1998/09/01 by Douglas H. Smith, Michio Nakamura, Tracy K. McIntosh +14 · 25 citations
Medicine · Biochemistry, Genetics and Molecular Biology · Agricultural and Biological Sciences · #Alzheimer's disease research and treatments #S100 Proteins and Annexins #Aluminum toxicity and tolerance in plants and animals
paper · pdf · doi:10.1016/s0002-9440(10)65643-x
Although brain trauma is a risk factor for Alzheimer's disease, no experimental model has been generated to explore this relationship. We developed a model of brain trauma in transgenic mice that overexpress mutant human amyloid precursor protein (PDAPP) leading to the appearance of Alzheimer's disease-like β-amyloid (Aβ) plaques beginning at 6 months of age. We induced cortical impact brain injury in the PDAPP animals and their wild-type littermates at 4 months of age, ie, before Aβ plaque formation, and evaluated changes in posttraumatic memory function, histopathology, and regional tissue levels of the Aβ peptides Aβ1–40 and Aβ1–42. We found that noninjured PDAPP mice had impaired memory function compared to noninjured wild-type littermates (P < 0.01) and that brain-injured PDAPP mice had more profound memory dysfunction than brain-injured wild-type littermates (P < 0.001). Although no augmentation of Aβ plaque formation was observed in brain-injured PDAPP mice, a substantial exacerbation of neuron death was found in the hippocampus (P < 0.001) in association with an acute threefold increase in Aβ1–40and sevenfold increase in Aβ1–42 levels selectively in the hippocampus (P < 0.01). These data suggest a mechanistic link between brain trauma and Aβ levels and the death of neurons. Although brain trauma is a risk factor for Alzheimer's disease, no experimental model has been generated to explore this relationship. We developed a model of brain trauma in transgenic mice that overexpress mutant human amyloid precursor protein (PDAPP) leading to the appearance of Alzheimer's disease-like β-amyloid (Aβ) plaques beginning at 6 months of age. We induced cortical impact brain injury in the PDAPP animals and their wild-type littermates at 4 months of age, ie, before Aβ plaque formation, and evaluated changes in posttraumatic memory function, histopathology, and regional tissue levels of the Aβ peptides Aβ1–40 and Aβ1–42. We found that noninjured PDAPP mice had impaired memory function compared to noninjured wild-type littermates (P < 0.01) and that brain-injured PDAPP mice had more profound memory dysfunction than brain-injured wild-type littermates (P < 0.001). Although no augmentation of Aβ plaque formation was observed in brain-injured PDAPP mice, a substantial exacerbation of neuron death was found in the hippocampus (P < 0.001) in association with an acute threefold increase in Aβ1–40and sevenfold increase in Aβ1–42 levels selectively in the hippocampus (P < 0.01). These data suggest a mechanistic link between brain trauma and Aβ levels and the death of neurons. Although circumstantial evidence suggests that traumatic brain injury is a risk factor for Alzheimer's disease (AD), the mechanisms underlying this relationship remain unknown. Previously, postmortem histopathological analysis of brains from boxers with dementia pugilistica (punch-drunk syndrome) revealed neurofibrillary tangles and diffuse plaques composed of β-amyloid peptides (Aβs) similar to AD lesions.1Tokuda T Ikeda of brains with to amyloid and of a of brain trauma in a of amyloid protein in brain of β-amyloid protein in the brain and a of brain trauma an risk for trauma a risk factor for Alzheimer's a of of β-amyloid precursor been brain trauma in and experimental of in the of amyloid and amyloid experimental brain injury in the brain injury in changes of β-amyloid precursor protein of injury human trauma for β-amyloid precursor and regional of traumatic brain a β-amyloid precursor protein in Although this suggests that for Aβ the of mechanisms brain trauma of Aβ has been the of experimental of brain trauma in to of in the of amyloid and amyloid experimental brain injury in the brain injury in changes of β-amyloid precursor protein Although for in Aβ to the of Aβ to of in the of amyloid and amyloid experimental brain injury in the this developed a model of brain trauma in transgenic mice that Aβ plaques in a brain beginning at 6 months of age. These mice generated a with the factor a human β-amyloid precursor protein the AD at T T T in transgenic mice β-amyloid precursor precursor protein and in a transgenic model of the evaluated