Cdk5 Inhibitory Peptide Prevents Loss of Neurons and Alleviates Behavioral Changes in p25 Transgenic Mice

Article type: Research Article

Authors: Huang, Yaowei^{a; 1} | Huang, Wei^{a; b; 1} | Huang, Yingwei^a | Song, Pingping^{a; c} | Zhang, Melanie^d | Zhang, Han-Ting^e | Pan, Suyue^{a; *} | Hu, Yafang^{a; *}

Affiliations: [a] Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P. R. China | [b] Department of Neurology, Shunde Hospital, Southern Medical University, Foshan, Guangdong, P. R. China | [c] Department of Neurology, First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, P. R. China | [d] Department of Neurobiology Northwestern University, Feinberg School of Medicine, Evanston, IL, USA | [e] Department of Behavioral Medicine & Psychiatry, Physiology & Pharmacology, and Neuroscience, The Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, USA

Correspondence: [*] Correspondence to: Yafang Hu and Suyue Pan, Department of Neurology, Nanfang Hospital, Guangzhou 510515, China. Tel.: +86 20 62786544; Fax: +86 20 62787664; E-mail: [email protected] (Yafang Hu) and Tel./Fax: +86 20 62787664; E-mail: [email protected] (Suyue Pan).

Note: [1] These authors contributed equally to this work.

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.

Keywords: Cdk5, Cdk5 inhibitory peptide, p25 transgenic mice, tau phosphorylation, neurodegeneration

DOI: 10.3233/JAD-191098

Journal: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1231-1242, 2020