Apolipoprotein E4 influences amyloid deposition but not cell loss after traumatic brain injury in a mouse model of Alzheimer's disease

Abstract

The epsilon4 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 APOE4+ 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-beta (Abeta) 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:E-/-). Mice were subjected to a unilateral cortical impact injury at 9-10 months of age and allowed to survive for 3 months. Abeta load, hippocampal/cortical volumes, and hippocampal CA3 cell loss were quantified using stereological methods. All of the groups contained mice with Abeta-immunoreactive deposits (56% PDAPP:E4, 20% PDAPP:E3, 75% PDAPP:E-/-), but thioflavine-S-positive Abeta (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 Abeta deposition at this age. After TBI, all of the Abeta deposits present in PDAPP:E3 and PDAPP:E-/- mice were diffuse plaques. In contrast to the effect of APOE4 on amyloid, PDAPP:E3, PDAPP:E4, and PDAPP:E-/- 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 Abeta.

Fig. 1.

A, Almost one-third of the total hippocampal Aβ load was contained in the ML of the dentate gyrus in PDAPP:E4 mice. Localization of Aβ deposition in the ML is associated with the formation of fibrillar amyloid. In contrast, no ML Aβ-IR deposits were found in PDAPP:E3 or PDAPP:E−/− mice 3 months after TBI. B, Photomicrographs show Aβ staining in the hippocampus (arrowheads delineate the borders of the ML).

Fig. 2.

A, No group differences were found for percentage of area loss in either the cortex or the hippocampus.B, Photomicrograph shows a cresyl violet-stained brain section with atrophy of the cortex and hippocampus in the injured hemisphere 3 months after TBI.

Fig. 3.

A, No group differences were found for neuronal loss within the inferior blade of CA3. B, Photomicrograph shows a DAPI-stained brain section revealing atrophy of the CA3 region (arrowheads delineate the borders of the CA3 inferior blade) 3 months after TBI.