Traumatic brain injury exacerbates neurodegenerative pathology: improvement with an apolipoprotein E-based therapeutic.
Cognitive impairment is common following traumatic brain injury (TBI), and neuroinflammatory mechanisms may predispose to the development of neurodegenerative disease. Apolipoprotein E (apoE) polymorphisms modify neuroinflammatory responses, and influence both outcome from acute brain injury and the risk of developing neurodegenerative disease. We demonstrate that TBI accelerates neurodegenerative pathology in double-transgenic animals expressing the common human apoE alleles and mutated amyloid precursor protein, and that pathology is exacerbated in the presence of the apoE4 allele. The administration of an apoE-mimetic peptide markedly reduced the development of neurodegenerative pathology in mice homozygous for apoE3 as well as apoE3/E4 heterozygotes. These results demonstrate that TBI accelerates the cardinal neuropathological features of neurodegenerative disease, and establishes the potential for apoE mimetic therapies in reducing pathology associated with neurodegeneration.
Laskowitz
Daniel T
DT
Department of Medicine (Neurology), Duke University Medical Center, Durham, North Carolina 27710, USA. danl@neuro.duke.edu
Song
Pingping
P
Wang
Haichen
H
Mace
Brian
B
Sullivan
Patrick M
PM
Vitek
Michael P
MP
Dawson
Hana N
HN
D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D001930:Brain Injuries / Q000473:pathology* / Q000628:therapy*; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy; D005911:Gliosis / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000473:pathology* / Q000628:therapy*; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D011597:Psychomotor Performance / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D016207:Cytokines; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016875:tau Proteins