LRP/LR specific antibody IgG1-iS18 impedes neurodegeneration in Alzheimer's disease mice

Ferreira, Eloise; Bignoux, Monique J; Otgaar, Tyrone C; Tagliatti, Nicolas; Jovanović, Katarina; Letsolo, Boitelo T.; Weiß, Stefan

doi:10.18632/oncotarget.25473

Cited by 7 publications

(5 citation statements)

References 53 publications

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“…As the pursuit of chemical compounds has been resulting in limited success, while two of the approved drugs for AD are naturally derived, extensive research efforts are now being directed toward the investigation of natural compounds (Howes and Perry, 2011). Recently, the intranasal application of an antibody in mice led to the reduction of beta-amyloid (Aβ) accumulation induced cytotoxicity (Ferreira et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

The Crocus sativus Compounds trans-Crocin 4 and trans-Crocetin Modulate the Amyloidogenic Pathway and Tau Misprocessing in Alzheimer Disease Neuronal Cell Culture Models

et al. 2019

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Crocus sativus L. natural compounds have been extensively used in traditional medicine for thousands of years. Recent research evidence is now emerging in support of its therapeutic potential for different pathologies including neurodegenerative diseases. Herein, the C. sativus L. natural compounds trans -crocin 4 and trans -crocetin were selected for in depth molecular characterization of their potentially protective effects against Alzheimer’s Disease (AD), utilizing two AD neuronal cell culture models (SH-SY5Y overexpressing APP and PC12 expressing hyperphosphorylated tau). Biologically relevant concentrations, ranging from 0.1 μM to 1 mM, applied for 24 h or 72 h, were well tolerated by differentiated wild type SH-SY5Y and PC12 cells. When tested on neuronally differentiated SH-SY5Y-APP both trans -crocin 4 and trans -crocetin had significant effects against amyloidogenic pathways. Trans -crocin 4 significantly decreased of β-secretase, a key enzyme of the amyloidogenic pathway, and APP-C99, while it decreased γ-secretases that generate toxic beta-amyloid peptides. Similarly, trans -crocetin treatment led to a reduction in β- and γ-secretases, as well as to accumulation of cellular AβPP. When tested on the neuronally differentiated PC12-htau cells, both compounds proved effective in suppressing the active forms of GSK3β and ERK1/2 kinases, as well as significantly reducing total tau and tau phosphorylation. Collectively, our data demonstrate a potent effect of trans -crocin 4 and trans -crocetin in suppressing key molecular pathways of AD pathogenesis, rendering them a promising tool in the prevention and potentially the treatment of AD.

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Section: Introductionmentioning

confidence: 99%

The Crocus sativus Compounds trans-Crocin 4 and trans-Crocetin Modulate the Amyloidogenic Pathway and Tau Misprocessing in Alzheimer Disease Neuronal Cell Culture Models

et al. 2019

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“…Furthermore, it was found that the IgG1-iS18 antibody-mediated rescuing of cells from cytotoxicity is dependent on PrP c due to the interaction between PrP c and Aβ42 [41]. Recently, an in vivo study, whereby B6SJL-Tg6799 AD transgenic mice were injected with the IgG1-iS18 antibody, confirmed the in vitro findings whereby a decrease in amyloid plaque formation and Aβ42 levels with a concomitant increase in both shortterm and learning memory was observed [42].…”

Section: Introductionmentioning

confidence: 69%

“…Recently, Otgaar et al, [36] found that an overexpression of LRP::FLAG increased both hTERT levels and telomerase activity with a concomitant reduction in senescent markers. Furthermore, Ferreira et al, [42] observed an increase in mTERT in mice treated with the anti-LRP/LR specific antibody, IgG1-iS18 with a concomitant decrease in Aβ peptides and amyloid plaques. In addition, an increase in telomerase activity and hTERT expression was observed with a concomitant reduction in Aβ shedding and intracellular Aβ levels in cells overexpressing LRP::FLAG [58].…”

Section: Introductionmentioning

confidence: 96%

LRP::FLAG reduces phosphorylated tau levels in Alzheimer’s Disease

Cuttler

Bignoux

Otgaar

et al. 2020

Preprint

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Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) plaque and neurofibrillary tangle formation, respectively. Neurofibrillary tangles form as a result of the intracellular accumulation of hyperphosphorylated tau. Telomerase activity and levels of the human reverse transcriptase (hTERT) subunit of telomerase are significantly decreased in AD. Recently it has been demonstrated that the 37kDa/67kDa laminin receptor (LRP/LR) interacts with telomerase and is implicated in Aβ pathology. Here we show that LRP/LR co-localizes with tau in the perinuclear cell compartment and FRET confirmed a direct interaction between LRP/LR and tau in HEK-293 cells. Overexpression of LRP::FLAG in HEK-293 and SH-SY5Y cells decreased total and phosphorylated tau levels with a concomitant decrease in PrP c levels, a tauopathy-related protein. Additionally, LRP::FLAG overexpression resulted in increased hTERT levels. These data indicate for the first time a role of LRP/LR in tauopathy of Alzheimer's Disease and recommend LRP::FLAG as a potential alternative therapeutic tool for Alzheimer's Disease treatment through rescuing cells from A induced cytotoxicity and, as shown in this report, decreased phosphorylated tau levels.

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“…LRP/LR also directly interacts with pTau (Cuttler et al, 2020) and modulates Aβ toxicity (Bignoux et al, 2019). An intranasally administered antibody targeted to LRP/LR decreases Aβ plaques and improves memory performances in 5XFAD AD model mouse (Ferreira et al, 2018).…”

Section: Molecular Control Of Oaβ42-dependent Modulation Of Memorymentioning

confidence: 99%

Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

Murphy¹

2021

Preprint

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Alzheimer’s Disease is defined as progressive memory loss coincident with accumulation of aggregated amyloid beta and phosphorylated tau. Identifying the relationship between these features has guided Alzheimer’s Disease research for decades, principally with the view that aggregated proteins drive a neurodegenerative process. Here I propose that amyloid beta and phospho-tau write-protect and tag neuroplastic changes as they form, protecting and insuring established neuroplasticity from corruption. In way of illustration, binding of oligomeric amyloid beta to the prion receptor is presented as an example possible mechanism. The write-protecting process is conjected to occur at least partially under the governance of isodendritic neuromodulators such as norepinephrine and acetylcholine. Coincident with aging, animals are exposed to accumulating amounts of memorable information. Compounded with recent increases in life expectancy and exposure to information-rich environments this causes aggregating proteins to reach unforeseen toxic levels as mnemonic circuits overload. As the brain cannot purposefully delete memories nor protect against overaccumulation of aggregating proteins, the result is catastrophic breakdown on cellular and network levels causing memory loss.

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LRP/LR specific antibody IgG1-iS18 impedes neurodegeneration in Alzheimer's disease mice

Cited by 7 publications

References 53 publications

The Crocus sativus Compounds trans-Crocin 4 and trans-Crocetin Modulate the Amyloidogenic Pathway and Tau Misprocessing in Alzheimer Disease Neuronal Cell Culture Models

The Crocus sativus Compounds trans-Crocin 4 and trans-Crocetin Modulate the Amyloidogenic Pathway and Tau Misprocessing in Alzheimer Disease Neuronal Cell Culture Models

LRP::FLAG reduces phosphorylated tau levels in Alzheimer’s Disease

Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

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