Beneficial effect of amyloid beta after controlled cortical impact.

Background: Worse functional outcomes after controlled cortical impact (CCI) in Bace1(-/-) mice have previously been demonstrated. This study investigated whether reconstitution of amyloid-beta (Aβ) after CCI in Bace1(-/-) animals would reverse the detrimental effect of Bace1 deletion.

Methods: Bace1(-/-) and wild type Bace1(+/+) (C57Bl/6) mice were subjected to CCI (n = 14-23/group) or sham injury (n = 6/group). After injury, mice underwent intracerebroventricular injections of Aβ40 (n = 23 Bace1(-/-) and 17 Bace1(+/+) per group) or vehicle (n = 14 Bace1(-/-) and 22 Bace1(+/+) per group). Functional outcomes were assessed with wire grip (motor) and Morris water maze (spatial memory). Soluble Aβ levels were assessed at 24 hours and 21 days after CCI. Lesion volume was assessed 21 days after injury.

Results: At 24 hours after injury, Aβ-treated Bace1(-/-) mice had Aβ40 levels similar to vehicle-treated Bace1(+/+) mice, but by 21 days after injury there were no differences between Aβ-treated versus vehicle-treated Bace1(-/-) mice. Reconstitution with Aβ40 improved motor but not spatial memory or histopathological outcome in injured Bace1(-/-) mice. In contrast, treatment with Aβ40 worsened motor performance in Bace1(+/+) mice.

Conclusions: The data suggest Aβ40 may have some beneficial effects after CCI in young adult mice and that therapies targeting BACE should be approached cautiously.