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

Johnson, Victoria E.; Stewart, William; Smith, Douglas H.

doi:10.1038/nrn2808

Cited by 480 publications

(432 citation statements)

References 178 publications

(182 reference statements)

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“…Neuropathological examination of autopsy acquired material from patients with survival greater than a year from a single moderate or severe TBI reveals an increased frequency of neurodegeneration-associated pathologies when compared to material from matched controls, including amyloid-² plaques, neurofibrillary tangles, inflammation and white matter degradation (13,17,18,20). Notably, the role of the BBB in neurodegeneration is of increasing interest, with evidence indicating that changes to the brain's microvasculature may actively contribute to development of AD pathology (for detailed review see (23)).…”

Section: Page 16 Of 22mentioning

confidence: 98%

“…In addition to the immediate health impacts of the injury, TBI is acknowledged as the strongest environmental risk factor for the development of neurodegenerative disease, typically reported as Alzheimer's disease (AD)(2-13) in type or, more recently, recognized as chronic traumatic encephalopathy (CTE) (14)(15)(16). Corresponding to this, autopsy studies in material from patients exposed to either single moderate or severe or repetitive mild brain injury reveal a complex of neurodegenerative pathologies including pathologies in tau, amyloid-² and TDP-43, neuronal loss, neuroinflammation and white matter degradation (13,(15)(16)(17)(18)(19)(20). However, the mechanisms driving these late, post-TBI neurodegenerative pathologies remain elusive.…”

Section: Introductionmentioning

confidence: 99%

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Blood-Brain Barrier Disruption Is an Early Event That May Persist for Many Years After Traumatic Brain Injury in Humans

Hay

Johnson

Young

et al. 2015

Journal of Neuropathology & Experimental Neurology

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108

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Traumatic brain injury (TBI) is a risk factor for dementia, with studies describing a mixed neurodegenerative pathology in late survivors. However, the mechanisms driving this post-TBI neurodegeneration remain elusive. Increasingly, blood brain barrier (BBB) disruption is recognized in a range of neurological disorders, including dementias; although little is known of the consequences of TBI on the BBB. From the Glasgow TBI Archive autopsy cases of single, moderate or severe TBI (n=70) were selected to include a range of survivals from acute (10h to 13days) to long-term (1 to 47years) survival, together with age-matched, uninjured controls (n=21). Multiple brain regions were examined for fibrinogen (FBG) and immunoglobulin G (IgG) immunohistochemistry. Following TBI, 40% of patients dying in the acute phase and 47% of those surviving a year or more from injury showed multi-focal, abnormal, perivascular and parenchymal FBG and IgG immunostaining localized to grey matter, with preferential distribution towards the crests of gyri and deep neocortical layers. In contrast, where present, controls showed only limited, localized immunostaining. These preliminary data demonstrate evidence of widespread BBB disruption in a proportion of TBI patients emerging in the acute phase and, intriguingly, persisting in a high proportion of late survivors.

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Section: Page 16 Of 22mentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Blood-Brain Barrier Disruption Is an Early Event That May Persist for Many Years After Traumatic Brain Injury in Humans

Hay

Johnson

Young

et al. 2015

Journal of Neuropathology & Experimental Neurology

Self Cite

108

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show abstract

“…Traumatic Brain Injury Traumatic brain injury (TBI) increases the risk for developing AD by 2-to 4.5-fold, depending on severity of the injury. 230 Individuals who die from TBI have elevated Ab plaques 231 and tau pathology is evident in those who have experienced repeated head injuries such as boxers, football players, and combat veterans. 230 Disruption of BBB occurs as an early response to TBI, but resolves by 1 week after injury.…”

