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Beneficial effects of the beta-secretase inhibitor GRL-8234 in 5XFAD Alzheimer’s transgenic mice lessen during disease progression


Year of Publication:
Contact PI Name:
Masuo Ohno
Contact PI Affiliation:
Ohio State University College of Medicine, Columbus, Ohio, USA
Latha Devi, Jordan Tang
Primary Reference (PubMED ID):
Funding Source:
Alzheimer's Art Quilt Initiative
National Institute on Aging (NIA)
Study Goal and Principal Findings:

BACE1 has a large catalytic site, and this has made it difficult to find small-molecule BACE1 inhibitors that can efficiently cross the blood-brain barrier and are still large enough to block the substrate-binding site of this enzyme. Remarkably, recent progress in medicinal chemistry has led to the development of selective and bioavailable BACE1 inhibitors, some of which have been advancing to phase II/III clinical trials in mild-to-moderate AD. Preclinical investigations of BACE1 inhibitors (e.g., GRL-8234 and TAK-070) successfully reveal mnemonic improvements concomitant with significant cerebral Aβ reduction in the Tg2576 mouse model of AD following systemic administration if the treatment is started during the relatively earlier or pre-pathological phase. In this study investigators compared the effects of the potent and selective small-molecule BACE1 inhibitor GRL-8234 in different pathological stages of the 5xFAD mouse model. GRL-8234  was administered once daily, from 2 months to 4 month age (with modest Abeta pathology)  and 10 month (with massive Abeta pathology) 5xFAD mice. The data show that chronic administration of GRL-8234 has beneficial effects on amyloidosis and memory deficits in 5XFAD mice if the treatment is initiated during earlier, but not advanced stages of Abeta accumulation. In 12-month-old 5XFAD mice treated with GRL-8234 only marginal reductions of Aβ42 were observed and their memory function remained impaired. Importantly, the authors reported that BACE1 and full-length APP expression were significantly elevated older 5XFAD mice with progressive Aβ accumulation; GRL-8234 treatment failed to affect these detrimental mechanisms that are predicted to further accelerate beta amyloid plaque deposition. Results suggest that a combination of the BACE1 inhibitor and agents that block BACE1-elevating pathways, could lower APP expression or remove Abeta plaques, (e.g., passive immunization), and may provide a more efficacious and safe strategy to treat memory deficits in AD with established amyloid pathology.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest
Experiment Notes

For PK properties of GRL-834 see the following: Chang WP, Huang X, Downs D, Cirrito JR, Koelsch G, Holtzman DM, et al. β-Secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice. FASEB J. 2011; 25:775–784. [PubMed: 21059748].


Outcome Measured
Outcome Parameters
Y Maze
beta Amyloid Load
Brain-beta Amyloid Peptide 42
Amyloid Precursor Protein (APP)
Soluble Amyloid Precursor Protein beta (sAPP beta)
APP-CTF99 (CTF beta)
beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)
Brain/Plasma Ratio
Area Under the Curve (AUC)
Target Engagement (Reduction Soluble Amyloid Precursor Protein beta)
Outcomes Notes:
Additional PD effects of plasma, CSF and ISF beta amyloid peptides can be found in: Chang WP, Huang X, Downs D, Cirrito JR, Koelsch G, Holtzman DM, et al. β-Secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice. FASEB J. 2011; 25:775–784. [PubMed: 21059748].