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Peripheral administration of antisense oligonucleotides targeting the amyloid-β protein precursor reverses AβPP and LRP-1 overexpression in the aged SAMP8 mouse brain

Bibliographic

Year of Publication:
2012
Contact PI Name:
William A. Banks
Contact PI Affiliation:
GRECC, Veterans Affairs Puget Sound Health Care System and University of Washington School of Medicine, Division of Gerontology and Geriatric Medicine, Department of Internal Medicine, Seattle, Washington, USA
Co-Authors:
Michelle A. Erickson, Michael L. Niehoff, Susan A. Farr, John E. Morley, Lucy A. Dillman, Kristin M. Lynch
Primary Reference (PubMED ID):
Funding Source:
Veterans Affairs Merit Reviews
National Institute on Aging (NIA)
Study Goal and Principal Findings:

The senescence accelerated mouse-prone 8 (SAMP8) mouse model of Alzheimer’s disease has a natural mutation leading to age-related increases in the amyloid-β protein precursor (AβPP) and amyloid-β (Aβ) in the brain, memory impairment, and deficits in Aβ removal from the brain. Previous studies show that centrally administered antisense oligonucleotide directed against AβPP can decrease AβPP expression and Aβ production in the brains of aged SAMP8 mice, and improve memory. The same antisense crosses the blood-brain barrier and reverses memory deficits when injected intravenously. Here, we give 6 g of AβPP or control antisense 3 times over 2 week intervals to 12 month old SAMP8 mice. Object recognition test was done 48 hours later, followed by removal of whole brains for immunoblot analysis of AβPP, low-density lipoprotein-related protein-1 (LRP-1), p-glycoprotein (Pgp), receptor for advanced glycation endproducts (RAGE), or ELISA of soluble Aβ40. Our results show that AβPP antisense completely reverses a 30% age-associated increase in AβPP signal (p < 0.05 versus untreated 4 month old SAMP8). Soluble Aβ40 increased with age, but was not reversed by antisense. LRP-1 large and small subunits increased significantly with age (147.7%, p < 0.01 and 123.7%, p < 0.05 respectively), and AβPP antisense completely reversed these increases (p < 0.05). Pgp and RAGE were not significantly altered with age or antisense. Antisense also caused improvements in memory (p < 0.001). Together, these data support the therapeutic potential of AβPP antisense and show a unique association between AβPP and LRP-1 expression in the SAMP8 mouse. 

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Antisense
Therapeutic Agent:
Antisense Oligonucleotides Targeting APP
Therapeutic Target:
Amyloid Precursor Protein (APP)

Animal Model

Model Information:
Species:
Mouse
Model Type:
Accelerated Aging
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
Biomarkers
Dose
Formulation
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

Outcomes

Outcome Measured
Outcome Parameters
Behavioral
Novel Object Recognition Test (NORT)
Biochemical
Receptor for Advanced Glycation Endproducts (RAGE)
P-Glycoprotein
Brain-Detergent Soluble beta Amyloid Peptide 40
Amyloid Precursor Protein (APP)
Low Density Lipoprotein Receptor-Related Protein 1 (LRP1)
Pharmacodynamics
Target Engagement (Reduction Amyloid Precursor Protein-Brain)