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

作者：Huynh Tien Phat V; Liao Fan; Francis Caroline M; Robinson Grace O; Serrano Javier Remolina; Jiang Hong; Roh Joseph; Finn Mary Beth; Sullivan Patrick M; Esparza Thomas J; Stewart Floy R; Mahan Thomas E; Ulrich Jason D; Cole Tracy; Holtzman David M^*

来源：Neuron, 2017, 96(5): 1013-+.

DOI：10.1016/j.neuron.2017.11.014

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 A beta 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-epsilon 4 or APOE-epsilon 3 allele. ASO treatment starting after birth led to a significant decrease in A beta pathology when assessed at 4 months. Interestingly, ASO treatment starting at the onset of amyloid deposition led to an increase in A beta 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 A beta pathology while lowering apoE after A beta seeding modulates plaque size and toxicity.

• 出版日期2017-12-6