Apolipoprotein E4 Influences Amyloid Deposition But Not Cell Loss after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

Abstract

The ⑀4 allele of apolipoprotein E (APOE) and traumatic brain injury (TBI) are both risk factors for the development of Alzheimer's disease (AD). These factors may act synergistically, in that APOE4ϩ individuals are more likely to develop dementia after TBI. Because the mechanism underlying these effects is unclear, we questioned whether APOE4 and TBI interact either through effects on amyloid-␤ (A␤) or by enhancing cell death/tissue injury. We assessed the effects of TBI in PDAPP mice (transgenic mice that develop AD-like pathology) expressing human APOE3 (PDAPP: E3), human APOE4 (PDAPP:E4), or no APOE (PDAPP:EϪ/Ϫ). Mice were subjected to a unilateral cortical impact injury at 9-10 months of age and allowed to survive for 3 months. A␤ load, hippocampal/cortical volumes, and hippocampal CA3 cell loss were quantified using stereological methods. All of the groups contained mice with A␤-immunoreactive deposits (56% PDAPP: E4, 20% PDAPP:E3, 75% PDAPP:EϪ/Ϫ), but thioflavine-Spositive A␤ (amyloid) was present only in the molecular layer of the dentate gyrus in the PDAPP:E4 mice (44%). In contrast, our previous studies showed that in the absence of TBI, PDAPP:E3 and PDAPP:E4 mice have little to no A␤ deposition at this age. After TBI, all of the A␤ deposits present in PDAPP:E3 and PDAPP: EϪ/Ϫ mice were diffuse plaques. In contrast to the effect of APOE4 on amyloid, PDAPP:E3, PDAPP:E4, and PDAPP:EϪ/Ϫ mice did not differ in the amount of brain tissue or cell loss. These data support the hypothesis that APOE4 influences the neurodegenerative cascade after TBI via an effect on A␤.Key words: Alzheimer's disease; amyloid; APP; traumatic brain injury; apoE; hippocampus The ⑀4 allele of apolipoprotein E (APOE) and traumatic brain injury (TBI) are both risk factors for the development of Alzheimer's disease (AD). It was first found that APOE4 was a risk factor for AD in 1993 (Strittmatter et al., 1993), and numerous studies have confirmed this association. Several studies have found that individuals who sustained moderate to severe head injury are more likely to develop dementia and AD (Mayeux et al., 1993(Mayeux et al., , 1995Plassman et al., 2000). These risk factors appear to act synergistically, in that individuals who are APOE4ϩ are even more likely to develop dementia if they sustain TBI at some time in their life. For example, APOE4ϩ individuals were 10 times more likely to develop AD after TBI than those who were APOE4Ϫ, whereas APOE4 in the absence of injury was associated with only twice the risk (Mayeux et al., 1995;Tang et al., 1996).Although the mechanisms underlying these effects are unclear, some evidence suggests that both APOE4 and TBI may influence the risk of AD via interactions with the amyloid-␤ (A␤) peptide.For example, A␤ deposition can be found in ϳ30% of people who die shortly after TBI (Roberts et al., 1991(Roberts et al., , 1994; a significant percentage of these patients are APOE4ϩ (Nicoll et al., 1995(Nicoll et al., , 1996. In addition, analysis of CSF from TBI patients revealed elevated levels of ...

Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury

“…Reports have shown that following controlled cortical impact (CCI), the APP-YAC mice do not develop plaques when evaluated acutely after injury (Murai et al 1998), and in PD-APP mice, CCI produces a marked ipsilateral hippocampal atrophy, almost complete CA3-CA2 cell loss and diminished Ab deposition during aging (Smith et al 1998;Nakagawa et al 1999Nakagawa et al , 2000. On the contrary, in PD-APP mice subjected to CCI brain injury, amyloid deposition is accelerated only in the presence of APO-E4 while cell loss is not influenced (Hartman et al 2002).…”

Activation of the Amyloid Cascade in Apolipoprotein E4 Transgenic Mice Induces Lysosomal Activation and Neurodegeneration Resulting in Marked Cognitive Deficits

“…The steps of the amyloid cascade that are affected by apoE4 and the cellular and molecular mechanisms that underlie the resulting pathological effects are not known. Because the increased A␤ deposition in apoE4 ϫ APP transgenic mice is apparent only in old mice (Holtzman et al, 2000;Fryer et al, 2005), and it does not seem to be associated with neuritic degeneration and neuronal loss (Holtzman et al, 2000;Hartman et al, 2002), there is a great need for models that reproduce the pathological interactions between apoE4 and A␤ in more detail. We have shown recently that intracerebroventricular infusion of thiorphan, which inhibits the A␤-degrading enzyme neprilysin in wild-type mice, induces A␤ deposition and fibrilization, and that similar treatments in apoE3 and apoE4 transgenic mice result in marked and isoform-specific enhancement of the nucleation and aggregation of A␤ in apoE4 mice Michaelson, 2004, 2006).…”

Long-Term Cognitive Correlates of Traumatic Brain Injury across Adulthood and Interactions with APOE Genotype, Sex, and Age Cohorts

“…This process can persist chronically (Chen, Johnson, Uryu, Trojanowski, & Smith, 2009). While some studies suggest that APP plays a protective role post-TBI (Thornton, Vink, Blumbergs, & VanDen Heuvel, 2006), individuals with APOE ε4 + genotype experience increased post-injury Aβ deposition and reduced Aβ clearance (Hartman et al, 2002), which may in turn lead to an increased risk of Aβ plaque formation characteristic of dementia pathology. Compared to APOE ε3, the APOE ε4 isoform of the apolipoprotein E is also less able to repair synapses and protect neurons in the event of injury (Zhong, Scearce-Levie, Ramaswamy, & Weisgraber, 2008) (Katzman et al, 1996;Rohling et al, 2011;Sundstrom et al, 2007;Tang et al, 1996).…”