Association of Increased Cortical Soluble Aβ42 Levels With Diffuse Plaques After Severe Brain Injury in Humans

Abstract

Traumatic brain injury (TBI) is an environmental risk factor for developing Alzheimer disease. This may be due, in part, to changes associated with beta-amyloid (Abeta) plaque formation, which can occur within hours after injury, regardless of the patient's age. In addition to being precursors of toxic fibrils that deposit into plaques, soluble (nonfibrillar) Abeta peptides are posited to disrupt synaptic function and are associated with cognitive decline in Alzheimer disease. Changes in soluble Abeta levels and their relationship to Abeta plaque formation following TBI are unknown. To quantify brain tissue levels of soluble Abeta peptides and their precursor protein in relation to Abeta plaque formation after TBI in humans. Surgically resected temporal cortex tissue from patients with severe TBI was processed for biochemical assays of soluble Abeta peptides with COOH-termini ending in amino acid 40 (Abeta(40)) or 42 (Abeta(42)) and Abeta precursor protein to compare patients with cortical Abeta plaques and those without. Patients Nineteen subjects admitted to the University of Pittsburgh Medical Center for treatment of severe closed head injury. Patients with severe TBI and cortical plaques had higher levels of soluble Abeta(1-42) but not Abeta(1-40); half of them were apolipoprotein E (APOE) epsilon4 allele carriers. The lowest Abeta levels were in 1 patient without plaques who was the only subject with an APOE epsilon2 allele. beta-Amyloid precursor protein levels were comparable in the 2 TBI groups. Selective increases in soluble Abeta(1-42) after TBI may predispose individuals with a brain injury to Alzheimer disease pathology. This may be influenced by the APOE genotype, and it may confer increased risk for developing Alzheimer disease later in life.