Neural oscillations during cognitive processes in an App knock-in mouse model of Alzheimer’s disease pathology

Abstract

Multiple animal models have been created to gain insight into Alzheimer’s disease (AD) pathology. Among the most commonly used models are transgenic mice overexpressing human amyloid precursor protein (APP) with mutations linked to familial AD, resulting in the formation of amyloid β plaques, one of the pathological hallmarks observed in AD patients. However, recent evidence suggests that the overexpression of APP by itself can confound some of the reported observations. Therefore, we investigated in the present study the AppNL-G-Fmodel, an App knock-in (App-KI) mouse model that develops amyloidosis in the absence of APP-overexpression. Our findings at the behavioral, electrophysiological, and histopathological level confirmed an age-dependent increase in Aβ1–42 levels and plaque deposition in these mice in accordance with previous reports. This had apparently no consequences on cognitive performance in a visual discrimination (VD) task, which was largely unaffected in AppNL-G-F mice at the ages tested. Additionally, we investigated neurophysiological functioning of several brain areas by phase-amplitude coupling (PAC) analysis, a measure associated with adequate cognitive functioning, during the VD task (starting at 4.5 months) and the exploration of home environment (at 5 and 8 months of age). While we did not detect age-dependent changes in PAC during home environment exploration for both the wild-type and the AppNL-G-F mice, we did observe subtle changes in PAC in the wild-type mice that were not present in the AppNL-G-F mice.

Impact of Hyperhomocysteinemia and Different Dietary Interventions on Cognitive Performance in a Knock-in Mouse Model for Alzheimer’s Disease

“…In the touchscreen PAL [ 41 ], male WT animals completed the maximum number of all 36 trials per session, accompanied by decreasing session duration. The increase in the percentage of correct trials is in accordance with observations in a similar study [ 42 ]. In the IntelliCage setup [ 43 , 44 ], learning curves indicated a constant learning effect in the female WT animals.…”

“…One year later, Jacob et al observed neither consequences on cognitive performance in a touchscreen task nor age-dependent changes in a phase-amplitude coupling analysis, which was used as a measure of neurophysiological functioning, in 4.5 month old App NL-G-F mice. In accordance with our findings in the App NL-G-F model, these mice displayed a higher variability than WT control mice [ 42 ].…”

The Roles of Long-Term Hyperhomocysteinemia and Micronutrient Supplementation in the AppNL–G–F Model of Alzheimer’s Disease

“…The amounts of cerebral Aβ peptides, i.e., the humanized and modified Aβ42 from the App NL–G–F KI mice, were determined in this study using ELISA (KHB3441, Invitrogen, ThermoFisher). The Aβ extraction protocol reported here is similar to that in other studies using App NL–G–F KI mice ( Jacob et al, 2019 ; Rice et al, 2020 ). Initially, brain tissue sections of about 100 mg were thawed on ice in 1 mL of pre-cooled extraction buffer, which consisted of 5 M guanidine hydrochloride (GuHCl), 50 mM TRIS, and 1x protease inhibitor cocktail (Sigma-Aldrich), adjusted to pH = 8.…”

Alterations to parvalbumin-expressing interneuron function and associated network oscillations in the hippocampal – medial prefrontal cortex circuit during natural sleep in AppNL-G-Fmice

“…Behaviours that carry negative emotional valence are likely to generate strong memories that only partially reflect the full spectrum of memory function, and therefore arguably do not represent an accurate depiction of memory decline in APP NL-G-F mice 92 . Moreover, the use of inappropriate controls can be found in several studies assessing spatial memory, such as comparisons with other knock-in models (APP NL-F and APP NL ) and non-littermate wild-type mice 89,90,93,94 . Behavioural correlates of memory loss are necessary for determining the extent of cognitive impairment.…”