Traumatic brain injury in young, amyloid‐β peptide overexpressing transgenic mice induces marked ipsilateral hippocampal atrophy and diminished Aβ deposition during aging

Nakagawa, Yasushi; Nakamura, Michio; McIntosh, Tracy K.; Rodriguez, Amaris; Berlin, Jesse A.; Smith, Douglas H.; Saatman, Kathryn E.; Raghupathi, Ramesh; Clemens, James A.; Saido, Takaomi C.; Schmidt, Maria Luiza Gava; Lee, V. M.-Y.; Trojanowski, John Q.

doi:10.1002/(sici)1096-9861(19990830)411:3<390::aid-cne3>3.0.co;2-#

Cited by 88 publications

(67 citation statements)

References 61 publications

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“…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. A␤ deposition after repetitive brain injury using different APP TG mice (Tg2576) and milder cortical impact has also been reported (Uryu et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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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%

“…In most animals, the inferior blade of the CA3 hippocampal field exhibited a focal lesion ipsilateral to the injury, also noted in rodent models of TBI (Nakagawa et al, 1999). CA3 neuronal counts were obtained using DAPI-stained sections through the entire extent of the hippocampus.…”

Section: Methodsmentioning

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 brains were fixed in 70% ethanol in 150 mmol/L NaCl, pH 7.4, or in 10% neutral buffered formalin and processed for IHC analyses using n847 and a panel of antibodies to other neurodegeneration-related proteins (see Table 2 for details on this antibody panel) as described previously. 35,36 The antibody-probed slides were developed with avidin-biotin complex (ABC) method (Vectastain ABC Kit, Vector Laboratories, Burlingame, CA) using positive and negative controls as described. 35,36 Semiquantitative analysis of n847-IR CA1 neurons was conducted by examining eight photographs of the CA1 region of each section from each case using 20X lens and a Nikon-FXA microscope.…”

Section: Immunohistochemical Analysismentioning

confidence: 99%

“…35,36 The antibody-probed slides were developed with avidin-biotin complex (ABC) method (Vectastain ABC Kit, Vector Laboratories, Burlingame, CA) using positive and negative controls as described. 35,36 Semiquantitative analysis of n847-IR CA1 neurons was conducted by examining eight photographs of the CA1 region of each section from each case using 20X lens and a Nikon-FXA microscope. Neurons with different n847 staining patterns were identified, counted, and statistically analyzed using analysis of variance.…”

Section: Immunohistochemical Analysismentioning

confidence: 99%

Nitration of Tau Protein Is Linked to Neurodegeneration in Tauopathies

Horiguchi

Uryu

Giasson

et al. 2003

The American Journal of Pathology

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Oxidative and nitrative injury is implicated in the pathogenesis of Alzheimer's disease (AD) and Down syndrome (DS), but no direct evidence links this type of injury to the formation of neurofibrillary tau lesions. To address this, we generated a monoclonal antibody (mAb), n847, which recognizes nitrated tau and ␣-synuclein. n847 detected nitrated tau in the insoluble fraction of AD, corticobasal degeneration (CBD), and Pick's disease (PiD) brains by Western blots. Immunohistochemistry (IHC) showed that n847 labeled neurons in the hippocampus and neocortex of AD and DS brains. Double-label immunofluorescence with n847 and an anti-tau antibody revealed partial co-localization of tau and n847 positive tangles, while n847 immmunofluorescence and Thioflavin-S double-staining showed that a subset of n847-labeled neurons were Thioflavin-S-positive. In addition, immuno-electron microscopy revealed that taupositive filaments in tangle-bearing neurons were also labeled by n847 and IHC of other tauopathies showed that some of glial and neuronal tau pathologies in CBD, progressive supranuclear palsy, PiD, and frontotemporal dementia with parkinsonism linked to chromosome 17 also were n847-positive. Finally, nitrated and Thioflavin-S-positive tau aggregates were generated in a oligodendrocytic cell line after treatment with peroxynitrite. Taken together, these findings imply that nitrative injury is directly linked to the formation of filamentous tau inclusions. (Am J

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“…A␤ peptides are directly neurotoxic by mechanisms involving oxidative stress, mitochondrial dysfunction, apoptosis, and hyperphosphorylation of tau, a microtubule-associated protein that becomes dysfunctional with hyperphosphorylation, causing thereby neurofibrillary tangle formation and abnormal neuronal functions (Behl et al, 1994;Goodman and Mattson, 1994;Busciglio et al, 1995;Meda et al, 1995;Anderson et al, 1996;London et al, 1996;Estus et al, 1997). A␤ also disturbs normal synaptic functions (Davies and Maloney, 1976;Beach et al, 2000) and increases brain susceptibility to injury (Nakagawa et al, 1999(Nakagawa et al, , 2000Lauderback et al, 2001;Koistinaho et al, 2002). In addition to its direct harmful effect on neurons, aggregated A␤ activates microglia and astrocytes (Akiyama et al, 2000) to secrete proinflammatory molecules, reactive oxygen species, and other neurotoxins, causing indirect neurotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Pyrrolidine Dithiocarbamate Activates Akt and Improves Spatial Learning in APP/PS1 Mice without Affecting β-Amyloid Burden

Malm¹,

Iivonen²,

Goldsteins³

et al. 2007

J. Neurosci.

146

108

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Pyrrolidine dithiocarbamate (PDTC) is a clinically tolerated inhibitor of nuclear factor-B (NF-B), antioxidant and antiinflammatory agent, which provides protection in brain ischemia models. In neonatal hypoxia-ischemia model, PDTC activates Akt and reduces activation of glycogen synthase kinase 3␤ (GSK-3␤). Because chronic inflammation, oxidative stress, and increased GSK-3␤ activity are features of Alzheimer's disease (AD) pathology, we tested whether PDTC reduces brain pathology and improves cognitive function in a transgenic animal model of AD. A 7 month oral treatment with PDTC prevented the decline in cognition in AD mice without altering ␤-amyloid burden or gliosis. Moreover, marked oxidative stress and activation of NF-B were not part of the brain pathology. Instead, the phosphorylated form of GSK-3␤ was decreased in the AD mouse brain, and PDTC treatment increased the phosphorylation of Akt and GSK-3␤. Also, PDTC treatment increased the copper concentration in the brain. In addition, PDTC rescued cultured hippocampal neurons from the toxicity of oligomeric A␤ and reduced tau phosphorylation in the hippocampus of AD mice. Finally, astrocytic glutamate transporter GLT-1, known to be regulated by Akt pathway, was decreased in the transgenic AD mice but upregulated back to the wild-type levels by PDTC treatment. Thus, PDTC may improve spatial learning in AD by interfering with Akt-GSK pathway both in neurons and astrocytes. Because PDTC is capable of transferring external Cu 2ϩ into a cell, and, in turn, Cu 2ϩ is able to activate Akt, we hypothesize that PDTC provides the beneficial effect in transgenic AD mice through Cu 2ϩ -activated Akt pathway.

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Traumatic brain injury in young, amyloid‐β peptide overexpressing transgenic mice induces marked ipsilateral hippocampal atrophy and diminished Aβ deposition during aging

Cited by 88 publications

References 61 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

Nitration of Tau Protein Is Linked to Neurodegeneration in Tauopathies

Pyrrolidine Dithiocarbamate Activates Akt and Improves Spatial Learning in APP/PS1 Mice without Affecting β-Amyloid Burden

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