Experimental Traumatic Brain Injury Induces Rapid Aggregation and Oligomerization of Amyloid-Beta in an Alzheimer's Disease Mouse Model

Washington, Patricia M.; Morffy, Nicholas; Parsadanian, Maia; Zapple, David N.; Burns, Mark P.

doi:10.1089/neu.2013.3017

Cited by 91 publications

(63 citation statements)

References 61 publications

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“…This rationale also holds true for the lack of an increase in Ab, or a shift in solubility of Ab, after 30 rmTBIs. We, and others, have previously shown that the abnormal production of Ab after TBI occurs at sites of axonal injury, 23,59,62 and in the absence of APP-positive varicosities, it is unlikely that Ab is being produced in higher amounts in our 3xTg-AD mice.…”

Section: Rmtbi Does Not Induce Amyloid or Tau Pathology In 3xtg-ad Micementioning

confidence: 73%

Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma

Winston

Noël

Neustadtl

et al. 2016

The American Journal of Pathology

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Mild traumatic brain injury (mTBI) is an emerging risk for chronic behavioral, cognitive, and neurodegenerative conditions. Athletes absorb several hundred mTBIs each year; however, rodent models of repeat mTBI (rmTBI) are often limited to impacts in the single digits. Herein, we describe the effects of 30 rmTBIs, examining structural and pathological changes in mice up to 365 days after injury. We found that single mTBI causes a brief loss of consciousness and a transient reduction in dendritic spines, reflecting a loss of excitatory synapses. Single mTBI does not cause axonal injury, neuroinflammation, or cell death in the gray or white matter. Thirty rmTBIs with a 1-day interval between each mTBI do not cause dendritic spine loss; however, when the interinjury interval is increased to 7 days, dendritic spine loss is reinstated. Thirty rmTBIs cause white matter pathology characterized by positive silver and Fluoro-Jade B staining, and microglial proliferation and activation. This pathology continues to develop through 60 days, and is still apparent at 365 days, after injury. However, rmTBIs did not increase b-amyloid levels or tau phosphorylation in the 3xTg-AD mouse model of Alzheimer disease. Our data reveal that single mTBI causes a transient loss of synapses, but that rmTBIs habituate to repetitive injury within a short time period. rmTBI causes the development of progressive white matter pathology that continues for months after the final impact. (Am J Pathol 2016, 186: 552e567; http://dx.doi.org/ 10.1016/j.ajpath.2015 Athletes participating in contact sports are at high risk of exposure to large numbers of concussive and subconcussive mild traumatic brain injuries (mTBIs). Recent studies using head impact telemetry systems have begun to reveal how many head impacts an individual football player can receive in the process of playing his or her sport. In a study of high school football players, the number of helmet impacts >20 g recorded in a single season ranged from a low of 226 (average, 4.7 per session) to a high of 1855 (average, 38.6 per session). 1 Most of these impacts do not result in the clinical diagnosis of a concussion; however, it is not known if the cumulative effects of these impacts can result in increased damage to the brain. mTBI has been extensively modeled in mice and rats. 2 Most of these rodent models use fewer than five mTBIs, and report adverse events, including intracerebral bleeding, skull fractures, severe axonal injury, neuronal cell death, and increased mortality.

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Section: Rmtbi Does Not Induce Amyloid or Tau Pathology In 3xtg-ad Micementioning

confidence: 73%

Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma

Winston

Noël

Neustadtl

et al. 2016

The American Journal of Pathology

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“…27 Experimental data indicate that TBI in triple transgenic AD model mice causes accumulation and aggregation of Ab oligomers in the brain, which may contribute to developing AD later in life. 40 Genetic factors, such as presence of an ApoE4 allele 44 or neprilysin gene transfer (GT) repeat polymorphism 45 may potentially explain the bimodal distribution of Ab42 after TBI. Testing such a hypothesis will require a larger sample size, as the number of patients in our cohort was too small to allow adequately powered allelic association studies.…”

Section: Discussionmentioning

confidence: 99%

Increases of Plasma Levels of Glial Fibrillary Acidic Protein, Tau, and Amyloid β up to 90 Days after Traumatic Brain Injury

