Knockdown of BACE1 by a multistage brain-targeting polyion complex improved memory and learning behaviors in APP/PS1 transgenic mouse model.

Cleavage of Amyloid precursor protein (APP) by the β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting step in the production of amyloid-β (Aβ) synaptotoxins. The siRNA-mediated silencing to attenuate the expression of BACE1 to ameliorate cognitive dysfunction in mice had been investigated. To improve therapeutic gene delivery to the central nervous system, cationic copolymer poly(ethylene glycol)-b-poly[N-(N'-{N''-[N'''-(2-aminoethyl)-2-aminoethyl]-2-aminoethyl}-2-aminoethyl)aspartamide]-cholesterol was synthesized, then RVG29 and Tet1 peptides were exploited as ligands to construct a dual-targeting brain gene delivery polyion complex (Tet1/RVG29-PIC).