title: Amyloid-beta levels are significantly reduced and spatial memory defects are rescued in a novel neuroserpin-deficient Alzheimer's disease transgenic mouse model.
abstract: Amyloid-beta (Aβ) plaques are a hallmark of Alzheimer's disease. Several proteases including plasmin are thought to promote proteolytic cleavage and clearance of Aβ from brain. The activity of both plasmin and tissue plasminogen activator are reduced in Alzheimer's disease brain, while the tissue plasminogen activator inhibitor neuroserpin is up-regulated. Here, the relationship of tissue plasminogen activator and neuroserpin to Aβ levels is explored in mouse models. Aβ(1-42) peptide injected into the frontal cortex of tissue plasminogen activator knockout mice is slow to disappear compared to wildtype mice, whereas neuroserpin knockout mice show a rapid clearance of Aβ(1-42). The relationship of neuroserpin and tissue plasminogen activator to Aβ plaque formation was studied further by knocking-out neuroserpin in the human amyloid precursor protein-J20 transgenic mouse. Compared to the J20-transgenic mouse, the neuroserpin-deficient J20-transgenic mice have a dramatic reduction of Aβ peptides, fewer and smaller plaques, and more active tissue plasminogen activator associated with plaques. Furthermore, neuroserpin-deficient J20-transgenic mice have near normal performances in the Morris water maze, in contrast to the spatial memory defects seen in J20-transgenic mice. These results support the concept that neuroserpin inhibition of tissue plasminogen activator plays an important role both in the accumulation of brain amyloid plaques and loss of cognitive abilities.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Shay
authors.initials: S
authors.lastname: Fabbro
authors.forename: Kristin
authors.initials: K
authors.lastname: Schaller
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Seeds
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000172:deficiency* / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency; D015843:Serpins / Q000172:deficiency* / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000097522:Neuroserpin
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D009479:Neuropeptides; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; D015843:Serpins; D010959:Tissue Plasminogen Activator; D000097522:Neuroserpin; C051321:SERPINE1 protein, human; C075222:amyloid beta-protein (1-42); C067262:PLAT protein, human