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Amyloid-beta reduction by memapsin 2 (beta-secretase) immunization


Year of Publication:
Contact PI Name:
Jordan Tang
Contact PI Affiliation:
Protein Studies Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
W.P. Chang, D. Downs, X.P. Huang, H. Da, K.M. Fung
Primary Reference (PubMED ID):
Funding Source:
Alzheimer's Association
National Institute of General Medical Sciences (NIGMS)
National Institute on Aging (NIA)
Study Goal and Principal Findings:

Memapsin 2 (beta-secretase, BACE1) is the protease that initiates cleavage of -amyloid precursor protein leading to the production of amyloid- beta (Abeta) and the onset of Alzheimer’s disease (AD). Reducing Abeta by targeting memapsin 2 is a major strategy in developing new AD therapy. Here, in a proof-of-concept study, we show that immunization of transgenic AD mice (Tg2576) with memapsin 2 resulted in A reduction and cognitive improvement. To study the basis of this therapy, we demonstrated that anti-memapsin 2 (anti-M2) antibodies were rapidly internalized and reduced A production in cultured cells. These antibodies also effectively crossed the blood-brain barrier to reach the brain. Two- and 10-month Tg2576 mice were immunized and monitored over 10 and 6 months, respectively. We observed a significant decrease of plasma and brain Abeta 40 and Abeta 42 (35%) in the immunized mice as compared to controls. Immunized mice also showed better cognitive performance than controls in both cohorts. Brain histological analyses found no evidence of T cell/microglia/astrocyte activation in the immunized mice, suggesting the absence of inflammatory responses. These results suggest that memapsin 2 immunization in Tg2576 was effective in reducing Abeta production and improving cognitive function and that the current approach warrants further investigation as a therapy for AD.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Immunotherapy(active)
Therapeutic Agent:
Memapsin 2 Ectodomain
Therapeutic Target:
Memapsin 2/BACE1
Therapy Type:
Biologic - Immunotherapy(passive)
Therapeutic Agent:
anti-M2 (anti Memapsin 2 Antibody)
Therapeutic Target:
Memapsin 2/BACE1

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:
Not Reported

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
Morris Water Maze
Hidden Platform Task
beta Amyloid Load
Activated Microglia
Activated Astrocytes
Dense-core/Compact Plaques
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
Plasma-beta Amyloid Peptide 40
Plasma-beta Amyloid Peptide 42
APP-CTF83 (CTF alpha)
APP-CTF99 (CTF beta)
Glial Fibrillary Acidic Protein (GFAP)
Brain-beta Amyloid Deposits
Cell Biology
Antibody Titers
Antibody Target Specificity
T Cell Response
Antibody Subcellular Localization
Plasma-beta Amyloid Peptide 40
Plasma-beta Amyloid Peptide 42
Blood Brain Barrier Penetration
Antibody Concentration-CSF
Antibody Concentration-Plasma
Target Engagement (Reduction beta Amyloid Peptide 40-Brain)
Target Engagement (Reduction beta Amyloid Peptide 42-Brain)