Amyloid β accumulation in axons after traumatic brain injury in humans

Smith, Douglas H.; Chen, Xiaohan; Iwata, Atsushi; Graham, David I.

doi:10.3171/jns.2003.98.5.1072

Cited by 197 publications

(165 citation statements)

References 29 publications

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“…Indeed, among patients suffering from head injury, 30% display A␤ deposition within 7 d (Roberts et al, 1991;Roses and Saunders, 1995). These findings suggest that acute brain injuries, such as TBI, may trigger deposition of A␤ (Smith et al, 1998(Smith et al, , 2003. In addition, a recent study pointed out the transient upregulation of ␤-secretase BACE-1 [␤-site amyloid precursor protein (APP) cleaving enzyme] expression 24 -72 h after TBI, accompanied by an elevation of its activity detected 48 h after onset (Blasko et al, 2004).…”

Section: Introductionmentioning

confidence: 85%

NMDA Receptor Activation Inhibits α-Secretase and Promotes Neuronal Amyloid-β Production

Lesné¹,

Ali²,

Gabriel³

et al. 2005

J. Neurosci.

178

127

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Acute brain injuries have been identified as a risk factor for developing Alzheimer's disease (AD). Because glutamate plays a pivotal role in these pathologies, we studied the influence of glutamate receptor activation on amyloid-␤ (A␤) production in primary cultures of cortical neurons. We found that sublethal NMDA receptor activation increased the production and secretion of A␤. This effect was preceded by an increased expression of neuronal Kunitz protease inhibitory domain (KPI) containing amyloid-␤ precursor protein (KPI-APP) followed by a shift from ␣-secretase to ␤-secretase-mediated APP processing. This shift is a result of the inhibition of the ␣-secretase candidate tumor necrosis factor-␣ converting enzyme (TACE) when associated with neuronal KPI-APPs. This KPI-APP/ TACE interaction was also present in AD brains. Thus, our findings reveal a cellular mechanism linking NMDA receptor activation to neuronal A␤ secretion. These results suggest that even mild deregulation of the glutamatergic neurotransmission may increase A␤ production and represent a causal risk factor for developing AD.

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Section: Introductionmentioning

confidence: 85%

NMDA Receptor Activation Inhibits α-Secretase and Promotes Neuronal Amyloid-β Production

Lesné¹,

Ali²,

Gabriel³

et al. 2005

J. Neurosci.

178

127

View full text Add to dashboard Cite

show abstract

“…As with AD and T2DM, insulin resistance is documented in stroke (Calleja et al, 2011), TBI (Mowery et al, 2009;Ley et al, 2011), and cerebral malaria (Eltahir et al, 2010b). Likewise, A␤ and hyperphosphorylated , the proteins widely regarded as AD hallmarks and appreciated to be indicators of chronically high TNF (section IV) and GSK-3 hyperactivation induced by insulin resistance (section VI), respectively, are also present in stroke (Irving et al, 1996;Nihashi et al, 2001;Wen et al, 2004b), TBI (Irving et al, 1996;Smith et al, 2003;Tran et al, 2011), and cerebral malaria (Medana et al, 2002(Medana et al, , 2005.…”

Section: The Broader Picture-stroke Traumatic Brain Injury and Imentioning

confidence: 99%

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

et al. 2012

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“…Traumatic axonal injury (TAI), also referred to as diffuse axonal injury (DAI), is thought to be a major contributor to cognitive dysfunction in patients following TBI Blumbergs et al, 1994;Gennarelli et al, 1982;Grady et al, 1993;King et al, 2005;Medana and Esiri, 2003;Meythaler et al, 2001;Nevin, 1967;Oppenheimer, 1968;Pilz, 1983;Povlishock et al, 1992;Povlishock and Katz, 2005;Smith et al, 2003a;Smith et al, 2003b;Strich, 1956;Strich, 1961).…”

Section: Introductionmentioning

confidence: 99%

Detection of traumatic axonal injury with diffusion tensor imaging in a mouse model of traumatic brain injury

Donald

Dikranian

Song

et al. 2007

Experimental Neurology

275

209

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Traumatic axonal injury (TAI) is thought to be a major contributor to cognitive dysfunction following traumatic brain injury (TBI), however TAI is difficult to diagnose or characterize non-invasively. Diffusion tensor imaging (DTI) has shown promise in detecting TAI, but direct comparison to histologically-confirmed axonal injury has not been performed. In the current study, mice were imaged with DTI, subjected to a moderate cortical controlled impact injury, and re-imaged 4-6 hours and 24 hours post-injury. Axonal injury was detected by amyloid beta precursor protein (APP) and neurofilament immunohistochemistry in pericontusional white matter tracts. The severity of axonal injury was quantified using stereological methods from APP stained histological sections. Two DTI parameters -axial diffusivity and relative anisotropy -were significantly reduced in the injured, pericontusional corpus callosum and external capsule, while no significant changes were seen with conventional MRI in these regions. The contusion was easily detectible on all MRI sequences. Significant correlations were found between changes in relative anisotropy and the density of APP tained axons across mice and across subregions spanning the spatial gradient of injury. The predictive value of DTI was tested using a region with DTI changes (hippocampal commissure) and a region without DTI changes (anterior commissure). Consistent with DTI predictions, there was histological detection of axonal injury in the hippocampal commissure and none in the anterior commissure.Corresponding Author: David Brody, MD PhD, Department of Neurology, Washington University, 660 S. Euclid, Campus Box 8111, St. Louis, MO 63110, Phone: 314-747-0286, Fax: 314-362-2244 Email: brodyd@neuro.wustl.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errorsmaybe discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. These results demonstrate that DTI is able to detect axonal injury, and support the hypothesis that DTI may be more sensitive than conventional imaging methods for this purpose. NIH Public Access

show abstract

Amyloid β accumulation in axons after traumatic brain injury in humans

Abstract: The results of this study indicate that damaged axons can serve as a large reservoir of Abeta, which may contribute to Abeta plaque formation after TBI in humans.

Cited by 197 publications

References 29 publications

NMDA Receptor Activation Inhibits α-Secretase and Promotes Neuronal Amyloid-β Production

NMDA Receptor Activation Inhibits α-Secretase and Promotes Neuronal Amyloid-β Production

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

Detection of traumatic axonal injury with diffusion tensor imaging in a mouse model of traumatic brain injury

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