Bogoslovsky

Wilson

Yao

et al. 2017

Journal of Neurotrauma

165

126

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Glial fibrillary acidic protein (GFAP), microtubule-associated protein tau, and amyloid b peptide (Ab42) have been proposed as diagnostic and prognostic biomarkers in traumatic brain injury (TBI). Single molecule array (Simoa) is a novel technology that employs highly sensitive immunoassays for accurate measurements of candidate biomarkers found at low concentration in biological fluids. Our objective was to trace the trajectory of tau, GFAP, and Ab42 levels in plasma from the acute through subacute stages after TBI, compared with controls. Samples from 34 TBI subjects enrolled in the Citicoline Brain Injury Treatment Trial (COBRIT) were studied. Injury severity was assessed by Glasgow Coma Scale (GCS) and admission CT. Glasgow Outcome Scale Extended (GOSE) was assessed 6 months after injury. Plasma was collected within 24 h (Day 0), and 30 and 90 days after the TBI. Plasma collected from 69 healthy volunteers was used for comparison. At every time point, increases were noted in plasma GFAP ( p < 0.0001 for all comparisons), tau ( p < 0.0001, p < 0.0001, and p = 0.0044, at Days 0, 30, and 90, respectively), and Ab42 ( p < 0.001, p < 0.0001, and p = 0.0203, respectively) in TBI cases compared with controls. The levels were maximal at Day 0 for GFAP and tau and at Day 30 for Ab42. Area under curve (AUC) analyses for Day 0 GFAP and tau were excellent for discrimination of complicated mild TBI (cmTBI) from controls (0.936 and 0.901, correspondingly). Discriminant component analysis (DCA) for all three biomarkers at Days 0 and 30 differentiated controls from cmTBI (91.1% and 89.7% correctly classified, at each time point). Duration of post-traumatic amnesia (PTA) correlated weakly with tau levels at 30 days (Spearman's r = 0.40; 95% CI 0.0003-0.60, p = 0.044). The Marshall CT Grade on admission correlated weakly with Day 30 tau levels (Spearman's r = 0.41; 95% CI 0.04-0.68, p = 0.027). Day 30 Ab42 correlated with GOSE (standardized b -0.486, p = 0.042). GFAP, tau and Ab42 were increased up to 90 days after TBI compared with controls. Total tau levels correlated with clinical and radiological variables of TBI severity. Plasma Ab42 correlated with clinical outcome. Combination of all three biomarkers at Days 0 and 30 can be used to differentiate controls from cmTBI populations, and may be useful as biomarkers of TBI in both acute and subacute phases.

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“…Mouse models of TBI suggest that aged mice were more sensitive to TBI induced a-synuclein pathology than younger mice 32 . There is also compelling experimental evidence of trauma induced amyloid-beta aggregation in mice 33 . Although the PD patients in this study were in the prodromal period and likely had extrastriatal pathology, it is possible that head trauma may have accelerated striatal protein aggregation with resultant onset of motor parkinsonism.…”

Section: Discussionmentioning

confidence: 99%

Traumatic brain injury in the prodromal period of Parkinson's disease: A large epidemiological study using medicare data

Camacho‐Soto

Warden

Nielsen

et al. 2017

Annals of Neurology

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Objective Studies suggest a greater risk of Parkinson disease (PD) after traumatic brain injury (TBI), but it is possible that the risk of TBI is greater in the prodromal period of PD. We aimed to examine the time-to-TBI in PD patients in their prodromal period compared to population-based controls. Methods We identified 89,790 incident PD cases and 118,095 comparable controls > 65 years of age in 2009 using Medicare claims data. Using data from the preceding five years, we compared time-to-TBI in PD patients in their prodromal period to controls. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for TBI in a Cox regression, while adjusting for age, sex, race/ethnicity, modified Charlson comorbidity index, smoking, and alcohol use. Results Risk of TBI was greater in PD patients in their prodromal period across all age and sex groups, with HRs consistently increasing with proximity to PD diagnosis. HRs ranged from 1.64 (95% CI 1.52, 1.77) five years prior to diagnosis to 3.93 (95% CI 3.74, 4.13) in the year prior. The interaction between PD, TBI, and time was primarily observed for TBI attributed to falls. Motor dysfunction and cognitive impairment, suggested by corresponding ICD-9 codes, partially mediated the PD-TBI association. Interpretation There is a strong association between PD and a recent TBI in the prodromal period of PD. This association strengthens as PD diagnosis approaches and may be a result of undetected non-motor and motor symptoms, but confirmation will be required.

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Experimental Traumatic Brain Injury Induces Rapid Aggregation and Oligomerization of Amyloid-Beta in an Alzheimer's Disease Mouse Model

Cited by 91 publications

References 61 publications

Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma

Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma

Increases of Plasma Levels of Glial Fibrillary Acidic Protein, Tau, and Amyloid β up to 90 Days after Traumatic Brain Injury

Traumatic brain injury in the prodromal period of Parkinson's disease: A large epidemiological study using medicare data

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