The Effect of the APOE4 Gene on Accumulation of Aβ (40) After Brain Injury Cannot Be Reversed by Increasing apoE4 Protein

The apolipoprotein E (apoE) protein is involved in clearance of β-amyloid (Aβ) from the brain; and the APOE4 gene is associated with Aβ plaque formation in humans following traumatic brain injury (TBI). Here, we examined the association between apoE and Aβ (40) after experimental TBI and the effects of APOE alleles on this relationship. We report a biphasic response of soluble apoE protein after TBI with an acute reduction at 1 day postinjury followed by an increase at 7 days postinjury. TBI-induced Aβ (40) levels decreased as soluble apoE levels increased. In APOE4 mice there was a diminished apoE response to TBI that corresponded to prolonged accumulation of TBI-induced Aβ (40) versus that in APOE3 mice. Amyloid precursor protein processing was similar in APOE3 and APOE4 mice suggesting that impaired clearance was responsible for the abnormal accumulation of Aβ (40) in the latter. Treatment of APOE4 mice with bexarotene for 7 days increased apoE4 protein levels but was not sufficient to reduce TBI-induced Aβ (40) . Thus, rapid clearance of TBI-induced Aβ (40) occurs in mice but these pathways are impaired in APOE4 carriers. These data may help explain the deposition of Aβ in APOE4 carriers and the increased incidence of brain Aβ plaques following TBI.