DeBay_2017_Brain.Res_1671_102

Alzheimer's disease (AD) is the most common neurodegenerative disorder causing dementia. One hallmark of the AD brain is the deposition of beta-amyloid (Abeta) plaques. AD is also a state of cholinergic dysfunction and butyrylcholinesterase (BChE) associates with Abeta pathology. A transgenic mouse (5XFAD) is an aggressive amyloidosis model, producing Abeta plaques with which BChE also associates. A derived strain (5XFAD/BChE-KO), with the BChE gene knocked out, has significantly lower fibrillar Abeta than 5XFAD mice at the same age. Therefore, BChE may have a role in Abeta 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-((18)F)fluoro-D-glucose ((18)FDG) administration. To determine whether hypometabolism is related to BChE-induced changes in fibrillar Abeta burden, whole brain and regional uptake of (18)FDG in 5XFAD and 5XFAD/BChE-KO mice was compared to corresponding wild-type (WT5XFAD and WTBChE-KO) strains at 5months. Diminished fibrillar Abeta 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 WTBChE-KO, while retention in hippocampal formation, amygdala and basal ganglia remained unchanged. This suggests that in knocking out BChE and reducing fibrillar Abeta, a possible protective effect on brain function may be conferred in a number of structures in 5XFAD/BChE-KO mice.