The main causes of Alzheimer's disease remain elusive. Previous data have implicated the BACE-1 protein as a central player in the pathogenesis of Alzheimer's disease. However, many inhibitors of BACE-1 have failed during preclinical and clinical trials for AD treatment. Therefore, uncovering the exact role of BACE-1 in AD may have significant impact on the future development of therapeutic age...

Alzheimer's disease (AD) is characterized by the brain accumulation of Aβ peptides and by the presence of neurofibrillary tangles. Aβ is believed to play an important role in AD and it has been shown that certain flavonoids can affect Aβ production. Recently, it was suggested that the Aβ lowering properties of flavonoids are mediated by a direct inhibition the β-secretase (BACE-1) activity, the...

One of the most important targets in Alzheimer disease is Beta site amyloid precursor protein cleaving enzyme-1 (BACE-1). It is a membrane associated protein and is one of the main enzymes responsible for amyloid β (Aβ) production. Up to now, a considerable number of peptidic and non-peptidic inhibitors of BACE-1 have been developed. Recently, small molecule BACE-1 inhibitors have attracted the...

The convergence of APP (substrate) and BACE-1 (enzyme) is a rate-limiting, obligatory event triggering the amyloidogenic pathway-a key step in Alzheimer's disease (AD) pathology. However, as both APP/BACE-1 are highly expressed in brain, mechanisms precluding their unabated convergence are unclear. Exploring dynamic localization of APP/BACE-1 in cultured hippocampal neurons, we found that after...

b-Site amyloid precursor protein cleavage enzyme (BACE)-1and BACE-2 are members of a novel family of membrane-bound aspartyl proteases. While BACE-1 is known to cleaveb-amyloid precursor protein (bAPP) at the b-secretase siteand to be required for the generation of amyloid b-peptide(Ab), the role of its homologue BACE-2 in amyloidogenesis isless clear. We now demonst...

BACKGROUND Formation of deposits of the insoluble amyloid beta-peptide is believed to be causally related with neurodegeneration in Alzheimer disease (AD). The beta-peptide originates from a larger amyloid precursor protein (APP) by the action of proteolytic enzymes. The first proteolytic event leading to amyloid formation is the cleavage of APP by the membrane-bound aspartyl protease BACE-1, a...

β-site amyloid precursor protein cleaving enzyme (BACE-1) is a validated target for Alzheimer therapy due to its distinctive role in pathogenesis of AD. In the present contribution, a series of new 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridine structures were synthesized as BACE-1 inhibitors (6a-6n). In vitro BACE-1 inhibitory activities were determined by enzymatic fluoresce...

The human β-amyloid (Aβ) cleaving enzyme (BACE-1) is a target for Alzheimer's disease (AD) treatments. This study was conducted to determine if acacetin extracted from the whole Agastache rugosa plant had anti-BACE-1 and behavioral activities in Drosophila melanogaster AD models and to determine acacetin's mechanism of action. Acacetin (100, 300, and 500 μM) rescued amyloid precursor protein (A...

Design, synthesis and evaluation of very potent and selective β-Secretase 2 (memapsin 1, BACE 2) inhibitors are described. The inhibitors were designed specifically to interact with the S2'-site of β-secretase 2 to provide >170,000-fold selectivity over β-secretase (BACE 1) and >15,000-fold selectivity over cathepsin D. BACE 2 is implicated in Type 2 diabetes. The studies serve as an important ...