Search

Recent new findings indicate significant biological roles of cysteine cathepsin proteases in secretory vesicles for production of biologically active peptides. Notably, cathepsin L in secretory vesicles functions as a key protease for proteolytic processing of proneuropeptides (and prohormones) into active neuropeptides that are released to mediate cell-cell communication in the nervous system for neurotransmission. Moreover, cathepsin B in secretory vesicles has been recently identified as a β-secretase for production of neurotoxic β- amyloid (Aβ) peptides that accumulate in Alzheimer's disease (AD), participating as a notable factor in the severe memory loss in AD. These secretory vesicle functions of cathepsins L and B for production of biologically active peptides contrast with the well-known role of cathepsin proteases in lysosomes for the degradation of proteins to result in their inactivation. The unique secretory vesicle proteome indicates proteins of distinct functional categories that provide the intravesicular environment for support of cysteine cathepsin functions. Features of the secretory vesicle protein systems insure optimized intravesicular conditions that support the proteolytic activity of cathepsins. These new findings of recently discovered biological roles of cathepsins L and B indicate their significance in human health and disease. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The cysteine protease cathepsin B is a potential drug target for reducing brain amyloid-β (Aβ) and improving memory in Alzheimer's disease (AD), as reduction of cathepsin B in transgenic mice expressing human wild-type amyloid-β protein precursor (AβPP) results in significantly decreased brain Aβ. Cathepsin B cleaves the wild-type β-secretase site sequence in AβPP to produce Aβ, and cathepsin B inhibitors administered to animal models expressing AβPP containing the wild-type β-secretase site sequence reduce brain Aβ in a manner consistent with β-secretase inhibition. But such inhibitors could act either by direct inhibition of cathepsin B β-secretase activity or by off-target inhibition of the other β-secretase, the aspartyl protease BACE1. To evaluate that issue, we orally administered a cysteine protease inhibitor, E64d, to normal guinea pigs or transgenic mice expressing human AβPP, both of which express the human wild-type β-secretase site sequence. In guinea pigs, oral E64d administration caused a dose-dependent reduction of up to 92% in brain, CSF, and plasma of Aβ40 and Aβ42, a reduction of up to 50% in the C-terminal β-secretase fragment (CTFβ), and a 91% reduction in brain cathepsin B activity, but increased brain BACE1 activity by 20%. In transgenic AD mice, oral E64d administration improved memory deficits and reduced brain Aβ40 and Aβ42, amyloid plaque, brain CTFβ, and brain cathepsin B activity, but increased brain BACE1 activity. We conclude that E64d likely reduces brain Aβ by inhibiting cathepsin B and not BACE1 β-secretase activity and that E64d therefore may have potential for treating AD patients. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic peptide secreted from the gastrointestinal tract in response to food intake. It enhances pancreatic islet β-cell proliferation and glucose-dependent insulin secretion, and lowers blood glucose and food intake in patients with type 2 diabetes mellitus (T2DM). A long-acting GLP-1 receptor (GLP-1 R) agonist, exendin-4 (Ex-4), is the first of this new class of antihyperglycemia drugs approved to treat T2DM. GLP-1Rs are coupled to the cAMP second messenger pathway and, along with pancreatic cells, are expressed within the nervous system of rodents and humans, where receptor activation elicits neurotrophic actions. We detected GLP-1R mRNA expression in both cultured embryonic primary cerebral cortical and ventral mesencephalic (dopaminergic) neurons. These cells are vulnerable to hypoxia- and 6-hydroxydopamine-induced cell death, respectively. We found that GLP-1 and Ex-4 conferred protection in these cells, but not in cells from Glp1r knockout (-/-) mice. Administration of Ex-4 reduced brain damage and improved functional outcome in a transient middle cerebral artery occlusion stroke model. Ex-4 treatment also protected dopaminergic neurons against degeneration, preserved dopamine levels, and improved motor function in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). Our findings demonstrate that Ex-4 can protect neurons against metabolic and oxidative insults, and they provide preclinical support for the therapeutic potential for Ex-4 in the treatment of stroke and PD. [ABSTRACT FROM AUTHOR]

Abnormal accumulation of neurotoxic β-amyloid peptides (Aβ) in brain represents a key factor in the progression of Alzheimer's disease (AD). Identification of small molecules that effectively reduce brain levels of Aβ is important for development of Aβ-lowering agents for AD. In this study, we demonstrate that in vivo Aβ levels in brain are significantly reduced by the cysteine protease inhibitor E64d and the related CA074Me inhibitor, which inhibits cathepsin B. Direct infusion of these inhibitors into brains of guinea pigs resulted in reduced levels of Aβ by 50–70% after 30 days of treatment. Substantial decreases in Aβ also occurred after only 7 days of inhibitor infusion, with a reduction in both Aβ40 and Aβ42 peptide forms. A prominent decrease in Aβ peptides was observed in brain synaptosomal nerve terminal preparations after CA074Me treatment. Analyses of APP-derived proteolytic fragments showed that CA074Me reduced brain levels of the CTFβ fragment, and increased amounts of the sAPPα fragment. These results suggest that CA074Me inhibits Aβ production by modulating APP processing. Animals appeared healthy after treatment with these inhibitors. These results, showing highly effective in vivo decreases in brain Aβ levels by these cysteine protease inhibitors, indicate the feasibility of using related compounds for lowering Aβ in AD. [ABSTRACT FROM AUTHOR]

Discusses the neuroprotective and neurotrophic functions of apolipoprotein E. Details on apolipoprotein E and Alzheimer's disease genetics; Role of apolipoprotein E in the metabolism of amyloid beta protein; Function of apolipoprotein E in neuronal repair and neurite outgrowth.

Discusses the role of amyloid beta protein in Alzheimer's disease. Association of genes in familial Alzheimer's disease; Details on the role of amyloid beta protein in inflammation and the disease; Effect of amyloid beta protein accumulation in mouse models.