Aged mice lacking interaction between FKBP51 and Hsp90 have normal cognition and memory
Zhe Zhao, Xuelian Sun, Lisha Wang, Jakub Wojcieszak, Bengt Winblad, Pavel F. Pavlov- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
FK506‐binding protein 51 kDa (FKBP51) is a heat shock protein 90 (Hsp90) associated co‐chaperone that has recently emerged as a possible AD therapeutic target. Increased expression of FKBP51 was found in brains of aged mice and AD patients and overexpression of FKBP51 in mice impairs cognitive function in vivo. Role of HSP90‐FKBP51 complex in cognition and memory remains to be characterized.
Methods
• Using CRISPR/Cas9‐mediated genome engineering we have created a new mouse strain (Fkbp5TPRmut) harboring point mutations disrupting FKBP51 binding to Hsp90.
• Genotype of mice was confirmed using PCR‐based assay.
• Behavior of adult was assessed at 12 months of age using a battery of tests, including open field, novel object recognition, Y‐maze, and fear conditioning.
Results
• Mutation of FKBP51 leads to reduced interaction with Hsp90.
• Mutation of FKBP51 is stable and inherited in Mendelian‐like manner. Mutant homozygotes, heterozygotes and wild type mice can be clearly distinguished.
• Fkbp5TPRmut mice do not suffer from any health or fertility issues.
• At 12 months of age Fkbp5TPRmut mice do not display any impairment in behavior, cognition or memory.
Conclusion
• Two‐point mutation of FKBP51 render it incapable of interacting with Hsp90.
• Fkbp5TPRmut mice do not display harmful phenotype, allowing for a broad use of this model.
Further research is granted to reveal functional significance of FKBP51‐Hsp90 interactions, especially in Alzheimer’s disease or stress‐related disorders.