Hippocampal functional connectivity across age in an App knock-in mouse model of Alzheimer's disease

Abstract

IntroductionAlzheimer's disease (AD) is a progressive neurodegenerative disease. The early processes of AD, however, are not fully understood and likely begin years before symptoms manifest. Importantly, disruption of the default mode network, including the hippocampus, has been implicated in AD.MethodsTo examine the role of functional network connectivity changes in the early stages of AD, we performed resting-state functional magnetic resonance imaging (rs-fMRI) using a mouse model harboring three familial AD mutations (AppNL-G-F/NL-G-F knock-in, APPKI) in female mice in early, middle, and late age groups. The interhemispheric and intrahemispheric functional connectivity (FC) of the hippocampus was modeled across age.ResultsWe observed higher interhemispheric functional connectivity (FC) in the hippocampus across age. This was reduced, however, in APPKI mice in later age. Further, we observed loss of hemispheric asymmetry in FC in APPKI mice.DiscussionTogether, this suggests that there are early changes in hippocampal FC prior to heavy onset of amyloid β plaques, and which may be clinically relevant as an early biomarker of AD.

Sex-Specific Effects of Anxiety on Cognition and Activity-Dependent Neural Networks: Insights from (Female) Mice and (Wo)Men

“…Additionally, decreased interhemispheric hippocampal connectivity has been reported in female 3xTg-AD mice (35). In Ctrl mice, female mice displayed increased connectivity compared to male mice, which is in agreement with a recent study reporting increased connectivity in female mice with age (36). Of particular interest, male AD mice displayed opposite connectivity patterns compared to female AD mice, possibly due to hyperexcitability, often observed in early-stage AD (24).…”

“…While female AD mice may still experience hyperexcitability, it may occur at an earlier age (i.e., when anxiety is increased). In agreement with this hypothesis, a recent study reported increased connectivity followed by a later decrease in female APP knock-in mice (36). Future studies will examine earlier timepoints for brain-wide connectivity patterns.…”

Temporal Alterations in White Matter in AnAppKnock-In Mouse Model of Alzheimer’s Disease

“…Animals were anesthetized using 1–2% isoflurane and imaged using a 9.4 T Agilent MRI system (Santa Clara, California, USA) as described previously ( Morrissey et al, 2023 ). Briefly, mice were secured using a bite bar to restrict head motion, and ambient temperature and respiratory rate were monitored continuously during the scan using an SAII gating and monitoring system for small animals (SA Instruments, New York, USA).…”

Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future

“…241 Consistent with the findings in humans, aging and AD animal models also show disruptions of functional connectivity in the DMN. 242 The salience network (SN) identifies salient stimuli and plays an important role in the coordination of the central executive (CEN) and the DMN, whose functional impairment is related to learning and episodic memory deficits in both amnestic mild cognitive impairment (aMCI) and AD. 243 There is an increased Aβ-PET signal within the CEN and the SN in the progression of AD.…”