Human APOE4 affects microglial reactivity and spatial cognition in a mouse model of alzheimer's disease risk
Year: 2014
Type: dissertation
Abstract: Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder that results in declarative memory deficits.Apolipoprotein e4 (APOE-ε4) is the strongest genetic risk factor for developing AD, and influences extracellular Aβ plaque deposition and neuroinflammation in humans and in mouse models.APOE-ε4 also influences neuronal morphology and cognitive performance in humans, independent of AD pathology.In this series of experiments, we examined the effects of APOE genotype on AD-related neuropathology and in normal brain function of mice to better understand its role as a potent risk-factor for developing AD.We analyzed Aβ plaque profiles and Aβ-induced glial activation in the brains of 6-month old EFAD transgenic mice (E2FAD, E3FAD, and E4FAD).Characterization of Aβ plaques revealed larger and more intensely stained plaques in E4FAD mice relative to E3FADs, and increased numbers of compact plaques in the subiculum.Reactive microglia and astrocytes were prominent in EFAD brains.Morphometric analyses revealed greater dystrophy, increased fluorescence intensity, and a higher density of reactive microglia surrounding cortical plaques in E4FAD mice than in E3FADs.Cortical levels of Interleukin1-β (IL-1β) were nearly two-fold greater in E4FAD mice relative to E3FADs.iv To investigate the impact of APOE genotype on cognitive performance in mice, we trained 3-month old APOE Targeted Replacement mice (APOE2, APOE3, and APOE4) in a spatial learning and memory task (Barnes maze).APOE4 mice exhibited impaired spatial learning and memory in the maze compared to APOE3 mice.Deficits in spatial learning were detected in a second cohort of 18-month old APOE4 mice.When we examined the dendritic morphology of neurons in the medial entorhinal cortex (MEC), we found significantly shorter dendrites and lower spine densities in basal shaft dendrites of APOE4 mice relative to APOE3, consistent with the deficits found in our young APOE4 mice.We also provide evidence to suggest that Liver X Receptor (LXR) activationwhich increases APOEsuppresses overall spiking activity and specifically burst counts in mature hippocampal networks recorded in a multielectrode array.These data suggest that APOE genotype modulates Aβ-induced neuroinflammatory responses in AD progression, and support a role for APOE in dendritic morphology and normal brain function.
Author: G Rodriguez
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2225433000