On 2015 Oct 01, Friedrich Thinnes commented:

Plasmalemmal VDAC-1 discussed as amyloid Aß-receptor

In 2010 I referred to a cell outside located GxxxG motif on the N-terminal helical stretch of plasmalemmal VDAC-1 (voltage dependent anion channel) and to a series of those inside the amyloid Aß peptide. The motifs are known to work as membrane perturbation motifs.

The hint included a first rational on an interaction of the molecules, VDAC-1 suddenly appearing to figure as a receptor of toxic Aß molecules. Another link to Alzheimer´s Dementia research arose from data pointing to amyloid Aß as an apoptotic opener of cell membrane-integrated VDAC-1 and to counteracting polyphenol preparations from several plants. Together, a revised version of the amyloid cascade hypothesis came up (F.P. Thinnes, 2015; www.futhin.de).

Accordingly, Alzheimer's disease – downstream of APP processing – can bee seen as resting on some form of extrinsic induced cell death, this via opening cell membrane-standing VDAC-1 (= receptor) and accumulating over time. The process is boosted by excessive amyloid Aß (= agonist) production via increased processing of the amyloid precursor protein (APP) of weakening cells of critical and redundant brain regions.

Recent data on the slow down of progress of Alzheimer Disease of proven Alzheimer patients in early states by monoclonal anti-amyloid antibodies that neutralize amyloid mono- or oligomers, from my point of view, corroborate plasmalemmal VDAC-1 as a receptor of those (E.R. Siemers et al., 2015)

However, a study presented by Y.H. Liu et al. (2015) reports on three monoclonal antibody preparations elaborated against different epitopes inside the amyloid Aß peptide. One of those called 6E10 a) in vitro disaggregates artificial amyloid fibrils and thus increases the number of Aß oligomers while b) injection of co-incubates into the lateral ventricle of 6-month-old C57 mice increased the neurotoxicity in vivo. Anyway, to raise amyloid Aß oligomers increases the risk of their docking to plasmalemmal VDAC-1 finally resulting in the induction of accumulating neuronal cell deaths. From here: To raise amyloid Aß oligomers accelerates AD progress.

The authors call the phenomenon dust-raising. It is tempting to think Alzheimer plaques formation as a salutary form of wipe-the-dust procedure that may even protect from Alzheimer Dementia. In other words: does plaque formation work as a buckler?

References

Thinnes, F.P. (2015) Phosphorylation, nitrosation and plasminogen K3 modulation make VDAC-1 lucid as part of the extrinsic apoptotic pathway-Resulting thesis: Native VDAC-1 indispensible for finalisation of its 3D structure. Biochim Biophys Acta. 1848:1410-1416. doi: 10.1016/j.bbamem.2015.02.031. Epub 2015 Mar 11. Review. PMID: 25771449

Siemers, E. R., Sundella, K. L., Carlson, C., Case, M., Sethuraman, G., Liu-Seifert, H., Dowsett, S. A., Pontecorvo, M. J., Dean, R.A., Demattos, R. (2015) Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer’s disease patients. Alzheimer’s & Dement. Aug 1. pii: S1552-5260(15)02148-2. doi: 10.1016/j.jalz.2015.06.1893. [Epub ahead of print].

Liu, Y. H., Bu, X. L., Liang, C. R., Wang, Y. R., Zhang, T., Jiao, S. S., Zeng, F., Yao, X. Q., Zhou, H. D., Deng, J., Wang, Y. J. (2015) An N-terminal antibody promotes the transformation of amyloid fibrils into oligomers and enhances the neurotoxicity of amyloid-beta: the dust-raising effect. J Neuroinflammation. 12:153. doi: 10.1186/s12974-015-0379-4.

On 2015 Oct 01, Friedrich Thinnes commented:

Plasmalemmal VDAC-1 discussed as amyloid Aß-receptor

In 2010 I referred to a cell outside located GxxxG motif on the N-terminal helical stretch of plasmalemmal VDAC-1 (voltage dependent anion channel) and to a series of those inside the amyloid Aß peptide. The motifs are known to work as membrane perturbation motifs.

The hint included a first rational on an interaction of the molecules, VDAC-1 suddenly appearing to figure as a receptor of toxic Aß molecules. Another link to Alzheimer´s Dementia research arose from data pointing to amyloid Aß as an apoptotic opener of cell membrane-integrated VDAC-1 and to counteracting polyphenol preparations from several plants. Together, a revised version of the amyloid cascade hypothesis came up (F.P. Thinnes, 2015; www.futhin.de).

Accordingly, Alzheimer's disease – downstream of APP processing – can bee seen as resting on some form of extrinsic induced cell death, this via opening cell membrane-standing VDAC-1 (= receptor) and accumulating over time. The process is boosted by excessive amyloid Aß (= agonist) production via increased processing of the amyloid precursor protein (APP) of weakening cells of critical and redundant brain regions.

Recent data on the slow down of progress of Alzheimer Disease of proven Alzheimer patients in early states by monoclonal anti-amyloid antibodies that neutralize amyloid mono- or oligomers, from my point of view, corroborate plasmalemmal VDAC-1 as a receptor of those (E.R. Siemers et al., 2015)

However, a study presented by Y.H. Liu et al. (2015) reports on three monoclonal antibody preparations elaborated against different epitopes inside the amyloid Aß peptide. One of those called 6E10 a) in vitro disaggregates artificial amyloid fibrils and thus increases the number of Aß oligomers while b) injection of co-incubates into the lateral ventricle of 6-month-old C57 mice increased the neurotoxicity in vivo. Anyway, to raise amyloid Aß oligomers increases the risk of their docking to plasmalemmal VDAC-1 finally resulting in the induction of accumulating neuronal cell deaths. From here: To raise amyloid Aß oligomers accelerates AD progress.

The authors call the phenomenon dust-raising. It is tempting to think Alzheimer plaques formation as a salutary form of wipe-the-dust procedure that may even protect from Alzheimer Dementia. In other words: does plaque formation work as a buckler?

References

Thinnes, F.P. (2015) Phosphorylation, nitrosation and plasminogen K3 modulation make VDAC-1 lucid as part of the extrinsic apoptotic pathway-Resulting thesis: Native VDAC-1 indispensible for finalisation of its 3D structure. Biochim Biophys Acta. 1848:1410-1416. doi: 10.1016/j.bbamem.2015.02.031. Epub 2015 Mar 11. Review. PMID: 25771449

Siemers, E. R., Sundella, K. L., Carlson, C., Case, M., Sethuraman, G., Liu-Seifert, H., Dowsett, S. A., Pontecorvo, M. J., Dean, R.A., Demattos, R. (2015) Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer’s disease patients. Alzheimer’s & Dement. Aug 1. pii: S1552-5260(15)02148-2. doi: 10.1016/j.jalz.2015.06.1893. [Epub ahead of print].

Liu, Y. H., Bu, X. L., Liang, C. R., Wang, Y. R., Zhang, T., Jiao, S. S., Zeng, F., Yao, X. Q., Zhou, H. D., Deng, J., Wang, Y. J. (2015) An N-terminal antibody promotes the transformation of amyloid fibrils into oligomers and enhances the neurotoxicity of amyloid-beta: the dust-raising effect. J Neuroinflammation. 12:153. doi: 10.1186/s12974-015-0379-4.