On 2015 Aug 12, Friedrich Thinnes commented:

Solanezumab: a therapeutic breakthrough including theoretical gain.

The exciting paper of Siemers et al. [1] on slowing down the progress of Alzheimer´s by Solanezumab antibodies, from my point of view, not only represent a therapeutic breakthrough. The effects observed also broaden the understanding of the pathogenesis of Alzheimer´s Disease, this by pointing to induced neuronal cell death as basic in AD.

Accordingly, I propose plasmalemmal VDAC-1 (Swiss Prot P21796) to work as a receptor of amyloid Aß mono- or oligomers.

In line, it has been shown that docking of those Aß forms to cell surfaces result in an opening of cell membrane-standing VDAC-1, a process finally ending in neuronal cell death.

In consequence, whenever critical brain regions and their redundant structures are affected this way neuronal loss must be expected. In contrary, to capture Aß by adequate mAbs should minimize Aß toxicity, in other words slow down AD progress.

The voltage dependent anion channel (VDAC) is an archaic channel and thus suggested to be involved in housekeeping functions. The channel is well established in the outer mitochondrial membrane, here playing its role in the intrinsic apoptotic pathway. It is thus of proven relevance for Alzheimer´s Dementia [2].

First data on an extra-mitochondrial came up in 1989 by showing that human lymphocytes carry a heavy load of the molecule in their plasmalemma. Those data, meanwhile, found manifold support by several laboratories using different approaches; for review see [3] and www.futhin.de.

After studies focussed on the regulatory volume decrease (RVD) of HeLa or murine respiratory epithelial cells, respectively, had shown that cell membrane-integrated type-1 VDAC is part of the cell volume regulatory system of mammalian cells [4,5] data came up indicating that plasmalemmal VDAC-1 plays its role in apoptosis.

In a first effort it was elaborated that opening of VDAC-1 in the plasma membrane precedes the activation of caspases in neuronal apoptosis, induced by staurosporine. In other words, the authors documented that keeping type-1 porin in the plasmalemma of neurons closed by different specific antibodies abolishes the apoptotic volume decrease (AVD) of the cells [6].

Next, studies on the toxic effect of amyloid Aß peptides on septal (SN56) and hippocampal (HT22) neurons corroborated that blocking VDAC in cell membranes means preventing an apoptotic development of cells, and additionally demonstrated that VDAC-1 and the estrogen receptor α (mERα) co-localize and interact in cell membrane caveolae, mERα working towards neuroprotection. The topographic relationship of the molecules was further specified demonstrating that both are integrated in caveolar lipid rafts [7].

To notice: plasmalemmal VDAC-1 carries a GxxxG motif cell outside, amyloid Aß40/42 includes several of them in series. However, GxxxG motifs are established aggregation and membrane perturbation motifs.

Given this background recent data on an enhancement of BACE1 expression of hypometabolic neurons [8] made me ask if amyloid Aß, cut from ubiquitous APP by ß-secretase BACE1 and γ-secretase, may occasionally induce neuronal cell death via opening ubiquitous VDAC-1 in cell membranes of critical brain regions - a proposal including a general model for an induction of cell death [9].

The authors, remembering cerebral hypometabolism and amyloid accumulation as prevailing neuropathological characteristics of Alzheimer's disease, had tried to define effects of neuronal hypoactivity on amyloid plaque pathogenesis in the Tg2576 transgenic mouse model of Alzheimer's disease. They found that unilateral naris-occlusion resulted in an elevation of the ß-secretase BACE1 in neuronal terminals of deprived bulb and piriform cortex in young adult mice [8].

Conclusion: taking for granted that 1) amyloid Aß mono- and/or oligomers dock to cell membrane-standing type-1 VDAC via GxxxG motifs, 2) the docking reactions result in plasmalemmal VDAC-1 channel opening followed by cell death, and 3) Solanezumab antibodies neutralize Aß oligomers by scavenging, a revised version of the amyloid cascade hypothesis of Alzheimers´s pathogenesis comes up.

