cathepsin-g and Alzheimer-Disease

Alzheimer's disease (AD) is the major cause of dementia in the elderly. It is characterized by a progressive deterioration in memory and cognitive functions, but also behavioral symptoms are common. Many different genes are possibly involved in Alzheimer's Disease: four genetic factors were confirmed in different studies, while at least 50 additional genes were tested with contrasting results. A major aim both for clinician and researchers would be the identification of the genes involved in AD, to better understand the biological mechanism of this disease and consequently to develop appropriate treatments. The aim of this review is to explore genetics of AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Cathepsin C; Cathepsin G; Cathepsins; DNA, Complementary; Gene Expression; Humans; Membrane Glycoproteins; Membrane Transport Proteins; N-Methylaspartate; Nerve Tissue Proteins; Neurofibrillary Tangles; Plaque, Amyloid; Serine Endopeptidases; Serotonin Plasma Membrane Transport Proteins; Synaptic Transmission; Tryptophan Hydroxylase

Alzheimer's disease (AD) is a multifactorial disease with a complex pathogenesis. Developing multitarget drugs could be a powerful strategy to impact the progressive loss of cognitive functions in this disease. The purpose of this study is to select a multitarget lead peptide candidate among a series of peptide variants derived from the neutrophil granule protein cathepsin G. We screened eight peptide candidates using the following criteria: (1) Inhibition and reversion of amyloid beta (Aβ) oligomers, quantified using an enzyme-linked immunosorbent assay (ELISA); (2) direct binding of peptide candidates to the human receptor for advanced glycation end-products (RAGE), the Toll-like receptor 4 (TLR4) and the S100 calcium-binding protein A9 (S100A9), quantified by ELISA; (3) protection against Aβ oligomer-induced neuronal cell death, using trypan blue to measure cell death in a murine neuronal cell line; (4) inhibition of TLR4 activation by S100A9, using a human TLR4 reporter cell line. We selected a 27-mer lead peptide that fulfilled these four criteria. This lead peptide is a privileged structure that displays inherent multitarget activity. This peptide is expected to significantly impact cognitive decline in mouse models of Alzheimer's disease, by targeting both neuroinflammation and neurodegeneration.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Calcium-Binding Proteins; Cathepsin G; Humans; Mice; Receptor for Advanced Glycation End Products; Toll-Like Receptor 4; Trypan Blue

A role for neutrophils in the pathogenesis of Alzheimer's disease (AD) is emerging. We previously showed that the neutrophil granule proteins cationic antimicrobial protein of 37 kDa (CAP37), cathepsin G (CG), and neutrophil elastase (NE) directly bind the amyloid-beta peptide Aβ. In this study, we compared the effects of these three proteins on Aβ. Using mass spectrometry and in vitro aggregation assay, we found that NE and CG efficiently cleave Aβ. We found that a peptide derived from CAP37 could mimic the quenching and inhibition of Aβ. These results shed light on the mechanisms of action of neutrophil granule proteins with regard to inhibition of Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antimicrobial Cationic Peptides; Blood Proteins; Cathepsin G; Humans; In Vitro Techniques; Leukocyte Elastase; Mice; Neutrophils; Peptide Fragments

Alzheimer's disease (AD) is a complex disease with the possible involvement of several genes. The APOE*4 allele has been documented to be a major risk factor for sporadic late-onset AD, but it is neither necessary nor sufficient to cause the disease. Cathepsin G, a serine protease found commonly in the azurophillic granules of neutrophils, has been reported to possess some beta-secretase like properties, and thus may be involved in the processing of amyloid precursor protein (APP). Recently, an A-->G polymorphism has been reported in exon 4 of the cathepsin G gene, which changes the codon AAC ((125) Asp) to AGC ((125)Ser). In this study, we have investigated the association of this polymorphism with sporadic late-onset AD. We screened DNA samples from 464 late-onset AD cases and 310 age-matched controls. No significant association was seen between this polymorphism and AD. When the data were stratified by the APOE*4 carrier status, no significant difference was seen either. Our data show no effect of this cathepsin G polymorphism in AD. Characterization of additional polymorphisms in this gene may provide more conclusive answers.

Topics: Aged; Alzheimer Disease; Cathepsin G; Cathepsins; Female; Genetic Linkage; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Risk Factors; Serine Endopeptidases

Amyloid deposits in Alzheimer's disease, Down's syndrome and aged brain are composed largely of A beta protein, which is generated by proteolytic processing of beta-amyloid precursor protein. Proteases responsible for liberating the A beta protein from the precursor have not yet been identified. Here, we examined the ability of cathepsin G, a chymotrypsin-like protease, to cleave two protease substrates: (i) a fluorogenic hexapeptide, whose sequence spans the cleavage site in the precursor for generating the A beta NH2-terminus, and (ii) recombinant human beta-amyloid precursor protein purified from a baculovirus expression system. Unlike two other members of the chymotrypsin family, cathepsin G readily degraded the hexapeptide. Furthermore, cathepsin G cleaved the beta-amyloid precursor protein to generate several breakdown products, including a prominent 11,500 mol. wt fragment immunoreactive with antibodies directed against the COOH-terminus of the protein. This COOH-terminal fragment co-migrated using two-dimensional isoelectric focusing/sodium dodecyl sulfate-polyacrylamide gel electrophoresis with C-100, a recombinant COOH-terminal segment of the beta-amyloid precursor, whose NH2-terminus is one residue upstream of the NH2-terminus of the A beta domain. We also examined the localization of cathepsin G in human brain. The distribution of cathepsin G-containing cells was examined by immunohistochemistry in the temporal cortex of both Alzheimer's and aged control samples. Cathepsin G-like immunoreactivity was contained specifically within neutrophils. As visualized by double-labeling with antibodies to cathepsin G and Factor VIII, neutrophils were most frequently found within meningeal or cortical blood vessels. In addition, occasional neutrophils could be identified without an apparent vascular surround, in the brain parenchyma. By simultaneous labeling with antibodies to cathepsin G and A beta protein, neutrophils were also sometimes found associated with both parenchymal and vessel amyloid deposits; however, these associations were rare. These findings indicate that cathepsin G is capable of cleaving the beta-amyloid precursor protein to liberate the free NH2-terminus of the A beta protein and may have access to areas where this material is deposited in Alzheimer's disease. However, since there is no physical association between neutrophils and deposited amyloid and no increase in the number of neutrophils in an Alzheimer's brain, cathepsin G seems

Topics: Alzheimer Disease; Amino Acid Sequence; Amyloid beta-Protein Precursor; Base Sequence; Cathepsin G; Cathepsins; Cerebral Cortex; Chymases; Chymotrypsin; Humans; Molecular Sequence Data; Molecular Weight; Nerve Tissue Proteins; Neutrophils; Peptide Fragments; Recombinant Proteins; Serine Endopeptidases; Temporal Lobe

Recent genetic linkage studies have implicated a gene on chromosome 14 in the pathogenesis of FAD. The identity of this gene remains unknown but it has been speculated that it may be involved in the cellular processing of the amyloid precursor protein (APP). We have analyzed the nucleotide sequence of the entire open reading frame of the cathepsin G gene located on chromosome 14q. No mutations were observed, suggesting that defects in this lysosomal protease are not responsible for aberrant accumulation of proteolytic products of APP in FAD brain tissue.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Base Sequence; Cathepsin G; Cathepsins; Chromosomes, Human, Pair 14; Genetic Linkage; Humans; Lysosomes; Molecular Sequence Data; Mutation; Oligonucleotide Probes; Open Reading Frames; Protein Processing, Post-Translational; Serine Endopeptidases