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Amyloid‐beta levels are significantly reduced and spatial memory defects are rescued in a novel neuroserpin‐deficient Alzheimer’s disease transgenic mouse model
Author(s) -
Fabbro Shay,
Schaller Kristin,
Seeds Nicholas W.
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07359.x
Subject(s) - plasmin , genetically modified mouse , tissue plasminogen activator , plasminogen activator , transgene , alzheimer's disease , proteases , biology , t plasminogen activator , amyloid beta , chemistry , microbiology and biotechnology , endocrinology , biochemistry , medicine , enzyme , peptide , disease , gene
J. Neurochem. (2011) 118 , 928–938. 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.