Modest reductions in BACE1 activity significantly reduce beta-amyloid plaque load and neuroinflammation in a mouse model of Alzheimer's disease

Abstract

Inhibiting the amyloidogenic processing of the amyloid precursor protein (APP) by blocking the activity of the β-site APP cleavage enzyme (BACE) has been extensively pursued as a therapeutic strategy for Alzheimer's disease (AD). Indeed, brief treatment with high doses of anti-BACE1 antibodies effectively reduced peripheral and central Aβ production in wild-type mice and nonhuman primates (Atwal et al., STM 2011), suggesting a potential therapeutic role for this antibody. However, it is still unclear what level of Aβ reduction could translate to a therapeutically meaningful impact on the progression of disease pathology if treatment were continued chronically. Therefore, to test the effectiveness of the anti-BACE1 antibodies for reducing/preventing A β plaque deposition and associated pathology, we treated transgenic mice expressing London mutant (V717I) human APP (hAPPlon) for four months starting at an age prior to the onset of plaque deposition. Female transgenic hAPPlon mice or non-transgenic littermate controls received either short-term treatment (3 IP injections, each separated by 4 days), with control antibody or anti-BACE1 antibodies (30mg/kg, 100mg/kg) starting at 2–3 months-of-age, or chronic treatment (weekly IP injections for 16 weeks) of a control antibody or anti-BACE1 antibody (100mg/kg), starting at 10.5 months-of-age. Serum, plasma and brain tissue was collected for PK/PD and pathology analysis. We found that short-term anti-BACE1 treatment (100mg/kg) modestly reduced guanidine-extracted total brain A β 40 and A β 42 levels by 17% and 31%, respectively, compared with control-treated hAPPlon mice when measured by ELISA. Chronic anti-BACE1 treatment significantly reduced A β plaques by ∼50% throughout the brain, compared with control-treated hAPPlon mice. This was associated with a reduction in total brain A β 40 and A β 42 levels by 73% and 55%, respectively. Plaque-associated neuroinflammation, as measured by microglia and astrocyte activation, was also significantly reduced. Modest but chronic inhibition of BACE1 activity with high affinity anti-BACE1 antibodies can significantly reduce A β plaque deposition and associated pathology in a mouse model of AD. This suggests that partial inhibition of BACE1 could be an effective therapeutic strategy in human AD patients as well.