β‐Secretase inhibitor GRL‐8234 rescues age‐related cognitive decline in APP transgenic mice

Abstract

Alzheimer disease is intimately linked to an excess amount of amyloid-β (Aβ) in the brain. Thus, therapeutic inhibition of Aβ production is an attractive clinical approach to treat this disease. Here we provide the first direct experimental evidence that the treatment of Tg2576 transgenic mice with an inhibitor of β-secretase, GRL-8234, rescues the age-related cognitive decline. We demonstrated that the injected GRL-8234 effectively enters the brain and rapidly decreases soluble Aβ in the brain of Tg2576 mice. The rescue of cognition, which was observed only after long-term inhibitor treatment ranging from 5 to 7.5 mo, was associated with a decrease of brain amyloid-β plaque load. We also found no accumulation of amyloid-β precursor protein after several months of inhibitor treatment. These observations substantiate the idea that Aβ accumulation plays a major role in the cognitive decline of Tg2576 mice and support the concept of Aβ reduction therapy as a treatment of AD.

Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models

“…It is known that soluble monomers turn over in hours (72)(73)(74)(75), whereas A␤ plaques last at least for months (74 -77). Both the PrP C -interacting and the total pool of soluble A␤ oligomer are stable over 7 days, showing that they have distinct metabolic kinetics from soluble monomers in mouse brain.…”

“…In one study with a ␤-secretase inhibitor, long term treatment improved memory only after several months of treatment (75). In a study of the ␥-secretase inhibitor, there were acute effects on memory function in normal rats (85) and pre-plaque Tg2576 (86), suggesting that drug action may or may not be related to APP, A␤, and AD.…”

“…It is documented that short term treatment with secretase inhibitors rapidly lowers soluble monomeric A␤ 40 and A␤ 42 within hours (72)(73)(74)(75). In contrast, levels of pre-existing plaque A␤ are stable during secretase inhibition such that accumulation is halted but plaques do not regress substantially even over many months of treatment (74 -77).…”

Brain Lipids in the Pathophysiology and Treatment of Alzheimer’s Disease

“…In fact, both genetic deletion of BACE-1 and administration of a BACE-1 inhibitor rescued cognitive deficits and lowered brain Aβ production in AD mouse models. Interestingly, although BACE-1 has other substrates, its inhibition was apparently free of side effects in AD mice [104,105]. The latest generation of small molecule BACE-1 inhibitors has achieved satisfactory brain penetration and a robust reduction in cerebral Aβ in preclinical animal models.…”

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

“…Knock-out animals lacking the catalytic components of γ-secretase (PSEN1 or PSEN2) fail to develop in to viable embryos, while gene knock-out of β-secretase is well tolerated (Luo et al 2001). Despite this, and despite promising results of BACE1 inhibitors in animal models (Fukumoto et al 2010;Chang et al 2011), very few β-secretase targeted therapies have reached clinical trial. One promising result was obtained in the case of CTS-21166, a well tolerated BACE1 inhibitor which passed phase I clinical trials in humans, eliciting a dose dependent decrease in plasma Aβ levels, although little has been published on the molecule (Panza et al 2009).…”