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Neuron. 2017 Dec 6;96(5):1013-1023.e4. doi: 10.1016/j.neuron.2017.11.014.

Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis.

Author information

1
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Medical Scientist Training Program (MSTP), Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
3
Department of Medicine, Duke University Medical Center, Durham Veterans Health Administration Medical Center's Geriatric Research, Education and Clinical Center, Durham, NC 27710, USA.
4
Ionis Pharmaceuticals, Inc., 2855 Gazelle Ct. Carlsbad, CA 92024, USA.
5
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: holtzman@wustl.edu.

Abstract

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease. Previous studies suggest that reduction of apoE levels through genetic manipulation can reduce Aβ pathology. However, it is not clear how reduction of apoE levels after birth would affect amyloid deposition. We utilize an antisense oligonucleotide (ASO) to reduce apoE expression in the brains of APP/PS1-21 mice homozygous for the APOE-ε4 or APOE-ε3 allele. ASO treatment starting after birth led to a significant decrease in Aβ pathology when assessed at 4 months. Interestingly, ASO treatment starting at the onset of amyloid deposition led to an increase in Aβ plaque size and a reduction in plaque-associated neuritic dystrophy with no change in overall plaque load. These results suggest that lowering apoE levels prior to plaque deposition can strongly affect the initiation of Aβ pathology while lowering apoE after Aβ seeding modulates plaque size and toxicity.

KEYWORDS:

APOE; ASO; Alzheimer disease; Aβ; amyloid-β; antisense oligonucleotides; apolipoprotein E

PMID:
29216448
PMCID:
PMC5728673
DOI:
10.1016/j.neuron.2017.11.014
[Indexed for MEDLINE]
Free PMC Article

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