Caspase inhibition therapy abolishes brain trauma-induced increases in Aβ peptide: Implications for clinical outcome

Abrahamson, Eric E.; Ikonomović, Miloš D.; Ciallella, John R.; Hope, Caroline E.; Paljug, William R.; Isanski, Barbara A.; Flood, Dorothy G.; Clark, Robert S. B.; DeKosky, Steven T.

doi:10.1016/j.expneurol.2005.10.011

Cited by 84 publications

(70 citation statements)

References 86 publications

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“…Also the levels of GGA3, an adaptor protein involved in BACE trafficking are decreased and inversely correlated with increased levels of BACE in AD [49]. Inhibition of caspase abolishes brain trauma-induced increases in Aβ peptide [1]. TD can lead to activation of caspases.…”

Section: Discussionmentioning

confidence: 99%

Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model

Karuppagounder

Shi

et al. 2009

Neurobiology of Aging

125

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Mitochondrial dysfunction, oxidative stress and reductions in thiamine-dependent enzymes have been implicated in multiple neurological disorders including Alzheimer's disease (AD). Experimental thiamine deficiency (TD) is an established model for reducing the activities of thiamine-dependent enzymes in brain. TD diminishes thiamine dependent enzymes throughout the brain, but produces a time-dependent selective neuronal loss, glial activation, inflammation, abnormalities in oxidative metabolism and clusters of degenerating neurites in only specific thalamic regions. The present studies tested how TD alters brain pathology in Tg19959 transgenic mice over expressing a double mutant form of the amyloid precursor protein (APP). TD exacerbated amyloid plaque pathology in transgenic mice and enlarged the area occupied by plaques in cortex, hippocampus and thalamus by 50%, 200% and 200%, respectively. TD increased Aβ 1-42 levels by about three-fold, β-CTF (C99) levels by 33% and β-secretase (BACE1) protein levels by 43%. TD induced inflammation in areas of plaque formation. Thus, the induction of mild impairment of oxidative metabolism, oxidative stress and inflammation induced by TD alters metabolism of APP and/or Aβ and promotes accumulation of plaques independent of neuron loss or neuritic clusters.

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Section: Discussionmentioning

confidence: 99%

Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model

Karuppagounder

Shi

et al. 2009

Neurobiology of Aging

125

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“…20 Ab accumulates very quickly after TBI because Ab deposits can be identified within as little as 2 h post-injury in the human brain. 13,15 Further, this accumulation of Ab also occurs in animal models of TBI, 12,17 including mouse CCI. 12,14,22. In the present study, we again report that CCI causes a significant and rapid accumulation of soluble Ab 40 species.…”

Section: Discussionmentioning

confidence: 99%

“…The rapid accumulation of Ab after TBI is well documented in both humans and experimental animal models. [12][13][14][15][16][17] Excess Ab is detrimental to dendritic spine health both in vivo 18 and in vitro 19 and, similar to spine loss after TBI, Ab-induced dendritic spine loss can be prevented with the calcineurin inhibitor FK506. 20 These data suggest that spine retraction after Ab and TBI may have a common mechanism of action through calcineurin activation.…”

Section: Introductionmentioning

confidence: 99%

Controlled Cortical Impact Results in an Extensive Loss of Dendritic Spines that Is Not Mediated by Injury-Induced Amyloid-Beta Accumulation

Winston

Chellappa

Wilkins

et al. 2013

Journal of Neurotrauma

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The clinical manifestations that occur after traumatic brain injury (TBI) include a wide range of cognitive, emotional, and behavioral deficits. The loss of excitatory synapses could potentially explain why such diverse symptoms occur after TBI, and a recent preclinical study has demonstrated a loss of dendritic spines, the postsynaptic site of the excitatory synapse, after fluid percussion injury. The objective of this study was to determine if controlled cortical impact (CCI) also resulted in dendritic spine retraction and to probe the underlying mechanisms of this spine loss. We used a unilateral CCI and visualized neurons and dendtritic spines at 24 h post-injury using Golgi stain. We found that TBI caused a 32% reduction of dendritic spines in layer II/III of the ipsilateral cortex and a 20% reduction in the dendritic spines of the ipsilateral dentate gyrus. Spine loss was not restricted to the ipsilateral hemisphere, however, with similar reductions in spine numbers recorded in the contralateral cortex (25% reduction) and hippocampus (23% reduction). Amyloid-b (Ab), a neurotoxic peptide commonly associated with Alzheimer disease, accumulates rapidly after TBI and is also known to cause synaptic loss. To determine if Ab contributes to spine loss after brain injury, we administered a c-secretase inhibitor LY450139 after TBI. We found that while LY450139 administration could attenuate the TBI-induced increase in Ab, it had no effect on dendritic spine loss after TBI. We conclude that the acute, global loss of dendritic spines after TBI is independent of c-secretase activity or TBI-induced Ab accumulation.

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“…Furthermore, it has also been noted that high levels of Aβ peptide may be neurotoxic in and of themselves [ 10 ]. Finally, because traumatic brain injury involves degradation of brain tissues, including axonal damage, necrotic cell death, and both delayed and acute products of neuronal apoptosis, a process activated by caspases, other groups have looked at caspase inhibition therapy as a means of decreasing TBI increases in Aβ peptide [ 11 ].…”

Section: Advancement In Development Of Serum Biomarkers For Detectionmentioning

confidence: 97%

Neuron Based Surgery: Are We There Yet? Technical Developments in the Surgical Treatment of Brain Injury and Disease

James

Lemole

2015

Technological Advances in Surgery, Trauma and Critical Care

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Caspase inhibition therapy abolishes brain trauma-induced increases in Aβ peptide: Implications for clinical outcome

Cited by 84 publications

References 86 publications

Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model

Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model

Controlled Cortical Impact Results in an Extensive Loss of Dendritic Spines that Is Not Mediated by Injury-Induced Amyloid-Beta Accumulation

Neuron Based Surgery: Are We There Yet? Technical Developments in the Surgical Treatment of Brain Injury and Disease

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