the of brain trauma in the PDAPP mice at 4 months of age, ie, months before the appearance of memory function, histopathology, and regional tissue levels of Aβ and brain a model of cortical that the model of cortical impact in the and brain trauma was induced a the a We induced brain trauma brain in PDAPP mice at 4 months of age. induced brain injury in wild-type has been in model of cortical impact in the and of memory dysfunction experimental brain injury the the is a in PDAPP and wild-type mice to to a found mice to to to the before brain animals that the to brain trauma and evaluated for their to the was and the mice in the a their memory was the of in the analysis of for a with for mice with an of and with brain injury at wild-type PDAPP wild-type PDAPP and months wild-type PDAPP brains and in in and with a of and that for the Aβ and brain injury in changes of β-amyloid precursor protein of and and diffuse amyloid plaques in Alzheimer's T of and in plaques with evidence that an is of plaques in Alzheimer's with and was the found an of and in the brain-injured PDAPP mice, of the hippocampus to neuron from brain in for to with in the of the hippocampus to These to brain in the and the from the of the to the of the of from of the for and to analysis of the neuron was a analysis of for a with for mice and wild-type littermates at 6 and the brains and a and These in of at at for was in evaluated with for Aβ peptides T T T in transgenic mice β-amyloid precursor and generated in human and their with the for to for Aβ with the a for of and for Aβ at and for Aβ at Aβ has a of for Aβ1–40 and Aβ1–42. and of amyloid protein amyloid protein precursor a analysis of for a with for found that wild-type mice the memory before of the transgenic animals and from the animals that found between evaluated for memory of the with wild-type brain-injured animals memory dysfunction compared to their (P < model of cortical impact in the and a of memory was found in the PDAPP mice compared to wild-type animals (P < 0.01). brain-injured PDAPP mice had a more profound of memory function than wild-type animals (P < 0.001) the of the mice in was that with a of that for the Aβ peptides revealed the of a in the that between the brain-injured and PDAPP Although PDAPP animals more with T T T in transgenic mice β-amyloid precursor precursor protein and in a transgenic model of was no in the of plaques between brain-injured months and brain trauma Aβ in the PDAPP a in in the brain-injured PDAPP the wild-type and the wild-type mice a of in a the and memory Aβ and amyloid plaques in transgenic the of the of the brain-injured PDAPP mice with no analysis of the and that the of in the of wild-type and PDAPP animals the injury in the wild-type and PDAPP mice induced a of in the and of the hippocampus compared to (P < 0.001). wild-type animals had a of compared to a for the PDAPP an in the the wild-type brain-injured mice a of the PDAPP brain-injured mice a compared to between was found to (P < 0.001). These in brain of the of PDAPP and wild-type mice brain neuron and of the hippocampus in a PDAPP of in the and of brain wild-type mice from brain-injured PDAPP mice an of neuron in the and of the hippocampus of brain wild-type and PDAPP < compared to < compared to brain wild-type and Aβ1–42 levels in from and brain-injured wild-type mice the of at no injury Aβ levels in the wild-type the PDAPP mice, the levels of Aβ1–40 and Aβ1–42 in the hippocampus at the found in the with the Aβ1–42 at levels similar to in PDAPP mice at 4 months T T T in transgenic mice β-amyloid precursor precursor protein and in a transgenic model of of Aβ1–40 and Aβ1–42 found in the and in the PDAPP trauma in PDAPP mice, a sevenfold increase in the of Aβ1–42 and threefold increase in Aβ1–40 observed in tissue (P < in cortical tissue (P < 0.01). the of the levels of to Aβ1–42 in the hippocampus animals Aβ1–42 was found at the of at the of Aβ1–42 than 6 Aβ1–40 and Aβ1–42 in the hippocampus had to and Aβ1–42 levels in the changes in Aβ brain injury in PDAPP the changes in the of Aβ and Aβ1–42 brain trauma in PDAPP mice in the hippocampus and < < compared to Aβ for wild-type mice their Aβ levels at the for that brain trauma in PDAPP mice neuron death selectively in the the of has been observed the levels of brain trauma in wild-type model of cortical impact in the and acute and in Aβ levels found selectively in the of PDAPP animals brain posttraumatic in Aβ brain trauma Aβ plaque formation months injury in PDAPP