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Early Hippocampal Sharp-Wave Ripple Deficits Predict Later Learning and Memory Impairments in an Alzheimer's Disease Mouse Model

Cell Reports, 2019-11-19

Video Abstract (AI generated) Paper Preprint Cell Reports

Alzheimer's disease (AD) is characterized by progressive memory loss, and there is a pressing need to identify early pathophysiological alterations that predict subsequent memory impairment. Hippocampal sharp-wave ripples (SWRs) - electrophysiological signatures of memory reactivation in the hippocampus - are a compelling candidate for doing so. Mouse models of AD show reductions in both SWR abundance and associated slow gamma (SG) power during aging, but these alterations have yet to be directly linked to memory impairments. In aged apolipoprotein E4 knock in (apoE4-KI) mice - a model of the major genetic risk factor for AD - we found that reduced SWR abundance and associated CA3 SG power predicted spatial memory impairments measured 1-2 months later. Importantly, SWR-associated CA3 SG power reduction in young apoE4-KI mice also predicted spatial memory deficits measured 10 months later. These results establish features of SWRs as potential functional biomarkers of memory impairment in AD.

Aβ induces acute oxidative stress leading to brain glucose hypometabolism and hyperactivity in Alzheimer’s disease pathogenesis

Video Abstract (AI generated) Paper Preprint Supplemental Materials

A paramount driver of sporadic Alzheimer′s disease (AD) is the synergy of oxidative stress and glucose hypometabolism in the brain. Oxidative stress damages macromolecules such as DNA, lipids and proteins, whereas glucose hypometabolism impairs cellular energy supply and antioxidant defense; Together, these cellular and functional alterations may be primary triggers of AD. However, the exact basis of AD-associated glucose hypometabolism has remained unknown. Here we report acute inhibition of brain glucose utilization by beta-amyloid peptide (Aβ1-42) and identify oxidative stress resulting from Aβ1-42 -induced activation of NADPH oxidase 2 (NOX2) as the trigger of brain glucose hypometabolism and network hyperactivity. We show that in hippocampal brain slices, Aβ1-42 application reduced network activity-driven glucose consumption and glycolysis by half, while NOX2 antagonism prevented this effect. In vivo, intracerebroventricular injection of Aβ1-42 exerted a profound inhibitory effect on brain glucose consumption, resulting in long-lasting network hyperactivity and changes in animal behavioral profile. Critically, the novel bioavailable NOX2 antagonist GSK2795039 prevented all of the observed Aβ-related detrimental effects. These data provide the first experimental evidence behind AD-related brain glucose hypometabolism and its consequences, and suggest that targeting NOX2-induced oxidative stress is a promising approach to both the prevention and treatment of AD. ### Competing Interest Statement The authors have declared no competing interest.

Dentate Gyrus and CA3 GABAergic Interneurons Bidirectionally Modulate Signatures of Internal and External Drive to CA1

Video Abstract (AI generated) Paper Preprint

Specific classes of GABAergic neurons are thought to play specific roles in regulating information processing in the brain. In the hippocampus, two major classes - parvalbumin-expressing (PV+) and somatostatin-expressing (SST+) neurons - differentially regulate endogenous firing patterns and target different subcellular compartments of principal cells, but how these classes regulate the flow of information throughout the hippocampus is poorly understood. We hypothesized that PV+ and SST+ interneurons in the dentate gyrus (DG) and CA3 might differentially modulate CA3 patterns of output, thereby altering the influence of CA3 on CA1. We found that while suppressing either interneuron type increased DG and CA3 output, the effects on CA1 were very different. Suppressing PV+ interneurons increased local field potential signatures of coupling from CA3 to CA1 and decreased signatures of coupling from entorhinal cortex to CA1; suppressing SST+ interneurons had the opposite effect. Thus, DG and CA3 PV+ and SST+ interneurons bidirectionally modulate the flow of information through the hippocampal circuit.