Reactive microglia specifically associated with amyloid plaques in Alzheimer's disease brain tissue express melanotransferrin

Jefferies, Wilfred A.; Food, Michael R.; Gabathuler, Reinhard; Rothenberger, Sylvia; Yamada, Tatsuo; Yasuhara, Osamu; McGeer, Patrick L.

doi:10.1016/0006-8993(95)01407-1

Cited by 127 publications

(58 citation statements)

References 27 publications

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“…Previous reports indicate that the neurofibrillary lesions and amyloid plaques that are diagnostic of AD and that are associated with elevated p97 concentrations in brain tissue (Jefferies et al 1996a) commence in the medial temporal lobe long before clinical symptoms appear (Nagy et al 1999;Delacourte et al 1999). This finding makes elevation of serum p97 concentration early in the clinical course of AD more understandable.…”

Section: Discussionmentioning

confidence: 98%

“…Another recently proposed marker is a novel molecule for iron uptake, melanotransferrin, also known as p97, that is expressed in capillary endothelium and in microglia associated with amyloid plaques in AD brain tissue (Jefferies et al 1996a). The investigators who reported this pathological finding also conducted a limited clinical study of 17 patients with AD and 15 normal control subjects.…”

mentioning

confidence: 99%

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Serum Melanotransferrin, p97 as a Biochemical Marker of Alzheimer's Disease

Kim¹,

Seo²,

Lim

et al. 2001

Neuropsychopharmacology

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Serum Melanotransferrin, p97 as a Biochemical Marker of Alzheimer's Disease

Kim¹,

Seo²,

Lim

et al. 2001

Neuropsychopharmacology

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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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“…Our results therefore suggest that P97 crosses the BBB at least as well as OX-26. Another advantage of using P97 is its very low concentration in the serum (100 000-fold lower than transferrin; Jefferies et al 1996;Kim et al 2001), which suggests that it could deliver P97-conjugate(s) directly into the CNS. However, as P97 was found to be associated with senile plaques in Alzheimer's disease, a better understanding of the physiological roles of P97 in normal and pathological conditions in the future will be helpful to estimate the safety for the utilisation of P97 as a drug vector.…”

Section: Discussionmentioning

confidence: 99%

High transcytosis of melanotransferrin (P97) across the blood–brain barrier

Demeule

Poirier

Jodoin

et al. 2002

Journal of Neurochemistry

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194

125

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The blood-brain barrier (BBB) performs a neuroprotective function by tightly controlling access to the brain; consequently it also impedes access of proteins as well as pharmacological agents to cerebral tissues. We demonstrate here that recombinant human melanotransferrin (P97) is highly accumulated into the mouse brain following intravenous injection and in situ brain perfusion. Moreover, P97 transcytosis across bovine brain capillary endothelial cell (BBCEC) monolayers is at least 14-fold higher than that of holo-transferrin, with no apparent intra-endothelial degradation. This high transcytosis of P97 was not related to changes in the BBCEC monolayer integrity. In addition, the transendothelial transport of P97 was sensitive to temperature and was both concentration-and conformationdependent, suggesting that the transport of P97 is due to receptor-mediated endocytosis. In spite of the high degree of sequence identity between P97 and transferrin, a different receptor than the one for transferrin is involved in P97 transendothelial transport. A member of the low-density lipoprotein receptor protein family, likely LRP, seems to be involved in P97 transendothelial transport. The brain accumulation, high rate of P97 transcytosis and its very low level in the blood suggest that P97 could be advantageously employed as a new delivery system to target drugs directly to the brain.

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Reactive microglia specifically associated with amyloid plaques in Alzheimer's disease brain tissue express melanotransferrin

Cited by 127 publications

References 27 publications

Serum Melanotransferrin, p97 as a Biochemical Marker of Alzheimer's Disease

Serum Melanotransferrin, p97 as a Biochemical Marker of Alzheimer's Disease

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

High transcytosis of melanotransferrin (P97) across the blood–brain barrier

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