The iron-binding protein lactotransferrin is present in pathologic lesions in a variety of neurodegenerative disorders: a comparative immunohistochemical analysis

Leveugle, Béatrice; Spik, Geneviève; Perl, Daniel P.; Bouras, Constantin; Fillit, Howard; Hof, Patrick R.

doi:10.1016/0006-8993(94)90202-x

Cited by 124 publications

(78 citation statements)

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“…11,12,[27][28][29][30] In vivo transport across the BBB of these proteins may also help explain the observations that MTf, lactoferrin and LRP accumulate in the brain of patients with neurological diseases such as Alzheimer's disease. [31][32][33][34] Interestingly, LRP-mediated transcytosis may only be a feature of endothelial cells, as in other cell types or organs, majority of these proteins, once internalized, are found to be degraded or recycled. [35][36][37] Differentiation stage of endothelial cells also appears to play a role in determining what pathway the protein uptake is taken.…”

Section: Discussionmentioning

confidence: 99%

Directing adenovirus across the blood–brain barrier via melanotransferrin (P97) transcytosis pathway in an in vitro model

et al. 2006

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Adenovirus serotype 5 (Ad5) is widely used in the development of gene therapy protocols. However, current gene therapy strategies involving brain are mostly based on intracranial injection. A major obstacle for systemically administered vectors to infect brain tissue is the blood-brain barrier (BBB). One strategy to cross the BBB is transcytosis, a transcellular transport process that shuttles a molecule from one side of the cell to the other side. Recently, melanotransferrin (MTf)/P97 was found to be able to cross the BBB and accumulate in brain. We thus hypothesize that re-directing Ad5 vectors to the MTf transcytosis pathway may facilitate Ad5 vectors to cross the BBB. To test this hypothesis, we constructed a bi-specific adaptor protein containing the extracellular domain of the coxsackie-adenovirus receptor (CAR) and the full-length melanotransferrin (sCAR-MTf), and investigated its ability to re-direct Ad5 vectors to the MTf transcytosis pathway. We found this adaptor protein could redirect Ad5 to the MTf transcytosis pathway in an in vitro BBB model, and the transcytosed Ad5 viral particles retained their native infectivity. The sCAR-MTf-mediated Ad5 transcytosis was temperature-and dose dependent. In addition, we examined the directionality of sCAR-MTf-mediated Ad5 transcytosis, and found the efficiency of apical-to-basal transcytosis was much higher than that of basal-to-apical direction, supporting a role of this strategy in transporting Ad5 vectors towards the brain. Taken together, our study demonstrated that re-directing Ad5 to the MTf transcytosis pathway could facilitate gene delivery across the BBB.

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Section: Discussionmentioning

confidence: 99%

Directing adenovirus across the blood–brain barrier via melanotransferrin (P97) transcytosis pathway in an in vitro model

et al. 2006

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“…Increased levels of iron were reported in the spinal cord from ALS subjects (206) and may possibly correlate with increased levels of oxidative damage through the induction of Fenton chemistry. Fe accumulation may be due to its increased uptake by its specific transporter, lactoferrin, which is reportedly increased in ALS-affected motor neurons (246). Increased Fe deposition conceivably could be due to increased levels of ferritin, as this iron-binding protein was found in SOD1-G93A mice just before end-stage disease.…”

Section: Fe Homeostasis In Alsmentioning

confidence: 99%

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Butterfield

Perluigi

Reed

et al. 2012

Antioxidants & Redox Signaling

157

142

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Several studies demonstrated that oxidative damage is a characteristic feature of many neurodegenerative diseases. The accumulation of oxidatively modified proteins may disrupt cellular functions by affecting protein expression, protein turnover, cell signaling, and induction of apoptosis and necrosis, suggesting that protein oxidation could have both physiological and pathological significance. For nearly two decades, our laboratory focused particular attention on studying oxidative damage of proteins and how their chemical modifications induced by reactive oxygen species/reactive nitrogen species correlate with pathology, biochemical alterations, and clinical presentations of Alzheimer's disease. This comprehensive article outlines basic knowledge of oxidative modification of proteins and lipids, followed by the principles of redox proteomics analysis, which also involve recent advances of mass spectrometry technology, and its application to selected age-related neurodegenerative diseases. Redox proteomics results obtained in different diseases and animal models thereof may provide new insights into the main mechanisms involved in the pathogenesis and progression of oxidativestress-related neurodegenerative disorders. Redox proteomics can be considered a multifaceted approach that has the potential to provide insights into the molecular mechanisms of a disease, to find disease markers, as well as to identify potential targets for drug therapy. Considering the importance of a better understanding of the cause/effect of protein dysfunction in the pathogenesis and progression of neurodegenerative disorders, this article provides an overview of the intrinsic power of the redox proteomics approach together with the most significant results obtained by our laboratory and others during almost 10 years of research on neurodegenerative disorders since we initiated the field of redox proteomics. Antioxid. Redox Signal. 17, 1610-1655.

