Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury

Deposition of amyloid- (A) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for A deposition including monomeric A40, A42 and A oligomers/protofibrils, A species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N-terminally intact and truncated A40 and A42, as well as A oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n=12; mean age 49.5 +/- 19 years) due to life-threatening brain swelling/hemorrhage within one week post-injury. The TBI tissues were compared to post-mortem AD brains (n=5), to post-mortem tissue of neurologically intact (NI) subjects (n=4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n=4). The levels of A40 and A42 were not elevated by TBI. The levels of A oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P<0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE epsilon 3/4; n=4) had increased levels of A oligomers/protofibrils (P<0.05) and of both N-terminally intact and truncated A42 (P<0.05) compared to APOE epsilon 3/4-negative TBI patients (n=8). Neuropathological analysis showed insoluble A aggregates (commonly referred to as A plaques) in three TBI patients, all of whom were APOE epsilon 3/4 carriers. We conclude that soluble intermediary A aggregates form rapidly after TBI, especially among APOE epsilon 3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short- and long-term outcome in TBI.