Brain Trauma Induces Massive Hippocampal Neuron Death Linked to a Surge in β-Amyloid Levels in Mice Overexpressing Mutant Amyloid Precursor Protein

Smith, Douglas H.; Nakamura, Michio; McIntosh, Tracy K.; Wang, Jun; Rodriguez, Amaris; Chen, Xiaohan; Raghupathi, Ramesh; Saatman, Kathryn E.; Clemens, James A.; Schmidt, Maria Luiza Gava; Lee, Virginia M.‐Y.; Trojanowski, John Q.

doi:10.1016/s0002-9440(10)65643-x

Cited by 134 publications

(96 citation statements)

References 27 publications

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“…In addition to human studies, the effects of TBI on A␤ and AD pathology have also been studied using TG mouse models of AD. Smith et al (1998) reported that TBI in PDAPP mice resulted in an 84% loss of CA3 neurons compared with only a 36% loss in non-TG mice. Nakagawa et al (1999Nakagawa et al ( , 2000 have reported that TBI in both young and old PDAPP mice induces atrophy and reduces A␤ deposition in the ipsilateral versus contralateral hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E4 Influences Amyloid Deposition But Not Cell Loss after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

et al. 2002

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The ⑀4 allele of apolipoprotein E (APOE) and traumatic brain injury (TBI) are both risk factors for the development of Alzheimer's disease (AD). These factors may act synergistically, in that APOE4ϩ individuals are more likely to develop dementia after TBI. Because the mechanism underlying these effects is unclear, we questioned whether APOE4 and TBI interact either through effects on amyloid-␤ (A␤) or by enhancing cell death/tissue injury. We assessed the effects of TBI in PDAPP mice (transgenic mice that develop AD-like pathology) expressing human APOE3 (PDAPP: E3), human APOE4 (PDAPP:E4), or no APOE (PDAPP:EϪ/Ϫ). Mice were subjected to a unilateral cortical impact injury at 9-10 months of age and allowed to survive for 3 months. A␤ load, hippocampal/cortical volumes, and hippocampal CA3 cell loss were quantified using stereological methods. All of the groups contained mice with A␤-immunoreactive deposits (56% PDAPP: E4, 20% PDAPP:E3, 75% PDAPP:EϪ/Ϫ), but thioflavine-Spositive A␤ (amyloid) was present only in the molecular layer of the dentate gyrus in the PDAPP:E4 mice (44%). In contrast, our previous studies showed that in the absence of TBI, PDAPP:E3 and PDAPP:E4 mice have little to no A␤ deposition at this age. After TBI, all of the A␤ deposits present in PDAPP:E3 and PDAPP: EϪ/Ϫ mice were diffuse plaques. In contrast to the effect of APOE4 on amyloid, PDAPP:E3, PDAPP:E4, and PDAPP:EϪ/Ϫ mice did not differ in the amount of brain tissue or cell loss. These data support the hypothesis that APOE4 influences the neurodegenerative cascade after TBI via an effect on A␤.Key words: Alzheimer's disease; amyloid; APP; traumatic brain injury; apoE; hippocampus The ⑀4 allele of apolipoprotein E (APOE) and traumatic brain injury (TBI) are both risk factors for the development of Alzheimer's disease (AD). It was first found that APOE4 was a risk factor for AD in 1993 (Strittmatter et al., 1993), and numerous studies have confirmed this association. Several studies have found that individuals who sustained moderate to severe head injury are more likely to develop dementia and AD (Mayeux et al., 1993(Mayeux et al., , 1995Plassman et al., 2000). These risk factors appear to act synergistically, in that individuals who are APOE4ϩ are even more likely to develop dementia if they sustain TBI at some time in their life. For example, APOE4ϩ individuals were 10 times more likely to develop AD after TBI than those who were APOE4Ϫ, whereas APOE4 in the absence of injury was associated with only twice the risk (Mayeux et al., 1995;Tang et al., 1996).Although the mechanisms underlying these effects are unclear, some evidence suggests that both APOE4 and TBI may influence the risk of AD via interactions with the amyloid-␤ (A␤) peptide.For example, A␤ deposition can be found in ϳ30% of people who die shortly after TBI (Roberts et al., 1991(Roberts et al., , 1994; a significant percentage of these patients are APOE4ϩ (Nicoll et al., 1995(Nicoll et al., , 1996. In addition, analysis of CSF from TBI patients revealed elevated levels of ...

