Butyrylcholinesterase-knockout reduces fibrillar beta-amyloid and conserves (18)FDG retention in 5XFAD mouse model of Alzheimer's disease

摘要

Alzheimer's disease (AD) is the most common neurodegenerative disorder causing dementia. One hallmark of the AD brain is the deposition of beta-amyloid (A(beta) plaques. AD is also a state of cholinergic dysfunction and butyrylcholinesterase (BChE) associates with A beta pathology. A transgenic mouse (5XFAD) is an aggressive amyloidosis model, producing A beta plaques with which BChE also associates. A derived strain (5XFAD/BChE-KO), with the BChE gene knocked out, has significantly lower fibrillar A beta than 5XFAD mice at the same age. Therefore, BChE may have a role in A beta pathogenesis. Furthermore, in AD, diminished glucose metabolism in the brain can be detected in vivo with positron emission tomography (PET) imaging following 2-deoxy-2-(F-18)fluoro-D-glucose ((18)FDG) administration. To determine whether hypometabolism is related to BChE-induced changes in fibrillar A beta burden, whole brain and regional uptake of (18)FDG in 5XFAD and 5XFAD/BChE-KO mice was compared to corresponding wild-type (WT5XFAD and WBChE-KO) strains at 5 months. Diminished fibrillar A beta burden was confirmed in 5XFAD/BChE-KO mice relative to 5XFAD. 5XFAD and 5XFAD/BChE-KO mice demonstrated reduction in whole brain (18)FDG retention compared to respective wild-types. Regional analysis of relevant AD structures revealed reduction in (18)FDG retention in 5XFAD mice in all brain regions analyzed (save cerebellum) compared to WT5XFAD Alternatively, 5XFAD/BChE-KO mice demonstrated a more selective pattern of reduced retention in the cerebral cortex and thalamus compared to WTBchz-KO while retention in hippocampal formation, amygdala and basal ganglia remained unchanged. This suggests that in knocking out BChE and reducing fibrillar A beta, a possible protective effect on brain function may be conferred in a number of structures in 5XFAD/BChE-KO mice. (C) 2017 Elsevier B.V. All rights reserved.