This is a single-site, single-arm, single-dose, Phase 1 study of the safety of bryostatin in participants with multiple sclerosis (MS) receiving any disease modifying therapy (DMT).

Start Date26 Jun 2024

Sponsor / Collaborator

The Cleveland Clinic Foundation

[+1]

NCT04538066 / CompletedPhase 2

A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Assessing Safety, Tolerability and Long-term Efficacy of Bryostatin in the Treatment of Moderately Severe Alzheimer's Disease Subjects Not Receiving Memantine Treatment

To evaluate the safety, tolerability, and long-term efficacy of bryostatin 1 (hereafter referred to as bryostatin) for the treatment of moderately severe Alzheimer's disease (AD).

Start Date30 Aug 2020

Sponsor / Collaborator

Synaptogenix, Inc.

[+2]

NCT03560245 / CompletedPhase 2

A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Assessing the Safety, Tolerability and Efficacy of Bryostatin in the Treatment of Moderately Severe to Severe Alzheimer's Disease Subjects Not Receiving Memantine Treatment

This is a randomized double-blind Placebo-controlled, Phase 2 study comparing bryostatin to placebo for the treatment of moderately severe to severe Alzheimer's disease in subjects not receiving memantine treatment. The study is 15 weeks in duration, including a safety and efficacy evaluation 30 days after the last dose of study drug. Subjects will receive 7 doses of study drug during the study. The primary efficacy endpoint is defined as the change from baseline to Week 13 in the Severe Impairment Battery (SIB) total score.

Start Date20 Jun 2018

Sponsor / Collaborator

Synaptogenix, Inc.

[+1]

100 Clinical Results associated with PKCδ x APP x PKCε

100 Translational Medicine associated with PKCδ x APP x PKCε

0 Patents (Medical) associated with PKCδ x APP x PKCε

Literatures (Medical) associated with PKCδ x APP x PKCε

01 Jan 2013·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Lysophosphatidic acid induces increased BACE1 expression and Aβ formation

Article

Author: Jing Shi ; Yunzhou Dong ; Mei Zhen Cui ; Xuemin Xu

The abnormal production and accumulation of β-amyloid peptide (Aβ), which is produced from amyloid precursor protein (APP) by the sequential actions of β-secretase and γ-secretase, are thought to be the initial causative events in the development of Alzheimer's disease (AD). Accumulating evidence suggests that vascular factors play an important role in the pathogenesis of AD. Specifically, studies have suggested that one vascular factor in particular, oxidized low density lipoprotein (oxLDL), may play an important role in regulating Aβ formation in AD. However, the mechanism by which oxLDL modulates Aβ formation remains elusive. In this study, we report several new findings that provide biochemical evidence suggesting that the cardiovascular risk factor oxLDL may contribute to Alzheimer's disease by increasing Aβ production. First, we found that lysophosphatidic acid (LPA), the most bioactive component of oxLDL induces increased production of Aβ. Second, our data strongly indicate that LPA induces increased Aβ production via upregulating β-secretase expression. Third, our data strongly support the notion that different isoforms of protein kinase C (PKC) may play different roles in regulating APP processing. Specifically, most PKC members, such as PKCα, PKCβ, and PKCε, are implicated in regulating α-secretase-mediated APP processing; however, PKCδ, a member of the novel PKC subfamily, is involved in LPA-induced upregulation of β-secretase expression and Aβ production. These findings may contribute to a better understanding of the mechanisms by which the cardiovascular risk factor oxLDL is involved in Alzheimer's disease.

01 Sep 2012·Journal of Molecular NeuroscienceQ3 · MEDICINE

Bryostatin-1 vs. TPPB: Dose-Dependent APP Processing and PKC-α, -δ, and -ε Isoform Activation in SH-SY5Y Neuronal Cells

Q3 · MEDICINE

Article

Author: J. S. Alexander ; L. Schrott ; P. Yi ; T. P. Castor

Activation of the α-secretase processing pathway of amyloid precursor protein (APP) is recognized as an important mechanism which diverts APP processing from production of beta-amyloid (Aβ) to non toxic sAPPα, decreasing Alzheimer's disease (AD) plaque formation and AD-associated cognitive deficits. Two potent classes of PKC modulators can activate the α-secretase pathway, the benzo/indolactams and bryostatin/bryologues. While both modulate PKC-dependent APP processing, no direct comparisons of their relative pharmacological potencies have been accomplished which could assist in the development of AD therapies. In this study, we measured the activation of α-secretase APP processing and PKC-α, -δ, and -ε induced by the benzolactam-APP modulator TPPB and bryostatin-1 in the neuroblastoma cell line SH-SY5Y which expresses APP and α- and β-secretase processing mechanisms. Bryostatin-1 produced a more rapid, potent, and sustained activation of α-secretase APP processing than TPPB and selectively activated PKC-δ and PKC-ε. Although TPPB also activated α-secretase, its potency was approximately 10- to 100-fold lower, possibly reflecting lower PKC-δ and -ε activation. Because bryostatin-1 is a highly potent PKC-δ and -ε activator which activates α-secretase APP processing, further characterization of bryostatin-1/bryologues may help refine their use as important tools for the clinical management of AD.

01 Jul 2011·Molecular and Cellular NeuroscienceQ2 · MEDICINE

ERK1-independent α-secretase cut of β-amyloid precursor protein via M1 muscarinic receptors and PKCα/ε

Q2 · MEDICINE

Article

Author: Leitges, Michael ; Cisse, Moustapha ; Vincent, Bruno ; Pages, Gilles ; Checler, Frederic ; Fisher, Abraham ; Braun, Ursula

The amyloid precursor protein (βAPP) undergoes several proteolytic cleavages. While β- and γ-secretases are responsible for the production of the 40-43 amino-acid long amyloid β peptide (Aβ), the α-secretase cut performed by the disintegrins ADAM10 and ADAM17, occurs in the middle of the Aβ sequence, thereby preventing its formation and leading to the secretion of the large sAPPα neuroprotective fragment. Here we showed that a series of M1 muscarinic receptor agonists dose-dependently stimulated sAPPα secretion without interfering with βAPP subcellular distribution. Carbachol- and PDBu-induced sAPPα secretions were blocked by the general PKC inhibitor GF109203X. We established that HEK293 and rhabdhomyosarcoma cells overexpressing constitutively active (CA) PKCα or PKCε secrete increased amounts of sAPPα while those expressing PKCδ were unable to modify sAPPα recovery. Conversely, the overexpression of PKCα or PKCε dominant negative (DN) constructs abolished PDBU-stimulated sAPPα secretion, whereas DN-PKCδ remained inert. In agreement, PKCα knockout lowered sAPPα recovery in primary cultured fibroblasts. We also demonstrated that the regulated α-secretase processing of βAPP is not controlled by the Extracellular-Regulated Kinase-1/MAP-ERK Kinase (ERK1/MEK) cascade and likely does not require ADAM17 phosphorylation on its threonine735 residue. Because the muscarinic-dependent α-secretase-like processing of PrP(c) is fully dependent on ADAM17 phosphorylation on its threonine735 residue by ERK1, these results indicate that a single extracellular signal triggers ADAM17-dependent regulated cleavages of βAPP and PrP(c) through distinct signalling cascades. This opens new potential therapeutic strategies aimed, in the context of Alzheimer's disease, at selectively activating ADAM17 towards βAPP without affecting the cleavages of its numerous other substrates.

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