Age-dependent effect of apolipoprotein E4 on functional outcome after controlled cortical impact in mice.
The apolipoprotein E4 (APOE4) gene leads to increased brain amyloid beta (Aβ) and poor outcome in adults with traumatic brain injury (TBI); however, its role in childhood TBI is controversial. We hypothesized that the transgenic expression of human APOE4 worsens the outcome after controlled cortical impact (CCI) in adult but not immature mice. Adult and immature APOE4 mice had worse motor outcome after CCI (P<0.001 versus wild type (WT)), but the Morris water maze performance was worse only in adult APOE4 mice (P=0.028 at 2 weeks, P=0.019 at 6 months versus WT), because immature APOE4 mice had performance similar to WT for up to 1 year after injury. Brain lesion size was similar in adult APOE4 mice but was decreased (P=0.029 versus WT) in injured immature APOE4 mice. Microgliosis was similar in all groups. Soluble brain Aβ(40) was increased at 48 hours after CCI in adult and immature APOE4 mice and in adult WT (P<0.05), and was dynamically regulated during the chronic period by APOE4 in adults but not immature mice. The data suggest age-dependent effects of APOE4 on cognitive outcome after TBI, and that therapies targeting APOE4 may be more effective in adults versus children with TBI.
Mannix
Rebekah C
RC
Division of Emergency Medicine, Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA. rebekah.Mannix@childrens.harvard.edu
Zhang
Jimmy
J
Park
Juyeon
J
Zhang
Xuan
X
Bilal
Kiran
K
Walker
Kendall
K
Tanzi
Rudolph E
RE
Tesco
Giuseppina
G
Whalen
Michael J
MJ
D000375:Aging / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics* / Q000502:physiology*; D001834:Body Water / Q000378:metabolism; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology; D001930:Brain Injuries / Q000235:genetics* / Q000473:pathology*; D003071:Cognition / Q000502:physiology; D018737:Hand Strength / Q000502:physiology; D007150:Immunohistochemistry; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D004856:Postural Balance / Q000502:physiology; D011597:Psychomotor Performance / Q000502:physiology; D020127:Recovery of Function; D013028:Space Perception / Q000502:physiology
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)