Section: Alzheimer's Disease Risk Factors and The Blood-brain Barriermentioning

confidence: 99%

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

Erickson

Banks

2013

J Cereb Blood Flow Metab

446

359

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The blood-brain barrier (BBB) plays critical roles in the maintenance of central nervous system (CNS) homeostasis. Dysfunction of the BBB occurs in a number of CNS diseases, including Alzheimer's disease (AD). A prevailing hypothesis in the AD field is the amyloid cascade hypothesis that states that amyloid-b (Ab) deposition in the CNS initiates a cascade of molecular events that cause neurodegeneration, leading to AD onset and progression. In this review, the participation of the BBB in the amyloid cascade and in other mechanisms of AD neurodegeneration will be discussed. We will specifically focus on three aspects of BBB dysfunction: disruption, perturbation of transporters, and secretion of neurotoxic substances by the BBB. We will also discuss the interaction of the BBB with components of the neurovascular unit in relation to AD and the potential contribution of AD risk factors to aspects of BBB dysfunction. From the results discussed herein, we conclude that BBB dysfunction contributes to AD through a number of mechanisms that could be initiated in the presence or absence of Ab pathology. Keywords: Alzheimer's disease; blood-brain barrier; cerebrospinal fluid; diabetes; inflammation; neurovascular unit INTRODUCTION Alzheimer's disease (AD) is the most common type of dementia, and affects B36 million individuals worldwide (http://www.alz. co.uk/research/world-report). The majority of individuals afflicted with AD initially present with symptoms of memory loss and cognitive impairment late in life (Z65 years old). These symptoms increase in severity as AD progresses, often become so debilitating that institutionalization is necessary, and are eventually fatal. Therefore, AD is a disease with tremendous socioeconomic cost. Because of the growing aged population and lack of treatments that can prevent or slow disease progression, future AD prevalence is expected to increase to an extent that it may threaten the sustainability of healthcare systems worldwide. This necessitates a global effort to better understand AD, with the goal of developing treatments that can prevent or slow AD progression. Journal of Cerebral BloodMuch of the focus in AD research has been on amyloid-b peptide (Ab) and tau, which are the protein constituents of the hallmark senile plaques and neurofibrillary tangles that pathologically define AD. The amyloid cascade hypothesis, initially proposed by Hardy and Higgins in 1992, 1 updated by Hardy and Selkoe in 2002, 2 and still a prevalent focus of AD research today, states that deposition of Ab in the brain is the initiating event in AD. Although the hypothesis remains generally accepted, it is also increasingly evident that Ab plays a complex, multifaceted role in AD progression. In rare, familial forms of AD, mutations in the Ab precursor protein (APP) or in presenilin proteins, the enzymes that cleave Ab from APP, cause increased Ab deposition. In the remainder of AD cases, it is thought that Ab deposition results from deficient clearance. 2 Multiple routes of clearance have been elucidat...

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“…This secondary brain injury (SBI) includes multiple long-lasting neurological impairments following TBI (Wang and Ma 2010) and has many common features with Alzheimer's disease (AD). These features include severe cognitive impairment, decrease of synaptic density, enhanced concentration of soluble Aβ oligomers, and apoptosis of neurons in specific brain areas (Johnson et al 2010;Reisberg and Saeed 2004). SBI, which increases the risk of AD four times, may be one of the causes of sporadic AD in aging humans (Ikonomovic et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Dynamics of endogenous Hsp70 synthesis in the brain of olfactory bulbectomized mice

Бобкова

Guzhova

Margulis

et al. 2013

Cell Stress and Chaperones

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Numerous epidemiological studies have established acute brain injury as one of the major risk factors for the Alzheimer's disease (AD). However, the lack of animal models of AD-like degeneration triggered by a defined injury hampered the development of adequate therapies. Here we report that the surgical damage of the olfactory bulbs triggers the development of several pathologies, including amyloid-β accumulation and strong decrease of neuron density in the cortex and hippocampus as well as significant disturbance of spatial memory. Characteristically, these harmful consequences of the olfactory bulbectomy (OBX) have a peculiar dynamics in time with maximal manifestation in periods of 1-1.5 months and 8 months after the surgery and, hence, exhibit biphasic pattern with almost complete recovery period taking place at 5-6 months after the operation. The quantitative determination of endogenous inducible form of Hsp70 in different brain areas of OBX mice demonstrated characteristic fluctuations of Hsp70 levels depending on the time after the operation and age of mice. Interestingly, maximal induction of Hsp70 synthesis in the hippocampus exhibits clear-cut coincidence with the recovery period in OBX animals. The observed correlation enables to suggest curing effect of Hsp70 synthesis at an earlier period of pathology development and establishes it as a possible therapeutic agent for secondary grave consequences of brain injury, such as AD-like degeneration, for which neuroprotective therapy is urgently needed.

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

Cited by 480 publications

References 178 publications

Blood-Brain Barrier Disruption Is an Early Event That May Persist for Many Years After Traumatic Brain Injury in Humans

Blood-Brain Barrier Disruption Is an Early Event That May Persist for Many Years After Traumatic Brain Injury in Humans

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

Dynamics of endogenous Hsp70 synthesis in the brain of olfactory bulbectomized mice

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