PMID- 31256130
OWN - NLM
STAT- MEDLINE
DCOM- 20201001
LR  - 20201001
IS  - 1875-8908 (Electronic)
IS  - 1387-2877 (Linking)
VI  - 70
IP  - 2
DP  - 2019
TI  - AAV9-Mediated Cdk5 Inhibitory Peptide Reduces Hyperphosphorylated Tau and 
      Inflammation and Ameliorates Behavioral Changes Caused by Overexpression of p25 
      in the Brain.
PG  - 573-585
LID - 10.3233/JAD-190099 [doi]
AB  - 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-alpha, which were significantly decreased by the administration of CIP. However, 
      Abeta 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.
FAU - Xu, Miaojing
AU  - Xu M
AD  - Department of Neurology, Nanfang Hospital, Southern Medical University, 
      Guangzhou, Guangdong, P. R. China.
AD  - Department of Neurology, the First Affiliated Hospital of Hainan Medical 
      University, Haikou, China.
FAU - Huang, Yingwei
AU  - Huang Y
AD  - Department of Neurology, Nanfang Hospital, Southern Medical University, 
      Guangzhou, Guangdong, P. R. China.
FAU - Song, Pingping
AU  - Song P
AD  - Department of Neurology, Nanfang Hospital, Southern Medical University, 
      Guangzhou, Guangdong, P. R. China.
FAU - Huang, Yaowei
AU  - Huang Y
AD  - Department of Neurology, Nanfang Hospital, Southern Medical University, 
      Guangzhou, Guangdong, P. R. China.
FAU - Huang, Wei
AU  - Huang W
AD  - Department of Neurology, Nanfang Hospital, Southern Medical University, 
      Guangzhou, Guangdong, P. R. China.
AD  - Department of Neurology, the First People's Hospital of Shunde, Southern Medical 
      University, Guangzhou, Guangdong, P. R. China.
FAU - Zhang, Han-Ting
AU  - Zhang HT
AD  - Department of Behavioral Medicine and Psychiatry and Department of Physiology and 
      Pharmacology, West Virginia University Health Sciences Center, Morgantown, WV, 
      USA.
FAU - Hu, Yafang
AU  - Hu Y
AD  - Department of Neurology, Nanfang Hospital, Southern Medical University, 
      Guangzhou, Guangdong, P. R. China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - J Alzheimers Dis
JT  - Journal of Alzheimer's disease : JAD
JID - 9814863
RN  - 0 (Cdk5 inhibitory peptide, human)
RN  - 0 (Cdk5r1 protein, mouse)
RN  - 0 (Mapt protein, mouse)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Peptide Fragments)
RN  - 0 (tau Proteins)
RN  - EC 2.7.- (Phosphotransferases)
SB  - IM
MH  - Animals
MH  - Brain/*metabolism/pathology
MH  - *Dependovirus/genetics
MH  - Gene Expression
MH  - HEK293 Cells
MH  - Humans
MH  - Inflammation/genetics/metabolism/pathology
MH  - Injections, Intraventricular
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Nerve Tissue Proteins/*metabolism
MH  - Peptide Fragments/*metabolism
MH  - Phosphorylation/physiology
MH  - Phosphotransferases/*biosynthesis/genetics
MH  - tau Proteins/antagonists & inhibitors/*metabolism
OTO - NOTNLM
OT  - Adeno-associated virus
OT  - Cdk5 inhibitory peptide
OT  - hyperphosphorylation of tau
OT  - neurodegeneration
OT  - p25
EDAT- 2019/07/01 06:00
MHDA- 2020/10/02 06:00
CRDT- 2019/07/01 06:00
PHST- 2019/07/01 06:00 [pubmed]
PHST- 2020/10/02 06:00 [medline]
PHST- 2019/07/01 06:00 [entrez]
AID - JAD190099 [pii]
AID - 10.3233/JAD-190099 [doi]
PST - ppublish
SO  - J Alzheimers Dis. 2019;70(2):573-585. doi: 10.3233/JAD-190099.