Unbiased Proteomic Approach Identifies Pathobiological Profiles inthe Brains of Preclinical Models of Repetitive Mild Traumatic Brain InjuryTauopathy and Amyloidosis

摘要

No concerted investigation has been conducted to explore overlapping and distinctpathobiological mechanisms between repetitive mild traumatic brain injury(r-mTBI) and tau/amyloid proteinopathies considering the long history ofassociation between TBI and Alzheimer’s disease. We address this problem byusing unbiased proteomic approaches to generate detailed time-dependent brainmolecular profiles of response to repetitive mTBI in C57BL/6 mice and in mousemodels of amyloidosis (with amyloid precursor protein KM670/671NL (Swedish) andPresenilin 1 M146L mutations [PSAPP]) and tauopathy (hTau). Brain tissues fromanimals were collected at different timepoints after injuries (24 hr–12 monthspost-injury) and at different ages for tau or amyloid transgenic models (3, 9,and 15 months old), encompassing the pre-, peri-, and post-“onset” of cognitiveand pathological phenotypes. We identified 30 hippocampal and 47 corticalproteins that were significantly modulated over time in the r-mTBI compared withsham mice. These proteins identified TBI-dependent modulation ofphosphatidylinositol-3-kinase/AKT signaling, protein kinase A signaling, andPPARα/RXRα activation in the hippocampus and protein kinase A signaling,gonadotropin-releasing hormone signaling, and B cell receptor signaling in thecortex. Previously published neuropathological studies of our mTBI model showeda lack of amyloid and tau pathology. In PSAPP mice, we identified 19 proteinssignificantly changing in the cortex and only 7 proteins in hTau mice versuswild-type littermates. When we explored the overlap between our r-mTBI model andthe PSAPP/hTau models, a fairly small coincidental change was observed involvingonly eight significantly regulated proteins. This work suggests a very distinctTBI neurodegeneration and also that other factors are needed to drivepathologies such as amyloidosis and tauopathy postinjury.