Subtle behavioral changes and increased prefrontal-hippocampal network synchronicity in APPNL−G−F mice before prominent plaque deposition

Abstract

Amyloid-β (Aβ) peptides occur in the brains of patients with Alzheimer's disease (AD), but their role in functional impairment is still debated. High levels of APP and APP fragments in mice that overexpress APP might confound their use in preclinical research. We examined the occurrence of behavioral, cognitive and neuroimaging changes in APP knock-in mice that display Aβ42 amyloidosis in the absence of APP overexpression. Female APP mice (carrying Swedish, Iberian and Arctic APP mutations) were compared to APP mice (APP Swedish) at 3, 7 and 10 months. Mice were subjected to a test battery that referred to clinical AD symptoms, comprising cage activity, open field, elevated plus maze, social preference and novelty test, and spatial learning, reversal learning and spatial reference memory performance. Our assessment confirmed that behavior at these early ages was largely unaffected in these mice in accordance with previous reports, with some subtle behavioral changes, mainly in social and anxiety-related test performance. Resting-state functional MRI (rsfMRI) assessed connectivity between hippocampal and prefrontal regions with an established role in flexibility, learning and memory. Increased prefrontal-hippocampal network synchronicity was found in 3-month-old APP mice. These functional changes occurred before prominent amyloid plaque deposition.

Insoluble Aβ overexpression in an App knock-in mouse model alters microstructure and gamma oscillations in the prefrontal cortex, and social and anxiety-related behaviours

“…However, unlike us, they compared App NL-G-F KI mice behaviour to that of App NL KI mice only, and not to control WT mice. They found App NL-G-F KI mice spent more time in the open arms at 6 months of age (Latif-Hernandez et al, 2017), which we replicated at 8 months of age. A very recent study has also found that 6-9 month old App NL-G-F KI mice spent more time in the elevated plus maze open arms (Sakakibara et al, 2018).…”

“…Accordingly, any dysfunction found in App NL-F KI but not App NL-G-F KI mice of ~9 months age, as here, can reasonably be attributed as the sequelae of specifically insoluble Aβ 42 aggregation. We therefore argue that specifically insoluble Distance travelled in the open field is significantly greater in 6 month old App NL-G-F KI mice, whilst at 8 months (the current study) and 10 months of age, there were no significant differences (Latif-Hernandez et al, 2017;Whyte et al, 2018), suggesting hyperactivity is only detectable in younger mice.…”

“…Although some microstructure changes were detected in the hippocampus of App NL-G-F KI mice (anterior hippocampal AD and posterior hippocampal RD), these were relatively inconsistent compared to the alterations observed within the prefrontal cortex. Another study found the ACC as being the most significantly altered brain region in App NL-G-F KI mice as detected by rsfMRI (Latif-Hernandez et al, 2017). This suggests that substantial changes are occurring in the ACC in App NL-G-F KI mice, as broadly consistent with ACC amyloid-beta load being high in MCI, and predicting faster conversion to AD (Okello et al, 2009).…”

“…Like our study, Latif-Hernandez et al (2017) also used the elevated plus maze to explore anxiety behaviours in App NL-G-F KI mice. However, unlike us, they compared App NL-G-F KI mice behaviour to that of App NL KI mice only, and not to control WT mice.…”

“…We next segmented two prefrontal cortical regions: the OFC and the ACC. In addition to roles for OFC and ACC regions in anxiety and social behaviours, resting state functional MRI (rsfMRI) has shown that connectivity of the medial prefrontal cortex to other regions is abnormal in App NL-G-F KI mice, with ACC being the most altered region (Latif-Hernandez et al, 2017). However, it is currently unknown as to whether structural changes in the ACC contributed to the rsfMRI result.…”