Neurodegeneration-Like Pathological and Behavioral Changes in an AAV9-Mediated p25 Overexpression Mouse Model
Authors: Zhou, Xiao | Huang, Jianou | Pan, Suyue | Xu, Miaojing | He, Rongni | Ji, Zhong | Hu, Yafang
Article Type: Research Article
Abstract: Background: The transgenic mice models overexpressing human p25 contribute greatly to the in vivo neurotoxic mechanism of p25 in neurodegenerative diseases. However, it is time-consuming to manipulate existing transgenic mice models. Objective: Here we aim to establish a novel mouse model of neurodegeneration by overexpressing p25 mediated by recombinant adeno-associated virus serotype 9 (rAAV9). Methods: AAV9-GFP-p25 encoding GFP-fused p25 driven by synapsin promoter, and the control, AAV9-GFP, were delivered in mice by tail-vein injection. Assessments of p25 expression, neurodegenerative pathology, and behavioral changes were performed. Results: GFP expression was detected by in vivo imaging as early as one week after …virus injection. Notably, widespread expression of p25 was obviously found in cortex, hippocampus, and cerebellum in AAV9-GFP-p25 mice. Moreover, decreased hippocampus volumes in AAV9-GFP-p25 mice were detected by 7T MRI examination about one month after injection. Further, these AAV9-GFP-p25 mice exhibited progressive memory impairment from three-month to six-month after virus injection. At last, hyperphosphorylated tau, neurofibrillary tangles, activated astrocytes and microglia cells were elevated in these p25 mice at about six months after virus delivery. However, amyloid-β plaques, overt neuronal loss, and apoptosis in the hippocampus and cortex were not significantly induced by AAV9-mediated p25 overexpression. Conclusion: The AAV9-mediated p25 overexpression mouse model, which is a practical model exhibiting neurodegeneration-like pathological and behavioral changes, provides an easier and time-saving method to explore the functions of p25 in vivo , as well as an alternative tool for development of drugs against neurotoxic of p25. Show more
Keywords: Adeno-associated virus 9, Alzheimer’s disease, cyclin-dependent kinase 5, disease models, magnetic resonance imaging, p25, transgenic mice
DOI: 10.3233/JAD-160191
Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 843-855, 2016
Cdk5 Inhibitory Peptide Prevents Loss of Neurons and Alleviates Behavioral Changes in p25 Transgenic Mice
Authors: Huang, Yaowei | Huang, Wei | Huang, Yingwei | Song, Pingping | Zhang, Melanie | Zhang, Han-Ting | Pan, Suyue | Hu, Yafang
Article Type: Research Article
Abstract: Background: Accumulation of p25 is thought to be a causative risk factor for Alzheimer’s disease (AD). As a cleaved product of p35, p25 binds to cyclin-dependent kinase 5 (Cdk5) and leads to the hyperactivity of Cdk5. Then, Cdk5/p25 phosphorylates many pathological substrates related to neurodegenerative diseases. p25 transgenic (Tg) mouse model recaptures some pathological changes of AD, including tau hyperphosphorylation, neurofibrillary tangles, neuroinflammation, and neuronal death, which can be prevented by transgenic expression of Cdk5 inhibitory peptide (CIP) before the insult of p25. Objective: In the present study, we would like to know whether adeno-associated virus serotype-9 (AAV9)-mediated CIP can …protect neurons after insult of p25 in p25Tg mice. Methods: Administration of AAV9-CIP or control virus were delivered in the brain of p25Tg mice via intracerebroventricular infusions following the induction of p25. Western blotting, immunohistochemistry and immunofluorescence assessment, and animal behavioral evaluation were performed. Results: Brain atrophy, neuronal death, tau phosphorylation and inflammation in the hippocampus, and cognitive decline were observed in p25Tg mice. Administration of CIP but not the control virus in p25Tg mice reduced levels of tau phosphorylation and inflammation in the hippocampus, which is correlated with inhibition of brain atrophy and neuronal apoptosis in the hippocampus, and improvement of cognitive decline. Conclusion: Our results provide further evidence that the neurotoxicity of p25 can be alleviated by CIP. Show more
Keywords: Cdk5, Cdk5 inhibitory peptide, p25 transgenic mice, tau phosphorylation, neurodegeneration
DOI: 10.3233/JAD-191098
Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1231-1242, 2020