No abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major component of the plaques, amyloid b peptide (Ab), is generated from amyloid precursor protein (APP) by b-and c-secretase-mediated cleavage. Because b-secretase/beta-site APP cleaving enzyme 1 (BACE1) knockout mice produce much less Ab and grow normally, a b-secretase inhibitor is thought to be one of the most attractive targets for the development of therapeutic interventions for AD without apparent side-effects. Here, we report the in vivo inhibitory effects of a novel b-secretase inhibitor, KMI-429, a transition-state mimic, which effectively inhibits b-secretase activity in cultured cells in a dosedependent manner. We injected KMI-429 into the hippocampus of APP transgenic mice. KMI-429 significantly reduced Ab production in vivo in the soluble fraction compared with vehicle, but the level of Ab in the insoluble fraction was unaffected. In contrast, an intrahippocampal injection of KMI-429 in wildtype mice remarkably reduced Ab production in both the soluble and insoluble fractions. Our results indicate that the b-secretase inhibitor KMI-429 is a promising candidate for the treatment of AD. Keywords: Alzheimer's disease, amyloid b peptide, b-secretase inhibitor, beta-site APP cleaving enzyme 1, hydroxymethylcarbonyl isostere, KMI inhibitor. Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose primary pathogenic event is the extracellular accumulation of amyloid b peptide (Ab), followed by oxidative damage to neurons that ultimately results in

A neuropathological hallmark of Alzheimer's disease is the presence of amyloid plaques in the brain. Amyloid-beta peptide (Abeta) is the major constituent of the plaques and is generated by proteolytic cleavages of amyloid precursor protein (APP) by beta- and gamma-secretases. Growing evidence shows that lipid rafts are critically involved in regulating the Abeta generation. In support of this, APP, Abeta, and presenilins have been found in lipid rafts. Although cholesterol plays a crucial role in maintaining lipid rafts, functions of other components in the generation of Abeta are unknown. Caveolins (CAVs) and flotillins (FLOTs) are principal proteins related to lipid rafts and have been suggested to be involved in APP processing. Here, we report that FLOT-1 binds to BACE1 (beta-site APP cleaving enzyme 1) and that overexpression of CAV-1 or FLOT-1 results in recruiting BACE1 into lipid rafts and influence on beta-secretase activity in cultured cells. Our results show that both CAV-1 and FLOT-1 may modulate beta-secretase activity by interacting with BACE1.