Changes in microtubule-associated protein 2 and amyloid precursor protein immunoreactivity following traumatic brain injury in rat: influence of MK-801 treatment

Lewén, Anders; Li, Gui Lin; Olsson, Yngve; Hillered, Lars

doi:10.1016/0006-8993(96)00081-9

Cited by 85 publications

(47 citation statements)

References 43 publications

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“…In wild-type mice, strong MAP-2 immunoreactivity was detected both in soma and in neuronal processes, whereas in APP + Becn1 +/-mice the immunoreactivity in neuronal processes was disrupted. These markers of synaptodendritic integrity have been used as sensitive, early indicators of neuronal degeneration in AD and various mouse models of the disease (29,(42)(43)(44)(45). A similar decrease in calbindin immunoreactivity, which was previously shown to correlate closely with APP-associated memory deficits in APP mice (46), was also observed in APP + Becn1 +/-mice ( Figure 5E).…”

Section: Beclin 1 Is Reduced In Brains Of Ad Patientssupporting

confidence: 65%

The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid β accumulation in mice

et al. 2008

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Autophagy is the principal cellular pathway for degradation of long-lived proteins and organelles and regulates cell fate in response to stress. Recently, autophagy has been implicated in neurodegeneration, but whether it is detrimental or protective remains unclear. Here we report that beclin 1, a protein with a key role in autophagy, was decreased in affected brain regions of patients with Alzheimer disease (AD) early in the disease process. Heterozygous deletion of beclin 1 (Becn1) in mice decreased neuronal autophagy and resulted in neurodegeneration and disruption of lysosomes. In transgenic mice that express human amyloid precursor protein (APP), a model for AD, genetic reduction of Becn1 expression increased intraneuronal amyloid β (Aβ) accumulation, extracellular Aβ deposition, and neurodegeneration and caused microglial changes and profound neuronal ultrastructural abnormalities. Administration of a lentiviral vector expressing beclin 1 reduced both intracellular and extracellular amyloid pathology in APP transgenic mice. We conclude that beclin 1 deficiency disrupts neuronal autophagy, modulates APP metabolism, and promotes neurodegeneration in mice and that increasing beclin 1 levels may have therapeutic potential in AD. IntroductionFamilial Alzheimer disease (AD) mutations increase the toxicity and amyloidogenicity of the amyloid β (Aβ) peptide, placing disruption of amyloid precursor protein (APP) metabolism and Aβ production at the center of AD pathogenesis (1). However, less than 2% of AD cases are caused by autosomal-dominant mutations. Familial AD caused by these mutations and the remaining nondominant sporadic AD cases are pathologically similar. Therefore, factors that disrupt APP metabolism and Aβ production, such as increased APP transcription, increased production of amyloidogenic Aβ (2), and decreased APP degradation, may contribute to the pathogenesis of sporadic AD as well.The etiology of AD is distinct from that of other neurodegenerative diseases, such as Parkinson disease and Huntington disease (HD), but all are characterized pathologically by the presence of abnormal protein aggregates and neuronal death (3, 4). Protein aggregates may form by abnormal folding or proteolytic processing of proteins or by the disturbance of intracellular protein degradation pathways (3,5). Autophagy is involved in the intracellular degradation of aggregation-prone α-synuclein (6) and huntingtin

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Section: Beclin 1 Is Reduced In Brains Of Ad Patientssupporting

confidence: 65%

The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid β accumulation in mice

et al. 2008

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“…Authors of other studies, however, have pointed out that trauma-induced neurodegeneration seems to be an ongoing process, revealed by an increase in cortical damage over time 10,12,85 and axonal damage occurring for weeks. 10,51,75 To assess more slowly developing histological alterations, a time point 8 weeks postinjury was also chosen. At either time point, the animals (seven-nine/time point/group) were given an overdose of anesthetic agent (sodium pentobarbital, 200 mg/kg) and were perfused intracardially with heparinized saline followed by 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4).…”

Section: Motor Functionmentioning

confidence: 99%

“…Because changes in immunoreactivity for MAP-2 are considered a sensitive indicator for cytoskeletal damage following TBI, 20,51,82 sections adjacent to those used for A-␤ and tau were deparaffinized and immunostained with anti-MAP-2 (concentration 1:1000) following a protocol recently established. 82 Staining for Tau.…”

Section: Acute Neurodegenerative Changesmentioning

confidence: 99%

Mild head injury increasing the brain's vulnerability to a second concussive impact

Laurer¹,

Bareyre²,

Lee³

et al. 2001

Journal of Neurosurgery

293

234

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Object. Mild, traumatic repetitive head injury (RHI) leads to neurobehavioral impairment and is associated with the early onset of neurodegenerative disease. The authors developed an animal model to investigate the behavioral and pathological changes associated with RHI. Methods. Adult male C57BL/6 mice were subjected to a single injury (43 mice), repetitive injury (two injuries 24 hours apart; 49 mice), or no impact (36 mice). Cognitive function was assessed using the Morris water maze test, and neurological motor function was evaluated using a battery of neuroscore, rotarod, and rotating pole tests. The animals were also evaluated for cardiovascular changes, blood—brain barrier (BBB) breakdown, traumatic axonal injury, and neurodegenerative and histopathological changes between 1 day and 56 days after brain trauma. No cognitive dysfunction was detected in any group. The single-impact group showed mild impairment according to the neuroscore test at only 3 days postinjury, whereas RHI caused pronounced deficits at 3 days and 7 days following the second injury. Moreover, RHI led to functional impairment during the rotarod and rotating pole tests that was not observed in any animal after a single impact. Small areas of cortical BBB breakdown and axonal injury, observed after a single brain injury, were profoundly exacerbated after RHI. Immunohistochemical staining for microtubule-associated protein—2 revealed marked regional loss of immunoreactivity only in animals subjected to RHI. No deposits of β-amyloid or tau were observed in any brain-injured animal. Conclusions. On the basis of their results, the authors suggest that the brain has an increased vulnerability to a second traumatic insult for at least 24 hours following an initial episode of mild brain trauma.

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“…At moderate and high injury severity, contralateral damage in these regions [38,73] as well as axonal injury in the adjacent white matter, corpus callosum, and internal capsule, especially with central trephination have been described [43,80]. However, these results have been contested with the use of sensitive immunohistochemical techniques that observed axonal changes after mild rigid indentation over the parietal cortex [81].…”

Section: B Rigid Indentation Injurymentioning

confidence: 76%

Models of Traumatic Brain Injury

Laurer

Lenzlinger

McIntosh

2000

European Journal of Trauma

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We present a review of the currently popular preclinical models of non-penetrating traumatic brain injury (TBI). This article focuses on animal models that cause TBI by applying mechanical energy to the head, skull or dura. It attempts to provide a compendium of the main characteristics of each of these experimental models of TBI in respect to acute and chronic histological findings and behavioral impairment in neurologic motor and cognitive function. Finally, several limitations of the described models are discussed briefly.

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Changes in microtubule-associated protein 2 and amyloid precursor protein immunoreactivity following traumatic brain injury in rat: influence of MK-801 treatment

Cited by 85 publications

References 43 publications

The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid β accumulation in mice

The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid β accumulation in mice

Mild head injury increasing the brain's vulnerability to a second concussive impact

Models of Traumatic Brain Injury

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