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Blocking the apolipoprotein E/amyloid-beta interaction as a potential therapeutic approach for Alzheimer's disease


Year of Publication:
Contact PI Name:
Martin J. Sadowski
Contact PI Affiliation:
New York University School of Medicine, New York, New York, USA
Joanna Pankiewicz, Henrieta Scholtzova, Pankaj D. Mehta, Frances Prelli, David Quartermain, Thomas Wisniewski
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Study Goal and Principal Findings:

The amyloid-beta (Abeta) cascade hypothesis of Alzheimer's disease (AD) maintains that accumulation of Abeta peptide constitutes a critical event in the early disease pathogenesis. The direct binding between Abeta and apolipoprotein E (apoE) is an important factor implicated in both Abeta clearance and its deposition in the brain's parenchyma and the walls of meningoencephalic vessels as cerebral amyloid angiopathy. With the aim of testing the effect of blocking the apoE/Abeta interaction in vivo as a potential novel therapeutic target for AD pharmacotherapy, was developed Abeta12-28P, which is a blood-brain-barrier-permeable nontoxic, and nonfibrillogenic synthetic peptide homologous to the apoE binding site on the full-length Abeta. Abeta12-28P binds with high affinity to apoE, preventing its binding to Abeta, but has no direct effect on Abeta aggregation. Abeta12-28P shows a strong pharmacological effect in vivo. Its systemic administration resulted in a significant reduction of Abeta plaques and cerebral amyloid angiopathy burden and a reduction of the total brain level of Abeta in two AD transgenic mice models. The treatment did not affect the levels of soluble Abeta fraction or Abeta oligomers, indicating that inhibition of the apoE/Abeta interaction in vivo has a net effect of increasing Abeta clearance over deposition and at the same time does not create conditions favoring formation of toxic oligomers. Furthermore, behavioral studies demonstrated that treatment with Abeta12-28P prevents a memory deficit in transgenic animals. These findings provide evidence of another therapeutic approach for AD.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Peptide
Therapeutic Agent:
beta Amyloid Peptide (12-28P)
Therapeutic Target:
Apolipoprotein E (ApoE)
Therapeutic Notes:
Apolipoprotein E has been nominated as a potential target for AD. Nominated targets are obtained from several sources, including the National Institute on Aging's Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) consortium. Targets have been identified using computational analyses of high-dimensional genomic, proteomic and/or metabolomic data derived from human samples. See Agora link for more information.

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
(C57B6/SJL x C57B6)(Swiss-Webster/B6D2F1 x B6D2F)
Model Type:
Strain/Genetic Background:
C57B6/SJL x C57B6

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


Outcome Measured
Outcome Parameters
Radial Arm Water Maze
beta Amyloid Deposits
beta Amyloid Load
Dense-core/Compact Plaques
Cerebral Amyloid Angiopathy (CAA)
Binding-beta Amyloid Fibrils
Plasma-Lipid Profile
Brain-beta Amyloid Oligomers
Binding-Apolipoprotein E
Brain-beta Amyloid Peptide-Total
Brain-Buffer Soluble beta Amyloid Peptides
Brain-beta Amyloid Peptide 42
Brain-beta Amyloid Peptide 40
Brain-Buffer Soluble beta Amyloid Peptide 40
Brain-Buffer Soluble beta Amyloid Peptide 42
Serum-Lipid Profile
beta Amyloid Aggregation
Apolipoprotein E (ApoE)
Brain-beta Amyloid Deposits
Anti-beta Amyloid Antibody Titers
Antibody Isotypes
Serum-Apolipoprotein E
Target Engagement (Reduction beta Amyloid Peptides-Brain)
Systemic Tissue Histotoxicity
Systemic Amyloidosis
General Behavior
Organ Histopathology
Competitive Inhibition
Binding Affinity