Accordingly, familial as well as sporadic Alzheimer's disease rests on a putative form of extrinsic cell death via opening cell membrane-standing VDAC-1 (= receptor), and is boosted by excessive amyloid Aß (= regulating agonist) production via processing of the amyloid precursor protein (APP) of weakening cells.

The synopsis of a series of solid data from several laboratories thus helps to further understand the pathogenesis of either form of AD.

Phenotypically mild at the beginning, increasing brain function disturbances evidenced by worsening stages of the disease point to a progressive process on the somatic level. First occasional or just a few cells being affected, over time a burden of cell deaths accumulates finally ending in Alzheimer dementia whenever critical brain regions and their redundant structures are affected. In line, to block free amyloid by antibodies, allows slowing down AD. Finally, t he model presented allows to formally explain the reverse relationship of AD and cancer [10].

References

[1] Siemers ER, Sundella KL, Carlson C, Michael Case, Sethuraman G, Liu-Seifert H, Dowsett SA, Pontecorvo MJ, Dean RA, Demattos R. Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer’s disease patients Alzheimer’s & Dementia 2015; epub ahead: 1-11.

[2] Demetrius LA, Magistretti PJ, Pellerin L. Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect. Front Physiol. 2015 Jan 14;5:522. doi: 10.3389/fphys.2014.00522. eCollection 2014.

[3] Thinnes FP.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. 2015; 1848:1410-1416. doi: 10.1016/j.bbamem.2015.02.031. Epub 2015 Mar 11. Review. PMID: 25771449

[4] Thinnes FP, Hellmann KP, Hellmann T, Merker R, Brockhaus-Pruchniewicz U, Schwarzer C, Walter G, Götz H, Hilschmann N. Studies on human porin XXII: cell membrane integrated human porin channels are involved in regulatory volume decrease (RVD) of HeLa cells. Mol Genet Metab. 2000; 69:331-337.

[5] Okada SF, O'Neal WK, Huang P, Nicholas RA, Ostrowski LE, Craigen WJ, Lazarowski ER, Boucher RC. Voltage-dependent anion channel-1 (VDAC-1) contributes to ATP release and cell volume regulation in murine cells. J Gen Physiol. 2004; 124:513-526. Epub 2004 Oct 11.

[6] Elinder F, Akanda N, Tofighi R, Shimizu S, Tsujimoto Y, Orrenius S, Ceccatelli S. Opening of plasma membrane voltage-dependent anion channels (VDAC) precedes caspase activation in neuronal apoptosis induced by toxic stimuli. Cell Death Differ. 2005; 12:1134-1140. PMID: 15861186 Free Article

[7] Marin R, Ramírez C, Morales A, González M, Alonso R, Díaz M. Modulation of Abeta-induced neurotoxicity by estrogen receptor alpha and other associated proteins in lipid rafts, Steroids 2008; 73:992–996.

[8] Zhang X-M, Xiong K, Cai Y, Cai H, Luo XG, Feng JC, Clough RW, Patrylo PR, Struble RG, Yan XX. Functional deprivation promotes amyloid plaque pathogenesis in Tg2576 mouse olfactory bulb and piriform cortex, Eur. J. Neurosci. 2010; 31: 710–721.

[9] Thinnes FP. Amyloid Aß, cut from APP by ß-secretase BACE1 and γ-secretase, induces apoptosis via opening type-1 porin/VDAC in cell membranes of hypometabolic cells-A basic model for the induction of apoptosis!? Mol Genet Metab. 2010; 101:301-303. doi: 10.1016/j.ymgme.2010.07.007. Epub 2010 Jul 15. No abstract available.

[10] Thinnes FP. Alzheimer disease controls cancer - concerning the apoptogenic interaction of cell membrane-standing type-1 VDAC and amyloid peptides via GxxxG motifs. Mol Genet Metab. 2012; 106:502-503. doi: 10.1016/j.ymgme.2012.06.004. Epub 2012 Jun 15. No abstract available.

