Journal • Alzheimer's Disease • CNS Disorders • Solid Tumor

Exacerbation of Alzheimer’s Disease Neuropathology and Cognitive Deficits by Seizures (AAN 2020) - "Seizures were associated with a significant increase in tau hyperphosphorylation on [Thr212, Ser214] (AT100) and phosphorylated S6 (a readout of mTOR) in AD patients. Our study indicates that seizures may aggravate neuropathology of AD through tau hyperphosphorylation and suggests that AD patients should be evaluated for seizures and treated accordingly. Additionally, rapamycin may be a potential therapeutic target in patients with AD and seizures as mTOR is involved in both epileptogensis and AD neuropathology."

Alzheimer's Disease • CNS Disorders • Epilepsy • Tauopathies And Synucleinopathies

INVOLVEMENT OF 14-3-3 IN TUBULIN INSTABILITY AND IMPAIRED AXON DEVELOPMENT MEDIATED BY TAU (ADPD 2017) - "In conclusion, These results show that 14-3-3б binds to Tau Ser 214 and Ser 324, this interaction facilitates the dissociation of Tau from microtubules, leading to tubulin instability and blocking axon development. These data suggest a rationale for a possible pharmacologic intervention of the Tau/14-3-3 interaction."

Alzheimer's Disease • Biosimilar • CNS Disorders • Parkinson's Disease

THE PHYSIOLOGIC PHOSPHORYLATION OF TAU IS CRITICALLY CHANGED IN FETAL BRAINS OF INDIVIDUALS WITH DOWN SYNDROME (ADPD 2017) - "...We observed a critical loss of physiologic phosphorylation of tau at several sites including Thr-181, Thr-212, Ser-214, Ser-202/Thr-205, and Thr-231 primarily in rhombencephalic structures...Our observations suggest functional tau disturbance in DS brains during development. This supports the role of tau as a further important player in the pathophysiology of cognitive impairment in DS and related AD."

Clinical • Alzheimer's Disease • Biosimilar • CNS Disorders • Parkinson's Disease

Once-Weekly Subcutaneous Delivery of Polymer-Linked Rotigotine (SER-214) Provides Continuous Plasma Levels in Parkinson's Disease Patients. (PubMed, Mov Disord) - "This study demonstrates that once-a-week subcutaneous administration of polymer-linked rotigotine provides relatively constant plasma levels of rotigotine and is safe and well tolerated. These findings suggest that this convenient method of delivery of rotigotine has the potential to treat or prevent motor complications in PD patients without the need for a surgical procedure or an infusion system. This approach may also prove applicable to other agents such as apomorphine that can be linked to this polymer"

Clinical • Journal

Temporal and regional progression of Alzheimer's disease-like pathology in 3xTg-AD mice. (PubMed, Aging Cell) - "Phosphorylated Tau at Ser202/Thr205 and Ser422 was apparent in the hippocampus of 100% of 6-month-old mice, while only 50% of mice showed tau phosphorylation at Thr212/Ser214 at this age...These neuropathological changes were clearly associated with progressive cognitive decline, which was first apparent at 6 months of age and became significantly worse as the mice aged. These data indicate a consistent and predictable progression of the AD-like pathology in female 3xTg-AD mice, and will facilitate the design of future studies using these mice."

Journal • Preclinical

Caniferolide A, a macrolide from Streptomyces caniferus, attenuates neuroinflammation, oxidative stress, amyloid-beta and tau pathology in vitro. (PubMed, Mol Pharm) - "Caniferolide A reduced Thr212 and Ser214 phosphorylation by targeting p38 and JNK MAPK kinases...The addition of caniferolide A to microglial cells produced a significant increase in the survival of neuroblastoma in both cases. These results indicate that the compound is able to target many pathological markers of AD, suggesting that caniferolide A could be an interesting drug lead for a polypharmacological approach to the illness."

Journal • Preclinical

Exacerbation of Alzheimer's Disease Neuropathology and Cognitive Deficits by Seizures (AAN 2020) - "Seizures were associated with a significant increase in tau hyperphosphorylation on [Thr212, Ser214] (AT100) and phosphorylated S6 (a readout of mTOR) in AD patients... Our study indicates that seizures may aggravate neuropathology of AD through tau hyperphosphorylation and suggests that AD patients should be evaluated for seizures and treated accordingly. Additionally, rapamycin may be a potential therapeutic target in patients with AD and seizures as mTOR is involved in both epileptogensis and AD neuropathology."

Aβ monomer induces phosphorylation of Tau at Ser-214 through β2AR-PKA-JNK signaling pathway. (PubMed, FASEB J) - "Aβ-M induced phosphorylation of Tau at Ser-214 through both β2AR-cAMP/PKA-JNK and β2AR-GRK signaling pathways. Mitogen-activated protein kinase kinase (MEK) mediated the phosphorylation of p70S6K induced by Aβ-M."

Journal • MAPK8