this found that PDAPP mice memory dysfunction before the appearance of with transgenic memory Aβ and amyloid plaques in transgenic and in mice the of the amyloid precursor Although to an exacerbation of posttraumatic memory dysfunction in the PDAPP mice compared to wild-type the of this to the in the noninjured PDAPP acute posttraumatic increase of Aβ1–42 in the PDAPP mice levels similar to found in noninjured PDAPP mice substantial Aβ is observed the T T T in transgenic mice β-amyloid precursor precursor protein and in a transgenic model of the levels of Aβ in the brain-injured PDAPP mice with plaque formation with neuron neuron death has been in the of brain injury in this of transgenic mice that overexpress mutant β-amyloid precursor and of amyloid plaques with transgenic mice Aβ and no in Aβ is with with in the PDAPP transgenic no of neuron death has been Aβ in of in of of with of β-amyloid protein in suggest that in Aβ a Aβ to neuron of this a to brain in of transgenic mice mutant to brain in transgenic mice the amyloid precursor Although was no in Aβ levels between and at levels of Aβ in the brains of transgenic a for AD Aβ is to neuron death a Aβ an acute and posttraumatic increase in the of Aβ1–40 and Aβ1–42 Aβ peptides in the posttraumatic suggest a mechanistic link in the of brain trauma and AD that brain trauma with a risk factor for brain in the acute of traumatic injury and in with Alzheimer's is with of amyloid a suggest that the of brain trauma in AD in the model Although circumstantial evidence suggests that traumatic brain injury is a risk factor for Alzheimer's disease (AD), the mechanisms underlying this relationship remain unknown. Previously, postmortem histopathological analysis of brains from boxers with dementia pugilistica (punch-drunk syndrome) revealed neurofibrillary tangles and diffuse plaques composed of β-amyloid peptides (Aβs) similar to AD lesions.1Tokuda T Ikeda of brains with to amyloid and of a of brain trauma in a of amyloid protein in brain of β-amyloid protein in the brain and a of brain trauma an risk for trauma a risk factor for Alzheimer's a of of β-amyloid precursor been brain trauma in and experimental of in the of amyloid and amyloid experimental brain injury in the brain injury in changes of β-amyloid precursor protein of injury human trauma for β-amyloid precursor and regional of traumatic brain a β-amyloid precursor protein in Although this suggests that for Aβ the of mechanisms brain trauma of Aβ has been the of experimental of brain trauma in to of in the of amyloid and amyloid experimental brain injury in the brain injury in changes of β-amyloid precursor protein Although for in Aβ to the of Aβ to of in the of amyloid and amyloid experimental brain injury in the this developed a model of brain trauma in transgenic mice that Aβ plaques in a brain beginning at 6 months of age. These mice generated a with the factor a human β-amyloid precursor protein the AD at T T T in transgenic mice β-amyloid precursor precursor protein and in a transgenic model of the evaluated the of brain trauma in the PDAPP mice at 4 months of age, ie, months before the appearance of memory function, histopathology, and regional tissue levels of Aβ and brain a model of cortical that the model of cortical impact in the and brain trauma was induced a the a We induced brain trauma brain in PDAPP mice at 4 months of age. induced brain injury in wild-type has been in model of cortical impact in the and of memory dysfunction experimental brain injury the the is a in PDAPP and wild-type mice to to a found mice to to to the before brain animals that the to brain trauma and evaluated for their to the was and the mice in the a their memory was the of in the analysis of for a with for mice with an of and with brain injury at wild-type PDAPP wild-type PDAPP and months wild-type PDAPP brains and in in and with a of and that for the Aβ and brain injury in changes of β-amyloid precursor protein of and and diffuse amyloid plaques in Alzheimer's T of and in plaques with evidence that an is of plaques in Alzheimer's with and was the found an of and in the brain-injured PDAPP mice, of the hippocampus to neuron from brain in for to with in the of the hippocampus to These to brain in the and the from the of the to the of the of from of the for and to analysis of the neuron was a analysis of for a with for mice and wild-type littermates at 6 and the brains and a and These in of at at for was in evaluated with for Aβ peptides T T T in transgenic