BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild‐type mice²

Abstract

Accumulation of amyloid beta peptide (Abeta) in brain is a hallmark of Alzheimer's disease (AD). Inhibition of beta-site amyloid precursor protein (APP)-cleaving enzyme-1 (BACE1), the enzyme that initiates Abeta production, and other Abetalowering strategies are commonly tested in transgenic mice overexpressing mutant APP. However, sporadic AD cases, which represent the majority of AD patients, are free from the mutation and do not necessarily have overproduction of APP. In addition, the commonly used Swedish mutant APP alters APP cleavage. Therefore, testing Abeta-lowering strategies in transgenic mice may not be optimal. In this study, we investigated the impact of BACE1 inhibition in non-transgenic mice with physiologically relevant APP expression. Existing Abeta ELISAs are either relatively insensitive to mouse Abeta or not specific to full-length Abeta. A newly developed ELISA detected a significant reduction of full-length soluble Abeta 1-40 in mice with the BACE1 homozygous gene deletion or BACE1 inhibitor treatment, while the level of x-40 Abeta was moderately reduced due to detection of non-full-length Abeta and compensatory activation of alpha-secretase. These results confirmed the feasibility of Abeta reduction through BACE1 inhibition under physiological conditions. Studies using our new ELISA in non-transgenic mice provide more accurate evaluation of Abeta-reducing strategies than was previously feasible. Keywords: Alzheimer's disease, amyloid beta, beta-site amyloid precursor protein-cleaving enzyme 1, enzyme-linked immunoabsorbance assay, secretase, soluble amyloid precursor protein alpha.

Cathepsins B and L Differentially Regulate Amyloid Precursor Protein Processing

“…2, C and D). Note that a similar reduction in A␤ with BACE1 siRNA was also evident, indicating that BACE1 is also involved in APP processing in primary neurons as previously reported (Kao et al, 2004;Nishitomi et al, 2006).…”

First Demonstration of Cerebrospinal Fluid and Plasma Aβ Lowering with Oral Administration of a β-Site Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor in Nonhuman Primates

“…Although these inhibitors are very active on the enzyme, their in vivo utility has been limited by poor membrane permeability and susceptibility to P-gp transport and thus poor brain penetration. Brain A␤ lowering has been demonstrated previously in mice models with transition state isosteres via direct intracranial administration (Asai et al, 2006;Nishitomi et al, 2006;Sankaranarayanan et al, 2008), parenteral administration (Chang et al, 2004;Stachel et al, 2006), or via oral codosing with P-gp inhibitors (Hussain et al, 2007), but none of these compounds were optimal in pharmacokinetic or brain exposure properties for testing in higher animals. TC-1 is a novel BACE1 inhibitor in which the previously reported isonicotinamide Stauffer et al, 2007) and isophthalate oxadiazole (Rajapakse et al, 2006) BACE1 inhibitors were merged to create a new structural class of inhibitors (Lindsley et al, 2007;Moore et al, 2007).…”

“…The structural requirements for binding also impart high susceptibility to P-glycoprotein (P-gp) transport, thus reducing brain concentrations of BACE-1 inhibitors (Mahar Doan et al, 2002). A few BACE1 inhibitors have been shown to lower brain A␤ levels after direct intracranial administration (Asai et al, 2006;Nishitomi et al, 2006;Sankaranarayanan et al, 2008) or via peripheral administration at relatively high doses in murine models (Chang et al, 2004;Stachel et al, 2006;Hussain et al, 2007;Stanton et al, 2007). However, the lack of potent inhibitors that also possess good pharmacokinetic and brain penetration properties have prevented evaluation of BACE1 inhibitors in larger animals, such as nonhuman primates.…”

In Vivo β-Secretase 1 Inhibition Leads to Brain Aβ Lowering and Increased α-Secretase Processing of Amyloid Precursor Protein without Effect on Neuregulin-1

“…Thus, a mechanism-based effect on peripheral or central myelination could potentially affect BACE1 inhibitor development as an AD therapeutic. Although BACE1 inhibitors have shown acute in vivo efficacy to lower brain A␤ levels in murine models when administered peripherally (Chang et al, 2004;Stachel et al, 2006;Hussain et al, 2007) or via direct intracranial injection (Asai et al, 2006;Nishitomi et al, 2006), their poor pharmacokinetic properties have prevented effective evaluation of subchronic to chronic BACE1 inhibition on brain APP processing and NRG-1 processing in adult mice.…”