Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Neuron (Cambridge, Mass.), 2017-12, Vol.96 (5), p.1013-1023.e4

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2017

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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. •ApoE has little effect on Aβ accumulation after the initial seeding stage•Decreasing apoE once fibrils have formed leads to an increase in plaque size•ApoE4 reduction decreases neuritic dystrophy, independent of Aβ plaque load•ApoE-targeted therapies aiming to reduce Aβ plaques should focus on prevention Huynh et al. demonstrated that apoE3 and apoE4 are critical factors in promoting amyloidosis during the early stages of Aβ plaque formation but not during the exponential growth phase. Importantly, reduction of apoE4 decreases neuritic dystrophy independent of Aβ pathology.