Expression of amyloid precursor protein after rat traumatic brain injury

Itoh, Tatsuki; Satou, Takao; Nishida, Shozo; Tsubaki, Masahiro; Hashimoto, Shigeo; Ito, Hiroyuki

doi:10.1179/016164108x323771

Cited by 72 publications

(51 citation statements)

References 29 publications

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“…Both axonal and neuronal abnormalities were identified that were broadly similar to findings reported in other forms of TBI (Blumbergs et al, 1995;Bramlett et al, 1997;Itoh et al, 2009;Kilbourne et al, 2009;Pierce et al, 1996;Stone et al, 2000). Abnormalities in b-APP were widespread, and involved deep brain regions away from subarachnoid hemorrhages.…”

Section: Prough 2009) Understanding This Complex Relationship Is Ofsupporting

confidence: 61%

Glyburide-Novel Prophylaxis and Effective Treatment for Traumatic Brain Injury

Simard¹

2011

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY)2. REPORT TYPE 3. DATES COVERED (From -To) 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail:5f. WORK UNIT NUMBER The overall subject of this project is blast-traumatic brain injury (blast-TBI) and the role of the SUR1-regulated NCCa-ATP channel in blast-TBI. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTThe specific objectives of this project include: (1) develop a standardized rat model of blast-TBI to study the direct transcranial effects of blast on the brain, independent of indirect transthoracic effects; (2) determine the role of the SUR1-regulated NCCa-ATP channel in blast-TBI; (3) in normal human volunteers, determine the safety of the SUR1 blocker, glyburide, as it might be used as prophylaxis against blast-TBI. During the third year of this project, we completed a key objective -the evaluation of our cranial-only blast injury apparatus (COBIA) as it relates to the effect of blast exposure on short term vestibulomotor performance and on long term cognitive performance. In addition, we completed experiments looking at the time course for upregulation and downregulation of SUR1 and TRPM4. The most important findings include: (i) SUR1 and TRPM4 begin to appear as early as 2 hours after injury, and are gone by 7 days after injury; (ii) the dose-response curve for blast intensity vs. biological response is very steep, making it difficult to accurately grade sublethal injuries based on peak overpressure alone; (iii) the apneac response immediate following blast is an excellent predictor of short-term vestibulomotor performance and of long term cognitive performance, making it a very useful independent variable for grading sublethal injuries when establishing the dose-response.blast-TBI, sulfonylurea receptor The ove...

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Section: Prough 2009) Understanding This Complex Relationship Is Ofsupporting

confidence: 61%

Glyburide-Novel Prophylaxis and Effective Treatment for Traumatic Brain Injury

Simard¹

2011

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“…APP expression has been shown to increase after neuronal injury due to TBI (Itoh et al, 2009;Murakami et al, 1998;Otsuka et al, 1991). The effect of the anti-CD11d treatment on neuronal damage was assessed in homogenates of the rat brains using Western blot analysis (Fig.…”

Section: Amyloid Precursor Protein (App)mentioning

confidence: 99%

A CD11d Monoclonal Antibody Treatment Reduces Tissue Injury and Improves Neurological Outcome after Fluid Percussion Brain Injury in Rats

Feng

Shultz

Hepburn

et al. 2012

Journal of Neurotrauma

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Traumatic brain injury (TBI) is an international health concern often resulting in chronic neurological abnormalities, including cognitive deficits, emotional disturbances, and motor impairments. An anti-CD11d monoclonal antibody that blocks the CD11d/CD18 integrin and vascular cell adhesion molecule (VCAM)-1 interaction following experimental spinal cord injury improves functional recovery, while reducing the intraspinal number of neutrophils and macrophages, oxidative activity, and tissue damage. Since the mechanisms of secondary injury in the brain and spinal cord are similar, we designed a study to evaluate fully the effects of antiCD11d treatment after a moderate lateral fluid percussion TBI in the rat. Rats were treated at 2 h after TBI with either the anti-CD11d antibody or an isotype-matched control antibody 1B7, and both short (24-to 72-h) and long (4-week) recovery periods were examined. The anti-CD11d integrin treatment reduced neutrophil and macrophage levels in the injured brain, with concomitant reductions in lipid peroxidation, astrocyte activation, amyloid precursor protein accumulation, and neuronal loss. The reduced neuroinflammation seen in anti-CD11d-treated rats correlated with improved performance on a number of behavioral tests. At 24 h, the anti-CD11d group performed significantly better than the 1B7 controls on several water maze measures of spatial cognition. At 4 weeks post-injury the anti-CD11d-treated rats had better sensorimotor function as assessed by the beam task, and reduced anxiety-like behaviors, as evidenced by elevated-plus maze testing, compared to 1B7 controls. These findings suggest that neuroinflammation is associated with behavioral deficits after TBI, and that anti-CD11d antibody treatment is a viable strategy to improve neurological outcomes after TBI.

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“…19,109 Furthermore, several studies have provided experimental evidence that traumatic head injury in rodents and humans can result in significant elevation in APP levels, 110,111 as well as Aβ generation and amyloid plaque deposition. 112,113 In line with the high turnover, rapid anterograde transport, and processing of APP in distal compartments, [114][115][116] genetically induced fibre tract degeneration in the gracile axonal dystrophy mouse provokes rapid axonal accumulation of APP and Aβ.…”

Section: Inflammation and Cellular Stressmentioning

confidence: 99%

Deciphering the mechanism underlying late-onset Alzheimer disease

2012

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Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-(A) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between A and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of A accumulation in late-onset AD. Abstract | Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence ...

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Expression of amyloid precursor protein after rat traumatic brain injury

Abstract: These results suggested that long-term overexpression of APP was confirmed by immunohistochemical and biologic technique after TBI. This may be related to the induction of Alzheimer type dementia and it is a very important risk factor for this disease.

Cited by 72 publications

References 29 publications

Glyburide-Novel Prophylaxis and Effective Treatment for Traumatic Brain Injury

Glyburide-Novel Prophylaxis and Effective Treatment for Traumatic Brain Injury

A CD11d Monoclonal Antibody Treatment Reduces Tissue Injury and Improves Neurological Outcome after Fluid Percussion Brain Injury in Rats

Deciphering the mechanism underlying late-onset Alzheimer disease

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