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“…Since a link between amyloid deposits and iron accumulation has been described (9,13,22), visualization of ironloaded amyloid deposits in the brain (23,24,25,26,27) definitely provides a potential basis for the in vivo detection of amyloid deposits using intrinsic MRI contrast parameters. It must be stressed that although the number of plaques will be underestimated our data showed that the method never yielded false-positive results.…”

Section: Iron and Amyloidmentioning

confidence: 99%

Noninvasive in vivo MRI detection of neuritic plaques associated with iron in APP[V717I] transgenic mice, a model for Alzheimer's disease

Vanhoutte¹,

Dewachter

Borghgraef

et al. 2005

Magnetic Resonance in Med

127

109

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Alzheimer's disease (AD) is characterized by a progressive decline of cognitive function, while the neuropathologic features include the occurrence of neurofibrillary tangles, neuritic plaques, decreased synaptic density, and loss of neurons. Neuritic plaques consist of extracellular ␤-amyloid (A␤) deposits surrounded by dystrophic neuritis (1). The plaques are neurotoxic and induce inflammatory responses. According to the amyloid cascade hypothesis, the increased amyloid deposition results in the onset and progression of AD (2,3,4,5) and therefore amyloid plaques became crucial as a target for many therapeutic approaches (6,7).Despite the impact of in vivo imaging techniques in daily clinical practice and also in neuroscience, typical Alzheimer plaques were never visualized in vivo in patients. To diagnose AD and to differentiate from other dementias, the detection of at least one typical hallmark, i.e., amyloid plaques or neurofibrillary tangles, appears essential. To date, accumulations of amyloid in AD patients have been observed only postmortem. Recently, however, significant progress has been made visualizing AD plaques using transgenic mouse models for AD. Skovronsky et al. (8) reported in vivo labeling of amyloid plaques in transgenic mice using a radiolabeled ligand but detection was still performed postmortem with fluorescence microscopy. Another attempt to demonstrate plaques postmortem used MRI and was based on injection of a specific derivative of the amyloid peptide with a high molecular specificity for amyloid as a label, i.e., putrescine-gadolinium-A␤ (9). Finally, Wadghiri et al. (10) used systemic injection of monocrystalline iron oxide nanoparticles or gadolinium (Gd) labeled A␤ 1-40 peptide with a high affinity for A␤ and were able to detect ex vivo but also in vivo amyloid plaques in the affected mouse brains. In this approach, the main obstacle for amyloid labeling remains the blood brain barrier and its transient opening using mannitol must be considered quite invasive. Another drawback may be the authentication of amyloid plaques and the exclusion of the involvement of blood vessels embedded with contrast agent, which requires subsequent histology of the brain.The first MRI study that demonstrated amyloid plaques without any exogenous labeling was performed by Benveniste et al. in 1999 (11). Three dimensional T 2 * images of postmortem human AD brain samples, acquired in more than 2.7 hr, revealed dark spots in the brain correlating with histologic amyloid staining. Recently, using T 2 MR contrast, identification of plaque-like structures in the cortex and hippocampus of fixed mouse brain was reported by Zhang et al. (12). However, the authors did not explain the source of the MR contrast in relation to the physiologic processes related with plaque formation and the evidence was only confirmed by the subsequent co registration of plaques by histology. Analogous to this finding, Helpern et al. (13) demonstrated a reduced T 2 value in the cortex and hippocampus in vivo in an AD mouse model,...

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The iron-binding protein lactotransferrin is present in pathologic lesions in a variety of neurodegenerative disorders: a comparative immunohistochemical analysis

Cited by 124 publications

References 50 publications

Directing adenovirus across the blood–brain barrier via melanotransferrin (P97) transcytosis pathway in an in vitro model

Directing adenovirus across the blood–brain barrier via melanotransferrin (P97) transcytosis pathway in an in vitro model

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Noninvasive in vivo MRI detection of neuritic plaques associated with iron in APP[V717I] transgenic mice, a model for Alzheimer's disease

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