Linked Life Data

16054018

Source:http://linkedlifedata.com/resource/pubmed/id/16054018

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2005-8-1
pubmed:abstractText
Amyloid beta peptide (Abeta) is not only a major constituent of extracellular fibrillary pathologies in Alzheimer's disease (AD) brains, but is also physiologically produced and metabolized in neurons. This fact led us to the notion that an age-related decrease in Abeta catabolism may contribute to the molecular pathogenesis of AD, providing a rationale for seeking proteolytic enzymes that degrade Abeta in the brain. Our recent studies have demonstrated that neprilysin is the most potent Abeta-degrading enzyme in vivo. Deficiency of endogenous neprilysin elevates the level of Abeta in brains of neprilysin-knockout mice in a gene dose-dependent manner, and an age-associated decline of neprilysin occurs in several regions of mouse brain. Neuropathological alterations in these same regions have been implicated in cognitive impairments of AD patients at an early stage of the disease. Furthermore, the level of neprilysin mRNA has been found to be significantly and selectively reduced in the hippocampus and temporal cortex of AD patients. A clarification of the role played by decreased neprilysin activity in the pathogenesis of AD has opened up the possibility of neprilysin up-regulation as a novel preventive and therapeutic approach to AD. Since the expression level and activity of neprilysin are likely to be regulated by neuropeptides and their receptors, non-peptidic agonists for these receptors might be effective agents to maintain a sufficient level of Abeta catabolism in brains of the elderly. In addition to Abeta deposits, intraneuronal fibrillary lesions, such as neurofibrillary tangles, are also a pathological hallmark of AD, and the extent of the resultant cytoskeletal disruptions may be dependent upon the activity levels of proteolytic enzymes. Among proteases for which major cytoskeletal components are good substrates, calpains were shown to participate in excitotoxic stress-induced neuritic degeneration in our recent analysis using genetically engineered mice. Moreover, we have found that this pathology can be reduced by controlling the activity of an endogenous calpain inhibitor known as calpastatin, providing a possible approach for the treatment of diverse neurodegenerative disorders, including AD.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Amyloid Precursor Protein Secretases, http://linkedlifedata.com/resource/pubmed/chemical/Amyloid beta-Peptides, http://linkedlifedata.com/resource/pubmed/chemical/Amyloid beta-Protein Precursor, http://linkedlifedata.com/resource/pubmed/chemical/Aspartic Acid Endopeptidases, http://linkedlifedata.com/resource/pubmed/chemical/BACE1 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Bace1 protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Calcium-Binding Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Calpain, http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Proteinase Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Endopeptidases, http://linkedlifedata.com/resource/pubmed/chemical/Neprilysin, http://linkedlifedata.com/resource/pubmed/chemical/calpastatin, http://linkedlifedata.com/resource/pubmed/chemical/tau Proteins
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0006-3002
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
1751
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
60-7
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Understanding molecular mechanisms of proteolysis in Alzheimer's disease: progress toward therapeutic interventions.
pubmed:affiliation
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. mhiguchi@brain.riken.jp
pubmed:publicationType
Journal Article, Review