Abstract
Isoprenoids and prenylated proteins have been implicated in the pathophysiology of Alzheimer disease (AD), including amyloid-β 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-β (Aβ)-associated neuropathology and learning/memory impairments in APPPS1 double transgenic mice, a well established model of AD. Heterozygous deletion of FT reduced Aβ deposition and neuroinflammation and rescued spatial learning and memory function in APPPS1 mice. Heterozygous deletion of GGT reduced the levels of Aβ 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.
Highlights
Protein prenylation may play an important role in Alzheimer disease
FT Haplodeficiency Enhances Nonamyloidogenic Processing of APP and Degradation of A—To investigate whether the decrease of A levels in the brain of APPPS1/FTϩ/Ϫ and APPPS1/GGTϩ/Ϫ mice was caused by a decrease in the generation of A from APP, we determined the steady-state levels of full-length APP, and carboxyl-terminal fragments (CTF) and soluble amino-terminal fragments of APP produced by ␣- and -secretase cleavages by immunoblot analyses
The majority of previous studies investigating the effects of isoprenoids and/or protein prenylation on Alzheimer disease (AD)-related processes/functions were conducted in vitro, and statins were often used as a pharmacological tool
Summary
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. 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. Some nonsteroidal anti-inflammatory drugs reduce the production of A42 by inhibiting the prenylated protein Rho and Rho-kinase (ROCK) [12], but others found no involvement of ROCK in the A42-lowering activity of nonsteroidal. Activation of the prenylated protein Rac has been shown to contribute to increased oxidative stress in AD [29, 30] These findings indicate that protein prenylation may play an important role in the development of AD. Our results demonstrate for the first time that haplodeficiency in farnesyltransferase but not geranylgeranyltransferase rescues cognitive function as well as attenuates A-associated neuropathology in APPPS1 mice
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