mice β-amyloid precursor and generated in human and their with the for to for Aβ with the a for of and for Aβ at and for Aβ at Aβ has a of for Aβ1–40 and Aβ1–42. and of amyloid protein amyloid protein precursor a analysis of for a with for brain a model of cortical that the model of cortical impact in the and brain trauma was induced a the a We induced brain trauma brain in PDAPP mice at 4 months of age. induced brain injury in wild-type brain a model of cortical that the model of cortical impact in the and brain trauma was induced a the a We induced brain trauma brain in PDAPP mice at 4 months of age. induced brain injury in wild-type has been in model of cortical impact in the and of memory dysfunction experimental brain injury the the is a in PDAPP and wild-type mice to to a found mice to to to the before brain animals that the to brain trauma and evaluated for their to the was and the mice in the a their memory was the of in the analysis of for a with for has been in model of cortical impact in the and of memory dysfunction experimental brain injury the the is a in PDAPP and wild-type mice to to a found mice to to to the before brain animals that the to brain trauma and evaluated for their to the was and the mice in the a their memory was the of in the analysis of for a with for mice with an of and with brain injury at wild-type PDAPP wild-type PDAPP and months wild-type PDAPP brains and in in and with a of and that for the Aβ and brain injury in changes of β-amyloid precursor protein of and and diffuse amyloid plaques in Alzheimer's T of and in plaques with evidence that an is of plaques in Alzheimer's with and was the found an of and in the brain-injured PDAPP mice, of the hippocampus to neuron from brain in for to with in the of the hippocampus to These to brain in the and the from the of the to the of the of from of the for and to analysis of the neuron was a analysis of for a with for mice with an of and with brain injury at wild-type PDAPP wild-type PDAPP and months wild-type PDAPP brains and in in and with a of and that for the Aβ and brain injury in changes of β-amyloid precursor protein of and and diffuse amyloid plaques in Alzheimer's T of and in plaques with evidence that an is of plaques in Alzheimer's with and was the found an of and in the brain-injured PDAPP mice, of the hippocampus to neuron from brain in for to with in the of the hippocampus to These to brain in the and the from the of the to the of the of from of the for and to analysis of the neuron was a analysis of for a with for Aβ mice and wild-type littermates at 6 and the brains and a and These in of at at for was in evaluated with for Aβ peptides T T T in transgenic mice β-amyloid precursor and generated in human and their with the for to for Aβ with the a for of and for Aβ at and for Aβ at Aβ has a of for Aβ1–40 and Aβ1–42. and of amyloid protein amyloid protein precursor a analysis of for a with for PDAPP mice and wild-type littermates at 6 and the brains and a and These in of at at for was in evaluated with for Aβ peptides T T T in transgenic mice β-amyloid precursor and generated in human and their with the for to for Aβ with the a for of and for Aβ at and for Aβ at Aβ has a of for Aβ1–40 and Aβ1–42. and of amyloid protein amyloid protein precursor a analysis of for a with for found that wild-type mice the memory before of the transgenic animals and from the animals that found between evaluated for memory of the with wild-type brain-injured animals memory dysfunction compared to their (P < model of cortical impact in the and a of memory was found in the PDAPP mice compared to wild-type animals (P < 0.01). brain-injured PDAPP mice had a more profound of memory function than wild-type animals (P < 0.001) the of the mice in was that with a of that for the Aβ peptides revealed the of a in the that between the brain-injured and PDAPP Although PDAPP animals more with T T T in transgenic mice β-amyloid precursor precursor protein and in a transgenic model of was no in the of plaques between brain-injured months and brain trauma Aβ in the PDAPP a in in the brain-injured PDAPP the wild-type and the wild-type mice a of in a the and memory Aβ and amyloid plaques in transgenic the of the of the brain-injured PDAPP mice with no analysis of the and that the of in the of wild-type and PDAPP animals the injury in the wild-type and PDAPP mice induced a of in the and of the hippocampus compared to (P < 0.001). wild-type animals had a of compared to a for the PDAPP an in the