Structural and mechanistic commonalities of amyloid-β and the prion protein

Dias, Bianca Da Costa; Jovanović, Katarina; Gonsalves, Danielle; Weiß, Stefan

doi:10.4161/pri.5.3.17025

Cited by 24 publications

(15 citation statements)

References 113 publications

(141 reference statements)

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“…However, co-localization has a resolution limit of 200 nm and therefore positive results may not necessarily be indicative of an association, but may simply demonstrate that proteins share similar cellular locations. This would be expected as Aβ has been reported to insert into the lipid raft region of the plasma membrane, the region to which LRP/LR is localized31. Therefore, in order to probe the potential of such an interaction existing under normal cellular conditions, Försters resonance energy transfer (FRET) was employed.…”

Section: Discussionmentioning

confidence: 99%

The 37kDa/67kDa Laminin Receptor acts as a receptor for Aβ42 internalization

Dias

Jovanović

Gonsalves

et al. 2014

Sci Rep

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Neuronal loss is a major neuropathological hallmark of Alzheimer's disease (AD). The associations between soluble Aβ oligomers and cellular components cause this neurotoxicity. The 37 kDa/67 kDa laminin receptor (LRP/LR) has recently been implicated in Aβ pathogenesis. In this study the mechanism underlying the pathological role of LRP/LR was elucidated. Försters Resonance Energy Transfer (FRET) revealed that LRP/LR and Aβ form a biologically relevant interaction. The ability of LRP/LR to form stable associations with endogenously shed Aβ was confirmed by pull down assays and Aβ-ELISAs. Antibody blockade of this association significantly lowered Aβ42 induced apoptosis. Furthermore, antibody blockade and shRNA mediated downregulation of LRP/LR significantly hampered Aβ42 internalization. These results suggest that LRP/LR is a receptor for Aβ42 internalization, mediating its endocytosis and contributing to the cytotoxicity of the neuropeptide by facilitating intra-cellular Aβ42 accumulation. These findings recommend anti-LRP/LR specific antibodies and shRNAs as potential therapeutic tools for AD treatment.

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Section: Discussionmentioning

confidence: 99%

The 37kDa/67kDa Laminin Receptor acts as a receptor for Aβ42 internalization

Dias

Jovanović

Gonsalves

et al. 2014

Sci Rep

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“…The interaction of PrP C s and p75 NTR induces neuronal apoptosis (Da Costa Dias et al, 2011;Della-Bianca et al, 2001).…”

Section: P75 Ntrmentioning

confidence: 99%

Relationships between cobalamin, epidermal growth factor, and normal prions in the myelin maintenance of central nervous system

Scalabrino

Veber

Tredici

2014

The International Journal of Biochemistry & Cell Biology

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“…The mechanisms underlying Aβ induction of neuronal loss (one of the key pathophysiological features of AD) are yet to be firmly established. However, it is proposed that Aβ may do so by eliciting alterations in signal transduction pathways through direct binding to cell surface receptors, such as N-Methyl-d-Aspartate (NMDA) receptors, insulin receptors or α-7 nicotinic receptors1011. Alternatively, Aβ may alter signal transduction pathways indirectly via incorporation into lipid membranes of the plasma membrane and to a lesser extent cellular organelles1112.…”

mentioning

confidence: 99%

Anti-LRP/LR specific antibodies and shRNAs impede amyloid beta shedding in Alzheimer's disease

Jovanović

Gonsalves

Dias

et al. 2013

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Alzheimer's disease (AD) is the most prevalent form of dementia. The amyloid beta (Aβ) peptide is the predominant candidate aetiological agent and is generated through the sequential proteolytic cleavage of the Amyloid Precursor Protein (APP) by beta (β) and gamma (γ) secretases. Since the cellular prion protein (PrPc) has been shown to regulate Aβ shedding, we investigated whether the cellular receptor for PrPc, namely the 37 kDa/67 kDa Laminin Receptor (LRP/LR) played a role in Aβ shedding. Here we show that LRP/LR co-localises with the AD relevant proteins APP, β- and γ-secretase, respectively. Antibody blockage and shRNA knock-down of LRP/LR reduces Aβ shedding, due to impediment of β-secretase activity, rather than alteration of APP, β- and γ-secretase levels. These findings indicate that LRP/LR contributes to Aβ shedding and recommend anti-LRP/LR specific antibodies and shRNAs as novel therapeutic tools for AD treatment.

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Structural and mechanistic commonalities of amyloid-β and the prion protein

Cited by 24 publications

References 113 publications

The 37kDa/67kDa Laminin Receptor acts as a receptor for Aβ42 internalization

The 37kDa/67kDa Laminin Receptor acts as a receptor for Aβ42 internalization

Relationships between cobalamin, epidermal growth factor, and normal prions in the myelin maintenance of central nervous system

Anti-LRP/LR specific antibodies and shRNAs impede amyloid beta shedding in Alzheimer's disease

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