Traumatic brain injury and amyloid-β pathology: a link to Alzheimer's disease?

University of Glasgow, University Avenue, Glasgow G12 8QQ, UK.
Nature Reviews Neuroscience (Impact Factor: 31.38). 03/2010; 11(5):361-70. DOI: 10.1038/nrn2808
Source: PubMed

ABSTRACT Traumatic brain injury (TBI) has devastating acute effects and in many cases seems to initiate long-term neurodegeneration. Indeed, an epidemiological association between TBI and the development of Alzheimer's disease (AD) later in life has been demonstrated, and it has been shown that amyloid-β (Aβ) plaques — one of the hallmarks of AD — may be found in patients within hours following TBI. Here, we explore the mechanistic underpinnings of the link between TBI and AD, focusing on the hypothesis that rapid Aβ plaque formation may result from the accumulation of amyloid precursor protein in damaged axons and a disturbed balance between Aβ genesis and catabolism following TBI.


Available from: William Stewart, Sep 15, 2014
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild traumatic brain injury. It is defined pathologically by the abnormal accumulation of tau in a unique pattern that is distinct from other tauopathies, including Alzheimer’s disease (AD). Although trauma has been suggested to increase amyloid β peptide (Aβ) levels, the extent of Aβ deposition in CTE has not been thoroughly characterized. We studied a heterogeneous cohort of deceased athletes and military veterans with neuropathologically diagnosed CTE (n = 114, mean age at death = 60) to test the hypothesis that Aβ deposition is altered in CTE and associated with more severe pathology and worse clinical outcomes. We found that Aβ deposition, either as diffuse or neuritic plaques, was present in 52 % of CTE subjects. Moreover, Aβ deposition in CTE occurred at an accelerated rate and with altered dynamics in CTE compared to a normal aging population (OR = 3.8, p < 0.001). We also found a clear pathological and clinical dichotomy between those CTE cases with Aβ plaques and those without. Aβ deposition was significantly associated with the presence of the APOE ε4 allele (p = 0.035), older age at symptom onset (p < 0.001), and older age at death (p < 0.001). In addition, when controlling for age, neuritic plaques were significantly associated with increased CTE tauopathy stage (β = 2.43, p = 0.018), co-morbid Lewy body disease (OR = 5.01, p = 0.009), and dementia (OR = 4.45, p = 0.012). A subset of subjects met the diagnostic criteria for both CTE and AD, and in these subjects both Aβ plaques and total levels of Aβ1-40 were increased at the depths of the cortical sulcus compared to the gyral crests. Overall, these findings suggest that Aβ deposition is altered and accelerated in a cohort of CTE subjects compared to normal aging and that Aβ is associated with both pathological and clinical progression of CTE independent of age.
    Acta Neuropathologica 05/2015; DOI:10.1007/s00401-015-1435-y · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Traumatic brain injury (TBI) is a major health issue comprising a heterogeneous and complex array of pathologies. Over the last several decades, numerous animal models have been developed to address the diverse nature of human TBI. The clinical relevance of these models has been a major point of reflection given the poor translation of pharmacologic TBI interventions to the clinic. While previously characterized broadly as either focal or diffuse, this classification is falling out of favor with increased awareness of the overlap in pathologic outcomes between models and an emerging consensus that no one model is sufficient. Moreover, an appreciation of injury biomechanics is essential in recapitulating and interpreting the spectrum of TBI neuropathology observed in various established models of dynamic closed-head TBI. While these models have replicated many specific features of human TBI, an enhanced context with clinical relevancy will facilitate the further elucidation of the mechanisms and treatment of injury. © 2015 Elsevier B.V. All rights reserved.
    Handbook of Clinical Neurology 01/2015; 127:115-28. DOI:10.1016/B978-0-444-52892-6.00008-8
  • [Show abstract] [Hide abstract]
    ABSTRACT: Epidemiological studies have associated increased risk of Alzheimer's disease (AD)-related clinical symptoms with a medical history of head injury. Currently, little is known about pathophysiology mechanisms linked to this association. Persistent neuroinflammation is one outcome observed in patients after a single head injury. Neuroinflammation is also present early in relevant brain regions during AD pathology progression. In addition, previous mechanistic studies in animal models link neuroinflammation as a contributor to neuropathology and cognitive impairment in traumatic brain injury (TBI) or AD-related models. Therefore, we explored the potential interplay of neuroinflammatory responses in TBI and AD by analysis of the temporal neuroinflammatory changes after TBI in an AD model, the APP/PS1 knock-in (KI) mouse. Discrete temporal aspects of astrocyte, cytokine, and chemokine responses in the injured KI mice were delayed compared with the injured wild-type mice, with a peak neuroinflammatory response in the injured KI mice occurring at 7 d after injury. The neuroinflammatory responses were more persistent in the injured KI mice, leading to a chronic neuroinflammation. At late time points after injury, KI mice exhibited a significant impairment in radial arm water maze performance compared with sham KI mice or injured wild-type mice. Intervention with a small-molecule experimental therapeutic (MW151) that selectively attenuates proinflammatory cytokine production yielded improved cognitive behavior outcomes, consistent with a link between neuroinflammatory responses and altered risk for AD-associated pathology changes with head injury. Copyright © 2015 the authors 0270-6474/15/356554-16$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2015; 35(16):6554-69. DOI:10.1523/JNEUROSCI.0291-15.2015 · 6.75 Impact Factor