Talk abstracts
Talk on Tuesday 03:45-04:00pm submitted by Sabrina Mackey-Alfonso
The Neuroinflammatory Impact of High Fat Diet on Memory and Synaptic Degradation in an AD Model
Sabrina Mackey-Alfonso (Neuroscience Graduate Program), Michael Butler (Institute for Behavioral Medicine Research), Ashton Taylor (Institute for Behavioral Medicine Research), Alberto Williams-Medina (Institute for Behavioral Medicine Research), Ruth Barrientos (Institute for Behavioral Medicine Research)
Abstract:
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by profound memory impairments, synaptic loss, neuroinflammation, and hallmark pathologies. The exacerbated neuroinflammation over activates the complement cascade, an arm of the immune system. This leads to tagging of healthy synapses for microglial pruning. High fat diet (HFD) consumption increases the risk of developing AD even after controlling for metabolic dysfunction pointing to a role of the diet itself. While the diet-AD link is strong, the underlying mechanisms are not well understood in part due to confounding variables associated with long-term regimens. Therefore, we experimented with a short-term diet in the 3xTg-AD model to isolate potential mechanisms. We hypothesized HFD would 1) impair memory, 2) increase neuroinflammation including complement, and 3) increase microglial synaptic pruning. Following the consumption of either standard chow or HFD, 3xTg-AD and WT mice were assessed for memory impairments, inflammatory markers, and complement. Lastly, we assessed synaptic microglial phagocytosis. Synapses were isolated from the hippocampus of 3xTg-AD chow or HFD-fed mice and conjugated to an indicator that glows red when engulfed by cells. We tracked the number of BV2 microglia that phagocytosed synapses over 4 hours. Finally, we incubated BV2 microglia with a complement receptor inhibitor and repeated the assay. Behavioral analyses revealed 3xTg-AD mice had impaired memory which was further impaired by HFD. HFD increased inflammatory markers and complement expression in 3xTg-AD mice. Synapses from HFD-fed 3xTg-AD mice were phagocytosed at a significantly higher rate, showing synapses were altered by HFD. The complement receptor inhibitor significantly blocked this effect in a dose-dependent manner. These data suggest HFD consumption increases neuroinflammation and over activates the complement cascade in AD resulting in increased synaptic stripping leading to poorer memory, although causality needs to be determined. These data point to complement as a mechanistic culprit and therapeutic target.
References:
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Keywords: neuroinflammation, Alzheimers disease, diet