the wild-type brain-injured mice a of the PDAPP brain-injured mice a compared to between was found to (P < 0.001). These in neuron in the and of the hippocampus of brain wild-type and PDAPP < compared to < compared to brain wild-type and Aβ1–42 levels in from and brain-injured wild-type mice the of at no injury Aβ levels in the wild-type the PDAPP mice, the levels of Aβ1–40 and Aβ1–42 in the hippocampus at the found in the with the Aβ1–42 at levels similar to in PDAPP mice at 4 months T T T in transgenic mice β-amyloid precursor precursor protein and in a transgenic model of of Aβ1–40 and Aβ1–42 found in the and in the PDAPP trauma in PDAPP mice, a sevenfold increase in the of Aβ1–42 and threefold increase in Aβ1–40 observed in tissue (P < in cortical tissue (P < 0.01). the of the levels of to Aβ1–42 in the hippocampus animals Aβ1–42 was found at the of at the of Aβ1–42 than 6 Aβ1–40 and Aβ1–42 in the hippocampus had to and Aβ1–42 levels in the changes in Aβ brain injury in PDAPP the changes in the of Aβ and Aβ1–42 brain trauma in PDAPP mice in the hippocampus and < < compared to Aβ for wild-type mice their Aβ levels at the for found that wild-type mice the memory before of the transgenic animals and from the animals that found between evaluated for memory of the with wild-type brain-injured animals memory dysfunction compared to their (P < model of cortical impact in the and a of memory was found in the PDAPP mice compared to wild-type animals (P < 0.01). brain-injured PDAPP mice had a more profound of memory function than wild-type animals (P < 0.001) the of the mice in was that We found that wild-type mice the memory before of the transgenic animals and from the animals that found between evaluated for memory of the with wild-type brain-injured animals memory dysfunction compared to their (P < model of cortical impact in the and a of memory was found in the PDAPP mice compared to wild-type animals (P < 0.01). brain-injured PDAPP mice had a more profound of memory function than wild-type animals (P < 0.001) the of the mice in was that with a of that for the Aβ peptides revealed the of a in the that between the brain-injured and PDAPP Although PDAPP animals more with T T T in transgenic mice β-amyloid precursor precursor protein and in a transgenic model of was no in the of plaques between brain-injured months and brain trauma Aβ in the PDAPP a in in the brain-injured PDAPP the wild-type and the wild-type mice a of in a the and memory Aβ and amyloid plaques in transgenic the of the of the brain-injured PDAPP mice with no analysis of the and that the of in the of wild-type and PDAPP animals the injury in the wild-type and PDAPP mice induced a of in the and of the hippocampus compared to (P < 0.001). wild-type animals had a of compared to a for the PDAPP an in the the wild-type brain-injured mice a of the PDAPP brain-injured mice a compared to between was found to (P < 0.001). These in with a of that for the Aβ peptides revealed the of a in the that between the brain-injured and PDAPP Although PDAPP animals more with T T T in transgenic mice β-amyloid precursor precursor protein and in a transgenic model of was no in the of plaques between brain-injured months and brain trauma Aβ in the PDAPP a in in the brain-injured PDAPP the wild-type and the wild-type mice a of in a the and memory Aβ and amyloid plaques in transgenic the of the of the brain-injured PDAPP mice with no analysis of the and that the of in the of wild-type and PDAPP animals the injury in the wild-type and PDAPP mice induced a of in the and of the hippocampus compared to (P < 0.001). wild-type animals had a of compared to a for the PDAPP an in the the wild-type brain-injured mice a of the PDAPP brain-injured mice a compared to between was found to (P < 0.001). These in Aβ and Aβ1–42 levels in from and brain-injured wild-type mice the of at no injury Aβ levels in the wild-type the PDAPP mice, the levels of Aβ1–40 and Aβ1–42 in the hippocampus at the found in the with the Aβ1–42 at levels similar to in PDAPP mice at 4 months T T T in transgenic mice β-amyloid precursor precursor protein and in a transgenic model of of Aβ1–40 and Aβ1–42 found in the and in the PDAPP trauma in PDAPP mice, a sevenfold increase in the of Aβ1–42 and threefold increase in Aβ1–40 observed in tissue (P < in cortical tissue (P < 0.01). the of the levels of to Aβ1–42 in the hippocampus animals Aβ1–42 was found at the of at the of Aβ1–42 than 6 Aβ1–40 and Aβ1–42 in the hippocampus had to and Aβ1–42 levels in