On 2015 Aug 12, Friedrich Thinnes commented:

Solanezumab: a therapeutic breakthrough including theoretical gain.

The exciting paper of Siemers et al. [1] on slowing down the progress of Alzheimer´s by Solanezumab antibodies, from my point of view, not only represent a therapeutic breakthrough. The effects observed also broaden the understanding of the pathogenesis of Alzheimer´s Disease, this by pointing to induced neuronal cell death as basic in AD.

Accordingly, I propose plasmalemmal VDAC-1 (Swiss Prot P21796) to work as a receptor of amyloid Aß mono- or oligomers.

In line, it has been shown that docking of those Aß forms to cell surfaces result in an opening of cell membrane-standing VDAC-1, a process finally ending in neuronal cell death.

In consequence, whenever critical brain regions and their redundant structures are affected this way neuronal loss must be expected. In contrary, to capture Aß by adequate mAbs should minimize Aß toxicity, in other words slow down AD progress.

The voltage dependent anion channel (VDAC) is an archaic channel and thus suggested to be involved in housekeeping functions. The channel is well established in the outer mitochondrial membrane, here playing its role in the intrinsic apoptotic pathway. It is thus of proven relevance for Alzheimer´s Dementia [2].

First data on an extra-mitochondrial came up in 1989 by showing that human lymphocytes carry a heavy load of the molecule in their plasmalemma. Those data, meanwhile, found manifold support by several laboratories using different approaches; for review see [3] and www.futhin.de.

After studies focussed on the regulatory volume decrease (RVD) of HeLa or murine respiratory epithelial cells, respectively, had shown that cell membrane-integrated type-1 VDAC is part of the cell volume regulatory system of mammalian cells [4,5] data came up indicating that plasmalemmal VDAC-1 plays its role in apoptosis.

In a first effort it was elaborated that opening of VDAC-1 in the plasma membrane precedes the activation of caspases in neuronal apoptosis, induced by staurosporine. In other words, the authors documented that keeping type-1 porin in the plasmalemma of neurons closed by different specific antibodies abolishes the apoptotic volume decrease (AVD) of the cells [6].

Next, studies on the toxic effect of amyloid Aß peptides on septal (SN56) and hippocampal (HT22) neurons corroborated that blocking VDAC in cell membranes means preventing an apoptotic development of cells, and additionally demonstrated that VDAC-1 and the estrogen receptor α (mERα) co-localize and interact in cell membrane caveolae, mERα working towards neuroprotection. The topographic relationship of the molecules was further specified demonstrating that both are integrated in caveolar lipid rafts [7].

To notice: plasmalemmal VDAC-1 carries a GxxxG motif cell outside, amyloid Aß40/42 includes several of them in series. However, GxxxG motifs are established aggregation and membrane perturbation motifs.

Given this background recent data on an enhancement of BACE1 expression of hypometabolic neurons [8] made me ask if amyloid Aß, cut from ubiquitous APP by ß-secretase BACE1 and γ-secretase, may occasionally induce neuronal cell death via opening ubiquitous VDAC-1 in cell membranes of critical brain regions - a proposal including a general model for an induction of cell death [9].

The authors, remembering cerebral hypometabolism and amyloid accumulation as prevailing neuropathological characteristics of Alzheimer's disease, had tried to define effects of neuronal hypoactivity on amyloid plaque pathogenesis in the Tg2576 transgenic mouse model of Alzheimer's disease. They found that unilateral naris-occlusion resulted in an elevation of the ß-secretase BACE1 in neuronal terminals of deprived bulb and piriform cortex in young adult mice [8].

Conclusion: taking for granted that 1) amyloid Aß mono- and/or oligomers dock to cell membrane-standing type-1 VDAC via GxxxG motifs, 2) the docking reactions result in plasmalemmal VDAC-1 channel opening followed by cell death, and 3) Solanezumab antibodies neutralize Aß oligomers by scavenging, a revised version of the amyloid cascade hypothesis of Alzheimers´s pathogenesis comes up.

