Alzheimer’s disease (AD) is a neurodegenerative disorder that causes dementia. Characteristic hallmarks of AD include the deposition of pathological β-amyloid plaques (Aβ) and neurofibrillary tangles (NFT) in the brain. The AD brain also exhibits cholinergic dysfunction; loss of cholinergic neurons contributes to the cognitive and behavioural symptoms of AD. Furthermore, cholinesterases such as butyrylcholinesterase (BuChE) associate with Aβ and NFT pathology. Recent work in our lab involving a novel BuChE knock-out mouse model of AD (5XFAD/BuChE-KO) has revealed that the absence of BuChE expression leads to diminished fibrillar forms of Aβ pathology in the brain. However, the exact role of BuChE on brain function in AD has not been determined. To further elucidate the effects of BuChE on metabolic regulation (thus brain function) in AD, we assessed cerebral glucose metabolism in this 5XFAD/BuChE-KO model using 18FDG-PET.
Male 5XFAD/BuChE-KO mice (n=5) and age-matched BuChE-KO wild type controls (n=2) at 5 months underwent PET scanning 30 min after 18FDG administration and subsequently imaged using CT and MRI. Whole brain ROIs were generated from co-registered PET/CT/MRI data. 18FDG standardized uptake values (SUVs) were then compared between 5XFAD/BuChE-KO and BuChE-KO groups.
At 5 months, significant Aβ deposition was present in the 5XFAD/BuChE-KO mouse brain. 5XFAD/BuChE-KO animals demonstrated a 23% decrease in whole brain SUVs compared to BuChE-KO controls (p=0.037). This significant decrease had not been observed in our previous investigations of cerebral metabolism in a BuChE expressing 5XFAD model (vs. control counterparts) at 5 months.
We have previously observed variation in cerebral glucose metabolism with Aβ pathology in 5XFAD mice. Our current investigations suggest that BuChE may also be a modulator of cerebral glucose metabolism in AD, whereby the presence/absence of BuChE could significantly impact not only pathology but also brain function over the course of AD. Comparison of these 5XFAD/BuChE-KO brain metabolism results with those in BuChE expressing 5XFAD counterparts is currently underway. Furthermore, regional assessment of brain metabolism and corroborating neuropathology in these animals may further implicate BuChE in the progression of AD and may highlight the potential role of targeted BuChE imaging approaches for AD diagnostics.
© 2015 Published by Elsevier Inc.