AAV9-Mediated Cdk5 Inhibitory Peptide Reduces Hyperphosphorylated Tau and Inflammation and Ameliorates Behavioral Changes Caused by Overexpression of p25 in the Brain
Affiliations: [a] Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P. R. China | [b] Department of Neurology, the First Affiliated Hospital of Hainan Medical University, Haikou, China
| [c] Department of Neurology, the First People’s Hospital of Shunde, Southern Medical University, Guangzhou, Guangdong, P. R. China | [d] Department of Behavioral Medicine and Psychiatry and Department of Physiology and Pharmacology, West Virginia University Health Sciences Center, Morgantown, WV, USA
Correspondence:
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Correspondence to: Dr. Yafang Hu, Department of Neurology, Nanfang Hospital, Guangzhou 510515, China. Tel.: +86 20 62786544; Fax: +86 20 62787664; E-mail: [email protected].
Note: [1] These authors contributed equally to this work.
Abstract: Background:Under stress stimulation, p25 is generated by cleavage of p35 and acts as an activator of cyclin-dependent kinase 5 (Cdk5) like p35. Unlike Cdk5/p35, which is important for brain development, aberrant activity of Cdk5/p25 plays a pathological role in neurodegenerative diseases, such as Alzheimer’s disease, by inducing hyperphosphorylation of downstream substrates related to pathological progression. A truncated fragment of the c-terminus of p35, the Cdk5 inhibitory peptide (CIP), selectively inhibits Cdk5/ p25 activity in cultured neurons and in CIP/p25 tetra-transgenic mice. Objective:First, we aimed to establish a p25 overexpression adult mouse model, then to evaluate whether CIP delivered by adeno-associated virus serotype 9 (AAV9) can ameliorate neuronal toxicity induced by p25. Methods:The p25 overexpression mouse model was established by intracerebroventricular (i.c.v.) injection of AAV8-GFP-p25 in 8-week-old mice. One month later, these mice were i.c.v. injected with AAV9-CIP-T2A-mCherry or AAV9 vector as control. Pathological and behavioral changes were assessed 3-months post-injection in all mice. Results:The p25 overexpression mice displayed hyperphosphorylation of tau at multiple sites, activation of astrocytes, and elevated inflammatory factors, including IL-1 and TNF-α, which were significantly decreased by the administration of CIP. However, Aβ deposition and microgliosis were not obvious in p25 overexpression mice. In addition, a significant learning decline and anxiety-like behavior were induced by p25 toxicity, and CIP treatment improved learning ability in p25 mice. Conclusion:AAV-mediated p25 overexpression mouse model is easy to construct to study p25-induced neuronal toxicity. Application of CIP after p25 insult reverses the pathological changes and behavioral abnormalities.
