Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer's disease modification.
Aged
Alzheimer Disease
/ metabolism
Amyloid beta-Peptides
/ cerebrospinal fluid
Animals
Biomarkers
/ cerebrospinal fluid
Brain
/ metabolism
Cognition
/ drug effects
Double-Blind Method
Enzyme-Linked Immunosorbent Assay
Hippocampus
/ metabolism
Humans
Male
Mice
Mice, Transgenic
Neurons
/ metabolism
Receptors, sigma
/ antagonists & inhibitors
Synapses
/ metabolism
Abeta oligomers
Alzheimer's disease
clinical trial
sigma-2 receptor
synapse
Journal
Alzheimer's & dementia : the journal of the Alzheimer's Association
ISSN: 1552-5279
Titre abrégé: Alzheimers Dement
Pays: United States
ID NLM: 101231978
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
revised:
16
12
2020
received:
20
10
2020
accepted:
02
01
2021
pubmed:
10
2
2021
medline:
20
11
2021
entrez:
9
2
2021
Statut:
ppublish
Résumé
Amyloid beta (Aβ) oligomers are one of the most toxic structural forms of the Aβ protein and are hypothesized to cause synaptotoxicity and memory failure as they build up in Alzheimer's disease (AD) patients' brain tissue. We previously demonstrated that antagonists of the sigma-2 receptor complex effectively block Aβ oligomer toxicity. CT1812 is an orally bioavailable, brain penetrant small molecule antagonist of the sigma-2 receptor complex that appears safe and well tolerated in healthy elderly volunteers. We tested CT1812's effect on Aβ oligomer pathobiology in preclinical AD models and evaluated CT1812's impact on cerebrospinal fluid (CSF) protein biomarkers in mild to moderate AD patients in a clinical trial (ClinicalTrials.gov NCT02907567). Experiments were performed to measure the impact of CT1812 versus vehicle on Aβ oligomer binding to synapses in vitro, to human AD patient post mortem brain tissue ex vivo, and in living APP CT1812 significantly and dose-dependently displaced Aβ oligomers bound to synaptic receptors in three independent preclinical models of AD, facilitated oligomer clearance into the CSF, increased synaptic number and protein expression in neurons, and improved cognitive performance in transgenic mice. CT1812 significantly increased CSF concentrations of Aβ oligomers in AD patient CSF, reduced concentrations of synaptic proteins and phosphorylated tau fragments, and reversed expression of many AD-related proteins dysregulated in CSF. These preclinical studies demonstrate the novel disease-modifying mechanism of action of CT1812 against AD and Aβ oligomers. The clinical results are consistent with preclinical data and provide evidence of target engagement and impact on fundamental disease-related signaling pathways in AD patients, supporting further development of CT1812.
Identifiants
pubmed: 33559354
doi: 10.1002/alz.12302
pmc: PMC8349378
mid: NIHMS1699785
doi:
Substances chimiques
Amyloid beta-Peptides
0
Biomarkers
0
Receptors, sigma
0
sigma-2 receptor
0
Banques de données
ClinicalTrials.gov
['NCT02907567']
Types de publication
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1365-1382Subventions
Organisme : NIA NIH HHS
ID : R44 AG055247
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS080576
Pays : United States
Organisme : NINDS NIH HHS
ID : R43 NS083175
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG054176
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG012435
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG066530
Pays : United States
Organisme : NIA NIH HHS
ID : R43 AG037337
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG051593
Pays : United States
Informations de copyright
© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
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