Exp Mol Med.  2012 Dec;44(12):740-748.

Expression of the plant viral protease NIa in the brain of a mouse model of Alzheimer's disease mitigates Abeta pathology and improves cognitive function

• Kim TK
• Han HE
• Kim H
• Lee JE
• Choi D
• Park WJ
• Han PL

Abstract

The plant viral protease, NIa, has a strict substrate specificity for the consensus sequence of Val-Xaa-His-Gln, with a scissoring property after Gln. We recently reported that NIa efficiently cleaved the amyloid-beta (Abeta) peptide, which contains the sequence Val-His-His-Gln in the vicinity of the cleavage site by alpha-secretase, and that the expression of NIa using a lentiviral system in the brain of AD mouse model reduced plaque deposition levels. In the present study, we investigated whether exogenous expression of NIa in the brain of AD mouse model is beneficial to the improvement of cognitive deficits. To address this question, Lenti-NIa was intracerebrally injected into the brain of Tg-APPswe/PS1dE9 (Tg-APP/PS1) mice at 7 months of age and behavioral tests were performed 15-30 days afterwards. The results of the water maze test indicated that Tg-APP/PS1 mice which had been injected with Lenti-GFP showed an increased latency in finding the hidden-platform and markedly enhanced navigation near the maze-wall, and that such behavioral deficits were significantly reversed in Tg-APP/PS1 mice injected with Lenti-NIa. In the passive avoidance test, Tg-APP/PS1 mice exhibited a severe deficit in their contextual memory retention, which was reversed by NIa expression. In the marble burying test, Tg-APP/PS1 mice buried marbles fewer than non-transgenic mice, which was also significantly improved by NIa. After behavioral tests, it was verified that the Tg-APP/PS1 mice with Lenti-NIa injection had reduced Abeta levels and plaque deposition when compared to Tg-APP/PS1 mice. These results showed that the plant viral protease, NIa, not only reduces Abeta pathology, but also improves behavioral deficits.

Keyword

Alzheimer disease; amyloid beta-peptides; disease models, animal; endopeptidases; maze learning

MeSH Terms

Alzheimer Disease/*metabolism/pathology/physiopathology
Amyloid beta-Peptides/*metabolism
Amyloid beta-Protein Precursor/genetics
Animals
Avoidance Learning
Brain/*metabolism/pathology/physiopathology
*Cognition
Cognition Disorders
Disease Models, Animal
Endopeptidases/*genetics/metabolism
Gene Expression
Maze Learning
Memory
Mice
Mice, Inbred C57BL
Mice, Transgenic
Plaque, Amyloid/metabolism/*pathology
Presenilin-1/genetics
Viral Proteins/*genetics/metabolism