The Effect of the APOE4 Gene on Accumulation of Aβ40 After Brain Injury Cannot Be Reversed by Increasing apoE4 Protein

The apolipoprotein E (apoE) protein is involved in clearance of beta-amyloid (A beta) from the brain; and the APOE4 gene is associated with A beta plaque formation in humans following traumatic brain injury (TBI). Here, we examined the association between apoE and A beta(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 A beta(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 A beta(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 A beta(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 A beta(40). Thus, rapid clearance of TBI-induced A beta(40) occurs in mice but these pathways are impaired in APOE4 carriers. These data may help explain the deposition of Ab in APOE4 carriers and the increased incidence of brain Ab plaques following TBI.