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

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-β (Aβ) peptide, which contains the sequence Val-His-His-Gln in the vicinity of the cleavage site by α-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 Aβ levels and plaque deposition when compared to Tg-APP/PS1 mice. These results showed that the plant viral protease, NIa, not only reduces Aβ pathology, but also improves behavioral deficits.

Hyperoxygenation revitalizes Alzheimer’s disease pathology through the upregulation of neurotrophic factors

“…We examined whether similar changes could occur in the AD‐like brain. Tg‐APP/PS1 mice, which express high levels of Aβ in the brain at 8 months of age (Kim et al, ), showed increased expression of hypoxia‐related markers, including Hif‐1α , Hmox1 , and Pdk2 , in the hippocampus, whereas Tg‐APP/PS1 mice treated with hyperoxygenation (HO 2 ; 100% O 2 , 2 ATA) for 1 hr daily for 28 days had reduced expression of these factors (Supporting information Figure e–f).…”

“…To address this, Tg‐APP/PS1 mice treated with HO 2 (100% O 2 , 2 ATA), starting from 7 months of age, for 1 hr daily for 2 weeks were placed in the indicated behavioral tests while continuing HO 2 treatment on the given schedule (Figure a). Tg‐APP/PS1 mice at 7.5 months of age display severe cognitive deficits (Kim et al, ). During the training phase of the water maze test, Tg‐APP/PS1 mice given HO 2 exhibited a markedly reduced latency to find the hidden platform compared to Tg‐APP/PS1 control mice (Figure b).…”

“…Tg‐APPswe/PS1dE9 (Tg‐APP/PS1) mice, which show plaque deposition from 6.5 months of age and severe cognitive deficits at 7–7.5 months of age (Kim et al, ), were used. All animals were handled in accordance with the animal care guidelines of the Ewha Womans University (IACUC 16‐019).…”

An Update of Animal Models of Alzheimer Disease with a Reevaluation of Plaque Depositions

“…Despite the plaque deposition and behavioral deficits at 6-8 months of age [45, 46], Tg-APPswe/PS1dE9 mice do not develop NFTs or neuronal loss. Tg-APPswe/PS1dE9 mice became popular partly due to the early availability from JAX (Table 1).…”

Intracellular Cleavage of Amyloid β by a Viral Protease NIa Prevents Amyloid β-Mediated Cytotoxicity

“…In an in vitro study, we demonstrated that NIa specifically cleaves Aβ, which contains the Val-His-His-Gln sequence near to its putative α-secretase cleavage site [23]. We further showed that lentivirus-mediated expression of NIa in the brain of AD mice significantly reduced Aβ pathology and improved behavioral deficits [23], [24].…”