ApoE4 Decreases Spine Density and Dendritic Complexity in Cortical NeuronsIn Vivo

Abstract

The three human alleles of apolipoprotein E (APOE) differentially influence outcome after CNS injury and affect one's risk of developing Alzheimer's disease (AD). It remains unclear how ApoE isoforms contribute to various AD-related pathological changes (e.g., amyloid plaques and synaptic and neuron loss). Here, we systematically examined whether apoE isoforms (E2, E3, E4) exhibit differential effects on dendritic spine density and morphology in APOE targeted replacement (TR) mice, which lack AD pathological changes. Using Golgi staining, we found age-dependent effects of APOE4 on spine density in the cortex. The APOE4 TR mice had significantly reduced spine density at three independent time points (4 weeks, 3 months, and 1 year, 27.7% Ϯ 7.4%, 24.4% Ϯ 8.6%, and 55.6% Ϯ 10.5%, respectively) compared with APOE3 TR mice and APOE2 TR mice. Additionally, in APOE4 TR mice, shorter spines were evident compared with other APOE TR mice at 1 year. APOE2 TR mice exhibited longer spines as well as significantly increased apical dendritic arborization in the cortex compared with APOE4 and APOE3 TR mice at 4 weeks. However, there were no differences in spine density across APOE genotypes in hippocampus. These findings demonstrate that apoE isoforms differentially affect dendritic complexity and spine formation, suggesting a role for APOE genotypes not only in acute and chronic brain injuries including AD, but also in normal brain functions.

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…3), thus providing a novel mechanism by which accelerated spine loss, increased tau phosphorylation (Kocherhans et al 2010), loss of network homeostasis Palop and Mucke 2010), and earlier disease onset through loss of neuroprotective compensatory bandwidth (Korwek et al 2009) can be readily explained. This mechanism is also consistent with the finding that ApoE4 reduces spine density and dendritic complexity in cortical neurons in vivo (Dumanis et al 2009). Moreover, Reelin expression levels are reduced in the brains of AD patients and in the entorhinal cortex of APP overexpressing mice , suggesting that Ab can reduce Reelin expression in a subset of entorhinal pyramidal neurons, thereby adding further support to a role of diminished Reelin signaling in AD progression (Herz and Chen 2006).…”

Differential Effects of ApoE Isoforms on Dendritic SpinesIn Vivo: Linking an Alzheimer's Disease Risk Factor with Synaptic Alterations

“…3]. No differences in cortical spine density between APOE2 and APOE3 mice were observed [Dumanis et al (2009), their Fig. 1, Fig.…”

“…In a recent article published in The Journal of Neuroscience, Dumanis et al (2009) characterized the effect of the apoE isoforms on dendritic spine density and branching in the murine brain. Dendritic spines, small protrusions along the length of the dendrite, play an important role in synapse function as the site of excitatory glutamatergic synaptic input.…”

“…The effect of apoE isoforms on dendrite structure and function has been extensively investigated in vitro with widely differing results depending on a variety of factors (Kim et al, 2009). The study by Dumanis et al (2009) is the first to systematically compare dendritic spines in vivo in mice in which the human APOE2, APOE3, or APOE4 gene has been substituted into the mouse APOE locus. Using the Golgi impregnation method, the authors analyzed spine density and morphology in brain sections from various regions obtained from mice at multiple ages.…”

“…3]. Based on these results, Dumanis et al (2009) proposed that apoE isoforms have differential effects on spine formation in the cortex. However, spine density reflects the balance between spine formation and elimination (Alvarez and Sabatini, 2007).…”