Alzheimer's pathology in human temporal cortex surgically excised after severe brain injury

Abstract

Traumatic brain injury (TBI) is a risk factor for the development of Alzheimer's disease (AD). This immunohistochemical study determined the extent of AD-related changes in temporal cortex resected from individuals treated surgically for severe TBI. Antisera generated against Aβ species (total Aβ, Aβ_1–42, and Aβ_1–40), the C-terminal of the Aβ precursor protein (APP), apolipoprotein E (apoE), and markers of neuron structure and degeneration (tau, ubiquitin, α-, β-, and γ-synuclein) were used to examine the extent of Aβ plaque deposition and neurodegenerative changes in 18 TBI subjects (ages 18–64 years). Diffuse cortical Aβ deposits were observed in one third of subjects (aged 35–62 years) as early as 2 h after injury, with only one (35-year old) individual exhibiting “mature”, dense-cored plaques. Plaque-like deposits, neurons, glia, and axonal changes were also immunostained with APP and apoE antibodies. In plaque-positive cases, the only statistically significant change in cellular immunostaining was increased neuronal APP (P = 0.013). There was no significant correlation between the distribution of Aβ plaques and markers of neuronal degeneration. Diffuse tau immunostaining was localized to neuronal cell soma, axons or glial cells in a larger subset of individuals. Tau-positive, neurofibrillary tangle (NFT)-like changes were detected in only two subjects, both of more advanced age and who were without Aβ deposits. Other neurodegenerative changes, evidenced by ubiquitin- and synuclein-immunoreactive neurons, were abundant in the majority of cases. Our results demonstrate a differential distribution and course of intra- and extra-cellular AD-like changes during the acute phase following severe TBI in humans. Aβ plaques and early evidence of neuronal degenerative changes can develop rapidly after TBI, while fully developed NFTs most likely result from more chronic disease- or injury-related processes. These observations lend further support to the hypothesis that head trauma significantly increases the risk of developing pathological and clinical symptoms of AD, and provide insight into the molecular mechanisms that initiate these pathological cascades very early during severe brain injury.

Introduction

Traumatic brain injury (TBI) is an environmental risk factor for the development of chronic neurodegenerative disorders, including Alzheimer's disease (AD). TBI correlates with accelerated cognitive decline in head-injured, aged subjects (Luukinen et al., 1999), and there is an increased risk for AD dementia in patients who, in adulthood, sustained a severe head injury Guo et al., 2000, McKenzie et al., 1994, Nemetz et al., 1999, Plassman et al., 2000, Roberts et al., 1991, Roberts et al., 1994, Roberts et al., 1993, Schofield et al., 1997. One of the detrimental consequences of TBI involves altered processing of amyloid precursor protein (APP), which potentially contributes to AD-like pathological cascades DeKosky et al., 1998, McIntosh et al., 1998. In AD, amyloid β peptide (Aβ) overproduction and deposition induce inflammatory cytokine infiltration with microglial activation and oxidative stress Altstiel and Sperber, 1991, Butterfield et al., 2002, Buxbaum et al., 1992, Forloni et al., 1992, Griffin et al., 1989, Griffin et al., 1995, the sequelae of which are also involved in trauma-related neurological dysfunction (Rothwell et al., 1997). TBI studies in both animal models Ciallella et al., 2002, Masumura et al., 2000, Murakami et al., 1998, Pierce et al., 1996, Smith et al., 1999, Uryu et al., 2002 and post-mortem human tissue Gentleman et al., 1993, Graham et al., 1995, McKenzie et al., 1994, Roberts et al., 1991, Roberts et al., 1994 demonstrated that increased APP production and/or accumulation can develop after injury. However, evidence of AD-like extracellular Aβ deposition has been described only in post-mortem human brain tissue so current knowledge of amyloidogenic APP metabolism and Aβ accumulation after human TBI derives almost exclusively from studies of victims of severe, lethal TBI (Roberts et al., 1994). Notably, AD-like neurodegenerative changes as well as intracellular accumulation of neurofibrillary tangle (NFT)-like pathologies were not found in these patients, with exception of subjects with repetitive head injury Geddes et al., 1999, Schmidt et al., 2001. In the present study, we collected freshly resected human brain tissue from subjects who underwent surgical treatment within hours of TBI and assessed the extent of AD-like extracellular and intracellular changes during this acute post-injury period. We further examined possible associations between these changes and variables such as subjects' age, primary lesion characteristics, hypothermia treatment, and functional outcome.