title: Farnesyltransferase haplodeficiency reduces neuropathology and rescues cognitive function in a mouse model of Alzheimer disease.
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.
authors.affiliation: Departments of Experimental and Clinical Pharmacology University of Minnesota, Minneapolis, MN, USA.
authors.forename: Shaowu
authors.initials: S
authors.lastname: Cheng
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Cao
authors.forename: David A
authors.initials: DA
authors.lastname: Hottman
authors.forename: LiLian
authors.initials: L
authors.lastname: Yuan
authors.forename: Martin O
authors.initials: MO
authors.lastname: Bergo
authors.forename: Ling
authors.initials: L
authors.lastname: Li
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D003071:Cognition; D004195:Disease Models, Animal; D051231:Farnesyltranstransferase / Q000172:deficiency* / Q000235:genetics*; D017353:Gene Deletion; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D059748:Proteolysis
chemical_list: D016229:Amyloid beta-Peptides; D051231:Farnesyltranstransferase
keywords: Alzheimers Disease; Amyloid; Isoprenoid; Learning and Memory; Neuroinflammation; Protein Prenylation; Transgenic Mice