the changes in Aβ brain injury in PDAPP Aβ1–40 and Aβ1–42 levels in from and brain-injured wild-type mice the of at no injury Aβ levels in the wild-type the PDAPP mice, the levels of Aβ1–40 and Aβ1–42 in the hippocampus at the found in the with the Aβ1–42 at levels similar to in PDAPP mice at 4 months T T T in transgenic mice β-amyloid precursor precursor protein and in a transgenic model of of Aβ1–40 and Aβ1–42 found in the and in the PDAPP trauma in PDAPP mice, a sevenfold increase in the of Aβ1–42 and threefold increase in Aβ1–40 observed in tissue (P < in cortical tissue (P < 0.01). the of the levels of to Aβ1–42 in the hippocampus animals Aβ1–42 was found at the of at the of Aβ1–42 than 6 Aβ1–40 and Aβ1–42 in the hippocampus had to and Aβ1–42 levels in the changes in Aβ brain injury in PDAPP that brain trauma in PDAPP mice neuron death selectively in the the of has been observed the levels of brain trauma in wild-type model of cortical impact in the and acute and in Aβ levels found selectively in the of PDAPP animals brain posttraumatic in Aβ brain trauma Aβ plaque formation months injury in PDAPP this found that PDAPP mice memory dysfunction before the appearance of with transgenic memory Aβ and amyloid plaques in transgenic and in mice the of the amyloid precursor Although to an exacerbation of posttraumatic memory dysfunction in the PDAPP mice compared to wild-type the of this to the in the noninjured PDAPP acute posttraumatic increase of Aβ1–42 in the PDAPP mice levels similar to found in noninjured PDAPP mice substantial Aβ is observed the T T T in transgenic mice β-amyloid precursor precursor protein and in a transgenic model of the levels of Aβ in the brain-injured PDAPP mice with plaque formation with neuron neuron death has been in the of brain injury in this of transgenic mice that overexpress mutant β-amyloid precursor and of amyloid plaques with transgenic mice Aβ and no in Aβ is with with in the PDAPP transgenic no of neuron death has been Aβ in of in of of with of β-amyloid protein in suggest that in Aβ a Aβ to neuron of this a to brain in of transgenic mice mutant to brain in transgenic mice the amyloid precursor Although was no in Aβ levels between and at levels of Aβ in the brains of transgenic a for AD Aβ is to neuron death a Aβ an acute and posttraumatic increase in the of Aβ1–40 and Aβ1–42 Aβ peptides in the posttraumatic suggest a mechanistic link in the of brain trauma and AD that brain trauma with a risk factor for brain in the acute of traumatic injury and in with Alzheimer's is with of amyloid a suggest that the of brain trauma in AD in the model These that brain trauma in PDAPP mice neuron death selectively in the the of has been observed the levels of brain trauma in wild-type model of cortical impact in the and acute and in Aβ levels found selectively in the of PDAPP animals brain posttraumatic in Aβ brain trauma Aβ plaque formation months injury in PDAPP this found that PDAPP mice memory dysfunction before the appearance of with transgenic memory Aβ and amyloid plaques in transgenic and in mice the of the amyloid precursor Although to an exacerbation of posttraumatic memory dysfunction in the PDAPP mice compared to wild-type the of this to the in the noninjured PDAPP acute posttraumatic increase of Aβ1–42 in the PDAPP mice levels similar to found in noninjured PDAPP mice substantial Aβ is observed the T T T in transgenic mice β-amyloid precursor precursor protein and in a transgenic model of the levels of Aβ in the brain-injured PDAPP mice with plaque formation with neuron neuron death has been in the of brain injury in this of transgenic mice that overexpress mutant β-amyloid precursor and of amyloid plaques with transgenic mice Aβ and no in Aβ is with with in the PDAPP transgenic no of neuron death has been Aβ in of in of of with of β-amyloid protein in suggest that in Aβ a Aβ to neuron of this a to brain in of transgenic mice mutant to brain in transgenic mice the amyloid precursor Although was no in Aβ levels between and at levels of Aβ in the brains of transgenic a for AD Aβ is to neuron death a Aβ an acute and posttraumatic increase in the of Aβ1–40 and Aβ1–42 Aβ peptides in the posttraumatic suggest a mechanistic link in the of brain trauma and AD that brain trauma with a risk factor for brain in the acute of traumatic injury and in with Alzheimer's is with of amyloid a suggest that the of brain trauma in AD in the model We for for the of this and for and in the of and and to the in for the and of of and