Val97Leu mutant presenilin-1 induces tau hyperphosphorylation and spatial memory deficit in mice and the underlying mechanisms.

Abstract

Although the pathological role of presenilin-1 mutation in early onset familial Alzheimer's disease has been widely studied, few focused on how the presenilin-1 mutations result in memory impairment and tau hyperphosphorylation. In the present study, we expressed human Val97Leu mutant presenilin-1, which is reported in Chinese pedigrees by our group, in transgenic mice and found that the mutant presenilin-1 induced spatial memory deficit and tau hyperphosphorylation at PHF-1, pS199/202, pT231 and pS396 epitopes, but not at pS214 and pS422 epitopes. Pearson analysis showed that the memory deficit was only significantly correlated with tau phosphorylation level at PHF-1, pS199/202, pT231 and pS396 epitopes. Additionally, the hyperphosphorylated tau and tangle-like argentophilic structures were detected at CA3 and CA4, but not CA1, region of hippocampus, and we also found tangle-like structure and wizened degenerative neurons in frontal cortex. We demonstrated the tau hyperphosphorylation at the same epitopes in N2a cells expressing the mutant presenilin-1, which is caused by inhibition of phosphoinositol-3 kinase/Akt and activation of glycogen synthase kinase-3 specifically. Our data demonstrated that human Val97Leu mutant presenilin-1 causes spatial memory deficit in mice and increases tau phosphorylation level in glycogen synthase kinase-3-dependent manner.

• Authors: Yue Wang, Zhe Cheng, Wei Qin, Jianping Jia
• Journal: Journal of neurochemistry (J Neurochem) Vol. 121 Issue 1 Pg. 135-45 (Apr 2012) ISSN: 1471-4159 [Electronic] England
• PMID: 21929538 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Chemical References

• PSEN1 protein, human
• Presenilin-1
• tau Proteins
• Glycogen Synthase Kinase 3
• Leucine
• Valine

Topics

• Animals
• Cell Line, Tumor
• Glycogen Synthase Kinase 3 (genetics, physiology)
• Humans
• Leucine (genetics)
• Maze Learning (physiology)
• Memory Disorders (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred ICR
• Mice, Transgenic
• Mutation (genetics)
• Phosphorylation (physiology)
• Presenilin-1 (genetics, physiology)
• Valine (genetics)
• tau Proteins (genetics, metabolism)