Thiorphan-induced neprilysin inhibition raises amyloid beta levels in rabbit cortex and cerebrospinal fluid.
Studies on the pathogenesis of Alzheimer's disease (AD) suggest overproduction of amyloid beta (Abeta) may not be the only pathogenic route to AD. Decreased degradation of Abeta is another possible disease mechanism. Neprilysin is a neutral endopeptidase that has been proposed to be the major enzyme responsible for Abeta degradation. Studies have reported correlations between Abeta deposition and neprilysin activity in the human brain. This study shows that intracerebroventricular infusion of thiorphan, a neprilysin inhibitor, raises cortical and cerebrospinal fluid (CSF) Abeta concentrations in rabbits. Rabbits treated with thiorphan for 5 days had levels of CSF and cortical Abeta40 that were 147 and 142% of the control group, respectively. Results for Abeta42 showed a similar trend. The results indicate that age-related decreases of neprilysin could lead to increased brain concentrations of Abeta, plaque formation, and AD.
Newell
Amanda J
AJ
Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA.
Sue
Lucia I
LI
Scott
Sarah
S
Rauschkolb
Paula K
PK
Walker
Douglas G
DG
Potter
Pamela E
PE
Beach
Thomas G
TG
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002540:Cerebral Cortex / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D015151:Immunoblotting; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D015260:Neprilysin / Q000187:drug effects*; D010446:Peptide Fragments; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D015244:Thiorphan / Q000008:administration & dosage / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011480:Protease Inhibitors; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D015244:Thiorphan; D015260:Neprilysin