期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 50, 页码 35952-35960出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.503904
关键词
Alzheimers Disease; Amyloid; Isoprenoid; Neuroinflammation; Transgenic Mice; Learning and Memory; Protein Prenylation
资金
- National Institutes of Health [AG031846]
- Alzheimer's Association [IIRG-09-131791]
- American Health Assistance Foundation/Bright Focus Foundation [A2010328]
- Academic Health Center of the University of Minnesota
Background: Protein prenylation may play an important role in Alzheimer disease. Results: Haplodeficiency in farnesyltransferase and geranylgeranyltransferase-1 attenuates neuropathology, but only reduction of farnesyltransferase rescues cognitive function in Alzheimer mice. Conclusion: Protein farnesylation and geranylgeranylation differentially affect the course of Alzheimer disease. Significance: Specific inhibition of protein farnesylation might be a potential strategy for effectively treating Alzheimer disease. Isoprenoids and prenylated proteins have been implicated in the pathophysiology of Alzheimer disease (AD), including amyloid- precursor protein metabolism, Tau phosphorylation, synaptic plasticity, and neuroinflammation. However, little is known about the relative importance of the two protein prenyltransferases, farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT), in the pathogenesis of AD. In this study, we defined the impact of deleting one copy of FT or GGT on the development of amyloid- (A)-associated neuropathology and learning/memory impairments in APPPS1 double transgenic mice, a well established model of AD. Heterozygous deletion of FT reduced A deposition and neuroinflammation and rescued spatial learning and memory function in APPPS1 mice. Heterozygous deletion of GGT reduced the levels of A and neuroinflammation but had no impact on learning and memory. These results document that farnesylation and geranylgeranylation play differential roles in AD pathogenesis and suggest that specific inhibition of protein farnesylation could be a potential strategy for effectively treating AD.
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