Butyrylcholinesterase-knockout reduces fibrillar β-amyloid and conserves 18FDG retention in 5XFAD mouse model of Alzheimer’s disease

Jul 22, 2017Brain research

Removing a specific enzyme lowers harmful amyloid buildup and preserves brain sugar use in an Alzheimer's mouse model

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Abstract

5XFAD/BChE-KO mice show significantly lower fibrillar Aβ compared to 5XFAD mice at the same age.

BChE may play a role in the pathogenesis of Aβ in Alzheimer's disease.
Both 5XFAD and 5XFAD/BChE-KO mice exhibited reduced whole brain glucose metabolism compared to their respective wild-type strains.
5XFAD mice showed decreased glucose metabolism in all analyzed brain regions except the cerebellum compared to wild-types.
5XFAD/BChE-KO mice demonstrated a selective reduction in glucose metabolism in the cerebral cortex and thalamus, while other regions remained unchanged.
The findings suggest that the knockout of BChE and the resulting reduction in fibrillar Aβ could have a protective effect on certain brain functions in 5XFAD/BChE-KO mice.

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Alzheimer's disease (AD) is the most common neurodegenerative disorder causing dementia. One hallmark of the AD brain is the deposition of β-amyloid (Aβ) plaques. AD is also a state of cholinergic dysfunction and butyrylcholinesterase (BChE) associates with Aβ pathology. A transgenic mouse (5XFAD) is an aggressive amyloidosis model, producing Aβ plaques with which BChE also associates. A derived strain (5XFAD/BChE-KO), with the BChE gene knocked out, has significantly lower fibrillar Aβ than 5XFAD mice at the same age. Therefore, BChE may have a role in Aβ 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)fluoro-D-glucose (FDG) administration. To determine whether hypometabolism is related to BChE-induced changes in fibrillar Aβ burden, whole brain and regional uptake ofFDG in 5XFAD and 5XFAD/BChE-KO mice was compared to corresponding wild-type (WTand WT) strains at 5months. Diminished fibrillar Aβ burden was confirmed in 5XFAD/BChE-KO mice relative to 5XFAD. 5XFAD and 5XFAD/BChE-KO mice demonstrated reduction in whole brainFDG retention compared to respective wild-types. Regional analysis of relevant AD structures revealed reduction inFDG retention in 5XFAD mice in all brain regions analyzed (save cerebellum) compared to WT. Alternatively, 5XFAD/BChE-KO mice demonstrated a more selective pattern of reduced retention in the cerebral cortex and thalamus compared to WT, while retention in hippocampal formation, amygdala and basal ganglia remained unchanged. This suggests that in knocking out BChE and reducing fibrillar Aβ, a possible protective effect on brain function may be conferred in a number of structures in 5XFAD/BChE-KO mice. 18 18 18 18 18 5XFAD BChE-KO5XFAD BChE-KO

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Butyrylcholinesterase-knockout reduces fibrillar β-amyloid and conserves 18FDG retention in 5XFAD mouse model of Alzheimer’s disease

Abstract

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