Accumulation of β-amyloid precursor protein and ubiquitin in axons after spinal cord trauma in humans: immunohistochemical observations on autopsy material

Ahlgren, Sara; Li, G. L.; Olsson, Yngve

doi:10.1007/s004010050488

Cited by 62 publications

(26 citation statements)

References 34 publications

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“…Secondary injury mechanisms include inflammation and reactive astrogliosis and microglial activation, which are involved in scar formation and impaired regeneration (Lu et al, 2000). Among the biochemical changes are increases in APP, its secretases, and Aβ shown in this and other studies of human and rat tissues (Ahlgren et al, 1996; Choo et al, 2008; Cornish et al, 2000; Kobayashi et al, 2010; Li et al, 1995). …”

Section: Discussionsupporting

confidence: 67%

“…We recently demonstrated that inhibiting the activity of APP secretases and Aβ is protective in a mouse model of TBI (Loane et al, 2009), suggesting that Aβ may be contributing to secondary injury cascades after TBI. APP is also increased after spinal cord injury (SCI), in both humans and rodents (Ahlgren et al, 1996; Choo et al, 2008; Cornish et al, 2000; Li et al, 1995). A recent study in rats shows that the increase in APP and PS1 is accompanied by an increase in Aβ peptide levels as early as 1 day after spinal cord hemisection.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of amyloid precursor protein secretases reduces recovery after spinal cord injury

et al. 2014

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Amyloid-β (Aβ) is produced through the enzymatic cleavage of amyloid precursor protein (APP) by β (Bace1) and γ -secretases. The accumulation and aggregation of Aβ as amyloid plaques is the hallmark pathology of Alzheimer’s disease and has been found in other neurological disorders, such as traumatic brain injury and multiple sclerosis. Although the role of Aβ after injury is not well understood, several studies have reported a negative correlation between Aβ formation and functional outcome. In this study we show that levels of APP, the enzymes cleaving APP (Bace1 and γ-secretase), and Aβ are significantly increased from 1 to 3 days after impact spinal cord injury (SCI) in mice. To determine the role of Aβ after SCI, we reduced or inhibited Aβ in vivo through pharmacological (using DAPT) or genetic (Bace1 knockout mice) approaches. We found that these interventions significantly impaired functional recovery as evaluated by white matter sparing and behavioral testing. These data are consistent

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Inhibition of amyloid precursor protein secretases reduces recovery after spinal cord injury

et al. 2014

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“…In our study, the YA cohort poses some specific challenges because these individuals died as the result of severe trauma and there was no additional information concerning their post-traumatic clinical course. Therefore, the mean holoAPP molecular levels observed in the YA Pc and PCG regions may represent a response to severe brain concussion as has been reported for acute traumatic brain injury with axonal damage [98]–[101].…”

Section: Discussionmentioning

confidence: 66%

Biochemical Assessment of Precuneus and Posterior Cingulate Gyrus in the Context of Brain Aging and Alzheimer’s Disease

et al. 2014

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Defining the biochemical alterations that occur in the brain during “normal” aging is an important part of understanding the pathophysiology of neurodegenerative diseases and of distinguishing pathological conditions from aging-associated changes. Three groups were selected based on age and on having no evidence of neurological or significant neurodegenerative disease: 1) young adult individuals, average age 26 years (n = 9); 2) middle-aged subjects, average age 59 years (n = 5); 3) oldest-old individuals, average age 93 years (n = 6). Using ELISA and Western blotting methods, we quantified and compared the levels of several key molecules associated with neurodegenerative disease in the precuneus and posterior cingulate gyrus, two brain regions known to exhibit early imaging alterations during the course of Alzheimer’s disease. Our experiments revealed that the bioindicators of emerging brain pathology remained steady or decreased with advancing age. One exception was S100B, which significantly increased with age. Along the process of aging, neurofibrillary tangle deposition increased, even in the absence of amyloid deposition, suggesting the presence of amyloid plaques is not obligatory for their development and that limited tangle density is a part of normal aging. Our study complements a previous assessment of neuropathology in oldest-old subjects, and within the limitations of the small number of individuals involved in the present investigation, it adds valuable information to the molecular and structural heterogeneity observed along the course of aging and dementia. This work underscores the need to examine through direct observation how the processes of amyloid deposition unfold or change prior to the earliest phases of dementia emergence.

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“…47 Spinal cord injury induces accumulation of β-amyloid precursor protein and β-amyloid peptide in the injured spinal cord, which is associated with the neurodegenerative processes of aging motor neuron. 47,48 Reactive oxygen species (ROS) that can induce DNA damage and accelerate cellular senescence are upregulated in the damaged neural tissue after SCI. [49][50][51][52] Recent studies revealed that an inhibition of mTOR decelerates cellular senescence and increases the lifespan in diverse organisms.…”

Section: Suppression Of Cellular Senescence and Organismalmentioning

confidence: 99%

The role of mTOR signaling pathway in spinal cord injury

et al. 2012

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T he mammalian target of rapamycin (mTOR) signaling pathway plays an important role in multiple cellular functions, such as cell metabolism, proliferation and survival. Many previous studies have shown that mTOR regulates both neuroprotective and neuroregenerative functions in trauma and various diseases in the central nervous system (CNS). Recently, we reported that inhibition of mTOR using rapamycin reduces neural tissue damage and locomotor impairment after spinal cord injury (SCI) in mice. Our results demonstrated that the administration of rapamycin at four hours after injury significantly increases the activity of autophagy and reduces neuronal loss and cell death in the injured spinal cord. Furthermore, rapamycintreated mice show significantly better locomotor function in the hindlimbs following SCI than vehicle-treated mice. These findings indicate that the inhibition of mTOR signaling using rapamycin during the acute phase of SCI produces neuroprotective effects and reduces secondary damage at lesion sites. However, the role of mTOR signaling in injured spinal cords has not yet been fully elucidated. Various functions are regulated by mTOR signaling in the CNS, and multiple pathophysiological processes occur following SCI. Here, we discuss several unresolved issues and review the evidence from related articles regarding the role and mechanisms of the mTOR signaling pathway in neuroprotection and neuroregeneration after SCI.

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Accumulation of β-amyloid precursor protein and ubiquitin in axons after spinal cord trauma in humans: immunohistochemical observations on autopsy material

Cited by 62 publications

References 34 publications

Inhibition of amyloid precursor protein secretases reduces recovery after spinal cord injury

Inhibition of amyloid precursor protein secretases reduces recovery after spinal cord injury

Biochemical Assessment of Precuneus and Posterior Cingulate Gyrus in the Context of Brain Aging and Alzheimer’s Disease

The role of mTOR signaling pathway in spinal cord injury

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