Accordingly, familial as well as sporadic Alzheimer's disease rests on a putative form of extrinsic cell death via opening cell membrane-standing VDAC-1 (= receptor), and is boosted by excessive amyloid Aß (= regulating agonist) production via processing of the amyloid precursor protein (APP) of weakening cells.

The synopsis of a series of solid data from several laboratories thus helps to further understand the pathogenesis of either form of AD.

Phenotypically mild at the beginning, increasing brain function disturbances evidenced by worsening stages of the disease point to a progressive process on the somatic level. First occasional or just a few cells being affected, over time a burden of cell deaths accumulates finally ending in Alzheimer dementia whenever critical brain regions and their redundant structures are affected. In line, to block free amyloid by antibodies, allows slowing down AD. Finally, t he model presented allows to formally explain the reverse relationship of AD and cancer [10].

References

[1] Siemers ER, Sundella KL, Carlson C, Michael Case, Sethuraman G, Liu-Seifert H, Dowsett SA, Pontecorvo MJ, Dean RA, Demattos R. Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer’s disease patients Alzheimer’s & Dementia 2015; epub ahead: 1-11.

[2] Demetrius LA, Magistretti PJ, Pellerin L. Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect. Front Physiol. 2015 Jan 14;5:522. doi: 10.3389/fphys.2014.00522. eCollection 2014.

[3] Thinnes FP.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. 2015; 1848:1410-1416. doi: 10.1016/j.bbamem.2015.02.031. Epub 2015 Mar 11. Review. PMID: 25771449

[4] Thinnes FP, Hellmann KP, Hellmann T, Merker R, Brockhaus-Pruchniewicz U, Schwarzer C, Walter G, Götz H, Hilschmann N. Studies on human porin XXII: cell membrane integrated human porin channels are involved in regulatory volume decrease (RVD) of HeLa cells. Mol Genet Metab. 2000; 69:331-337.

[5] Okada SF, O'Neal WK, Huang P, Nicholas RA, Ostrowski LE, Craigen WJ, Lazarowski ER, Boucher RC. Voltage-dependent anion channel-1 (VDAC-1) contributes to ATP release and cell volume regulation in murine cells. J Gen Physiol. 2004; 124:513-526. Epub 2004 Oct 11.

[6] Elinder F, Akanda N, Tofighi R, Shimizu S, Tsujimoto Y, Orrenius S, Ceccatelli S. Opening of plasma membrane voltage-dependent anion channels (VDAC) precedes caspase activation in neuronal apoptosis induced by toxic stimuli. Cell Death Differ. 2005; 12:1134-1140. PMID: 15861186 Free Article

[7] Marin R, Ramírez C, Morales A, González M, Alonso R, Díaz M. Modulation of Abeta-induced neurotoxicity by estrogen receptor alpha and other associated proteins in lipid rafts, Steroids 2008; 73:992–996.

[8] Zhang X-M, Xiong K, Cai Y, Cai H, Luo XG, Feng JC, Clough RW, Patrylo PR, Struble RG, Yan XX. Functional deprivation promotes amyloid plaque pathogenesis in Tg2576 mouse olfactory bulb and piriform cortex, Eur. J. Neurosci. 2010; 31: 710–721.

[9] Thinnes FP. Amyloid Aß, cut from APP by ß-secretase BACE1 and γ-secretase, induces apoptosis via opening type-1 porin/VDAC in cell membranes of hypometabolic cells-A basic model for the induction of apoptosis!? Mol Genet Metab. 2010; 101:301-303. doi: 10.1016/j.ymgme.2010.07.007. Epub 2010 Jul 15. No abstract available.

[10] Thinnes FP. Alzheimer disease controls cancer - concerning the apoptogenic interaction of cell membrane-standing type-1 VDAC and amyloid peptides via GxxxG motifs. Mol Genet Metab. 2012; 106:502-503. doi: 10.1016/j.ymgme.2012.06.004. Epub 2012 Jun 15. No abstract available.