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Section: Discussionmentioning

confidence: 99%

Apolipoprotein E4 Influences Amyloid Deposition But Not Cell Loss after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

et al. 2002

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“…Knockout APOE mice subjected to weight-drop brain injury were found to have exacerbated memory impairment and motor deficits, when compared to wild-type controls. In mouse studies, 10-fold over-expression of mutant APP leads to the development of plaques at 6 months of age, with TBI exacerbating cognitive impairments and hippocampal CA3 pathology compared with littermates (Smith et al, 1998). In addition to Alzheimer's disease, TBI may also be a risk factor for other neurodegenerative diseases, including Parkinson's disease, characterized by intracellular filament occlusions in neurons (Hubble et al, 1993).…”

Section: Genetic Aspects Of Stroke and Head Traumamentioning

confidence: 99%

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

Bramlett

Dietrich

2004

J Cereb Blood Flow Metab

567

358

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Summary: Current knowledge regarding the pathophysiology of cerebral ischemia and brain trauma indicates that similar mechanisms contribute to loss of cellular integrity and tissue destruction. Mechanisms of cell damage include excitotoxicity, oxidative stress, free radical production, apoptosis and inflammation. Genetic and gender factors have also been shown to be important mediators of pathomechanisms present in both injury settings. However, the fact that these injuries arise from different types of primary insults leads to diverse cellular vulnerability patterns as well as a spectrum of injury processes. Blunt head trauma produces shear forces that result in primary membrane damage to neuronal cell bodies, white matter structures and vascular beds as well as secondary injury mechanisms. Severe cerebral ischemic insults lead to metabolic stress, ionic perturbations, and a complex cascade of biochemical and molecular events ultimately causing neuronal death. Similarities in the pathogenesis of these cerebral injuries may indicate that therapeutic strategies protective following ischemia may also be beneficial after trauma. This review summarizes and contrasts injury mechanisms after ischemia and trauma and discusses neuroprotective strategies that target both types of injuries.

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“…66,85,87,88 Briefly, the MWM is a circular pool 1 m in diameter that is painted white inside. 65 The water (16-18˚C) filling the pool is made opaque by adding nontoxic, watersoluble white paint.…”

Section: Assessment Of Cognitive Functionmentioning

confidence: 99%

“…Scores were assigned according to time spent in various zones of the MWM, and a memory score was calculated weighting the time spent in each zone according to the proximity to the previous platform site. 66,85,87,88 To test for impairment of learning ability, a separate group of mice (15 sham-injured animals, 16 animals subjected to a single TBI, and 16 animals subjected to an RHI) received no training in the MWM prior to injury. At 56 days postinjury, these animals were tested for their ability to learn the visuospatial task in the MWM over a 2-day period, following the identical protocol described earlier, and were tested the following day (Day 58) for retention of the learned task (probe trial), details of which were originally described in the rat.…”

Section: Assessment Of Cognitive Functionmentioning

confidence: 99%

“…A broad variety of studies investigating posttraumatic sequelae in mouse models in our laboratory and others have been conducted with a planned animal survival time of 1 week after TBI. 11,66,67,78,87 It therefore seemed reasonable to begin a thorough investigation for transient histological effects at that specific time point. Authors of other studies, however, have pointed out that trauma-induced neurodegeneration seems to be an ongoing process, revealed by an increase in cortical damage over time 10,12,85 and axonal damage occurring for weeks.…”

Section: Motor Functionmentioning

confidence: 99%

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Mild head injury increasing the brain's vulnerability to a second concussive impact

Laurer¹,

Bareyre²,

Lee³

et al. 2001

Journal of Neurosurgery

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293

234

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Object. Mild, traumatic repetitive head injury (RHI) leads to neurobehavioral impairment and is associated with the early onset of neurodegenerative disease. The authors developed an animal model to investigate the behavioral and pathological changes associated with RHI. Methods. Adult male C57BL/6 mice were subjected to a single injury (43 mice), repetitive injury (two injuries 24 hours apart; 49 mice), or no impact (36 mice). Cognitive function was assessed using the Morris water maze test, and neurological motor function was evaluated using a battery of neuroscore, rotarod, and rotating pole tests. The animals were also evaluated for cardiovascular changes, blood—brain barrier (BBB) breakdown, traumatic axonal injury, and neurodegenerative and histopathological changes between 1 day and 56 days after brain trauma. No cognitive dysfunction was detected in any group. The single-impact group showed mild impairment according to the neuroscore test at only 3 days postinjury, whereas RHI caused pronounced deficits at 3 days and 7 days following the second injury. Moreover, RHI led to functional impairment during the rotarod and rotating pole tests that was not observed in any animal after a single impact. Small areas of cortical BBB breakdown and axonal injury, observed after a single brain injury, were profoundly exacerbated after RHI. Immunohistochemical staining for microtubule-associated protein—2 revealed marked regional loss of immunoreactivity only in animals subjected to RHI. No deposits of β-amyloid or tau were observed in any brain-injured animal. Conclusions. On the basis of their results, the authors suggest that the brain has an increased vulnerability to a second traumatic insult for at least 24 hours following an initial episode of mild brain trauma.

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Brain Trauma Induces Massive Hippocampal Neuron Death Linked to a Surge in β-Amyloid Levels in Mice Overexpressing Mutant Amyloid Precursor Protein

Cited by 134 publications

References 27 publications

Apolipoprotein E4 Influences Amyloid Deposition But Not Cell Loss after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

Apolipoprotein E4 Influences Amyloid Deposition But Not Cell Loss after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

Mild head injury increasing the brain's vulnerability to a second concussive impact

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