Peripheral Administration of Antisense Oligonucleotides Targeting the Amyloid-β Protein Precursor Reverses AβPP and LRP-1 Overexpression in the Aged SAMP8 Mouse Brain

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-beta protein precursor (A beta PP) and amyloid-beta (A beta) in the brain, memory impairment, and deficits in A beta removal from the brain. Previous studies show that centrally administered antisense oligonucleotide directed against A beta PP can decrease A beta PP expression and A beta 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 mu g of A beta PP 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 A beta PP, low-density lipoprotein-related protein-1 (LRP-1), p-glycoprotein (Pgp), receptor for advanced glycation endproducts (RAGE), or ELISA of soluble A beta(40). Our results show that A beta PP antisense completely reverses a 30% age-associated increase in A beta PP signal (p < 0.05 versus untreated 4 month old SAMP8). Soluble A beta(40) 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 A beta PP 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 A beta PP antisense and show a unique association between A beta PP and LRP-1 expression in the SAMP8 mouse.