APOE genotype alters glial activation and loss of synaptic markers in mice

Abstract

The E4 allele of the Apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), and affects clinical outcomes of chronic and acute brain damages. The mechanisms by which apoE affect diverse diseases and disorders may involve modulation of the glial response to various types of brain damages. We examined glial activation in a mouse model where each of the human APOE alleles are expressed under the endogenous mouse APOE promoter, as well as in APOE knock-out mice. APOE4 mice displayed increased glial activation in response to intracerebroventricular lipopolysaccharide (LPS) compared to APOE2 and APOE3 mice by several measures. There were higher levels of microglia/macrophage, astrocytes, and invading T-cells after LPS injection in APOE4 mice. APOE4 mice also displayed greater and more prolonged increases of cytokines (IL-1β, IL-6, TNF-α) than APOE2 and APOE3 mice. We found that APOE4 mice had greater synaptic protein loss after LPS injection, as measured by three different markers: PSD-95, Drebin, and synaptophysin. In all assays, APOE knock-out mice responded similar to APOE4 mice, suggesting that the apoE4 protein may lack anti-inflammatory characteristics of apoE2 and apoE3. Together, these findings demonstrate that APOE4 predisposes to inflammation, which could contribute to its association with Alzheimer's disease and other disorders.

Cognitive Deficits and Disruption of Neurogenesis in a Mouse Model of Apolipoprotein E4 Domain Interaction

“…Consequently, apoE4 also leads to increased phosphorylation of Tau and the formation of neurofibrillary tangles (58 -61). Other AD pathologies that may explain the effect of apoE4 on cognition includes increased synaptic degeneration, neuro-inflammation, and neuronal death (62). However, Arg-61 mice do not show any thioflavin S stained amyloid ␤ plaques nor neurofibrillary tangles even up to 24 months old (data not shown), yet their cognitive deficits are observable as early as 3 months of age.…”

Alzheimer's Disease Genetic Risk Factor APOE-ε4 Also Affects Normal Brain Function

“…ApoE reduces the inflammatory responses of macrophages [110; 111] and microglia [112] in vitro, and APOE4 TR mice are susceptible to brain damage related to inflammatory processes such as experimental autoinflammatory encephalitis [113], traumatic brain injury [114], and lipopolysaccharide (LPS) exposure [111; 115]. After LPS exposure, the APOE4 genotype in mice is associated with higher levels of pro-inflammatory cytokines [116], enhanced NF-kB signaling [117] and increased loss of synaptic markers [115]. Chronic low-level brain inflammation in the presence of apoE4 could leave the brain more susceptible to injuries that accumulate with aging [111; 118].…”

The role of leptin in the sporadic form of Alzheimer's disease. Interactions with the adipokines amylin, ghrelin and the pituitary hormone prolactin

“…Both molecules have been shown to cause inflammation, and LepR upregulation has been demonstrated in response to proinflammatory stimuli, such as treatments with LPS and TNFα [94]. In fact, transgenic animal models overexpressing human forms of Aβ or human apoE4, showed enhanced inflammatory reactions in the brain, including TNFα generation and gliosis [95,96]. Thus, it may be speculated that the initial up-regulation of LepR could result from the pro-inflammatory effects of Aβ or apoE4.…”