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Plasmalemmal VDAC-1 corroborated as amyloid Aß-receptor.

Thinnes FP - Front Aging Neurosci (2015)

View Article: PubMed Central - PubMed

Affiliation: Max-Planck-Gesellschaft München, Göttingen Germany †

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From my point of view the observations presented by Siemers et al. not only represent a therapeutic breakthrough... The effects observed also broaden the understanding of the pathogenesis of Alzheimer Disease, this by plainly pointing to induced neuronal cell death as basic in AD... The group meanwhile presented additional data to demonstrate that the interaction of VDAC and mERα in caveolae from human cortex is altered in Alzheimer disease (Ramírez et al., ; Marin, ), results which appear to be in line with an early 2D-electrophoresis report on differences in VDAC content of biopsies taken from normal or Alzheimer brains, respectively (Yoo et al., )... Finally, Reddy's laboratory elaborated relevant data on effects of amyloid Aß on VDAC-1, here mostly focussed on mitochondrial processes (Manczak et al., ; Manczak and Reddy, ; Reddy, )... Asking for a putative mechanism of interactions of cell membrane-standing type-1 VDAC and amyloid mono- and oligomers, it helps to notice that plasmalemmal VDAC-1 carries a critical GxxxG motif cell outside (Thinnes, ), while amyloid Aß40/42 includes several of them in series (Thinnes,, )... Given this background recent data on an enhancement of BACE1 expression of hypometabolic neurons (Zhang et al., ) made me ask if amyloid Aß, cut from ubiquitous amyloid precursor protein (APP) by ß-secretase BACE1 and γ-secretase, may spot wise induce neuronal cell death via opening ubiquitous VDAC-1 in cell membranes of critical brain regions - a process ending in Alzheimer Disease (Thinnes,, )... The authors, remembering cerebral hypometabolism and amyloid accumulation as prevailing neuropathological characteristics of Alzheimer 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 (Zhang et al., ; Xiao et al., )... Taking for granted that (1) neuronal cells having lost their balance show enhanced BACE1 expression and thus increased Aß production, (2) amyloid Aß mono- and/or oligomers dock to cell membrane-standing type-1 VDAC of neuronal cells via GxxxG motifs, (3) docking reactions result in plasmalemmal VDAC-1 channel opening followed by a form of extrinsic cell death, and (4) Solanezumab antibodies neutralize Aß oligomers by agonist scavenging, a revised version of the amyloid cascade hypothesis of Alzheimer pathogenesis comes up... However, my hope is that looking on Alzheimer pathogenesis in the context of induced cell death will stimulate the field, this the more as recent literature indicates that amyloid Aß may work this way in other places (Martí-Fàbregas et al., ; Kaffashian et al., ; Zetterberg, )... One of those called 6E10 a) in vitro disaggregates artificial amyloid fibrils and thus increases the number of Aß oligomers, while b) the injection of co-incubates into the lateral ventricle of 6-month-old C57 mice increased the neurotoxicity in vivo... However, 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.

No MeSH data available.


Model on the putative interaction of plasmalemmal VDAC-1 and Aß monomers via GxxxG motifs. Highly schematic two-dimensional projections of human type-1VDAC summarizing data from my own lab and the laboratories of Vito De Pinto, Roland Benz, Varda Shoshan-Barmatz, Carmen Mannella, and Jeff Abramson; modified fom Thinnes (2015b). Fully closed state and open state of native VDAC-1 are compared. Noteworthy, the GxxxG motif has been shown to work as an ATP binding site may putatively figure as a peptide interaction/membrane perturbation motif, too.
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Figure 1: Model on the putative interaction of plasmalemmal VDAC-1 and Aß monomers via GxxxG motifs. Highly schematic two-dimensional projections of human type-1VDAC summarizing data from my own lab and the laboratories of Vito De Pinto, Roland Benz, Varda Shoshan-Barmatz, Carmen Mannella, and Jeff Abramson; modified fom Thinnes (2015b). Fully closed state and open state of native VDAC-1 are compared. Noteworthy, the GxxxG motif has been shown to work as an ATP binding site may putatively figure as a peptide interaction/membrane perturbation motif, too.

Mentions: From my point of view the observations presented by Siemers et al. (2015) not only represent a therapeutic breakthrough. The effects observed also broaden the understanding of the pathogenesis of Alzheimer Disease, this by plainly pointing to induced neuronal cell death as basic in AD. The data thus support a proposal of mine first made in 2010 (Thinnes, 2010, 2011, 2012a,b). For a highly shematic trial to graphically demonstrate the concept see Figure 1.


Plasmalemmal VDAC-1 corroborated as amyloid Aß-receptor.

Thinnes FP - Front Aging Neurosci (2015)

Model on the putative interaction of plasmalemmal VDAC-1 and Aß monomers via GxxxG motifs. Highly schematic two-dimensional projections of human type-1VDAC summarizing data from my own lab and the laboratories of Vito De Pinto, Roland Benz, Varda Shoshan-Barmatz, Carmen Mannella, and Jeff Abramson; modified fom Thinnes (2015b). Fully closed state and open state of native VDAC-1 are compared. Noteworthy, the GxxxG motif has been shown to work as an ATP binding site may putatively figure as a peptide interaction/membrane perturbation motif, too.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588700&req=5

Figure 1: Model on the putative interaction of plasmalemmal VDAC-1 and Aß monomers via GxxxG motifs. Highly schematic two-dimensional projections of human type-1VDAC summarizing data from my own lab and the laboratories of Vito De Pinto, Roland Benz, Varda Shoshan-Barmatz, Carmen Mannella, and Jeff Abramson; modified fom Thinnes (2015b). Fully closed state and open state of native VDAC-1 are compared. Noteworthy, the GxxxG motif has been shown to work as an ATP binding site may putatively figure as a peptide interaction/membrane perturbation motif, too.
Mentions: From my point of view the observations presented by Siemers et al. (2015) not only represent a therapeutic breakthrough. The effects observed also broaden the understanding of the pathogenesis of Alzheimer Disease, this by plainly pointing to induced neuronal cell death as basic in AD. The data thus support a proposal of mine first made in 2010 (Thinnes, 2010, 2011, 2012a,b). For a highly shematic trial to graphically demonstrate the concept see Figure 1.

View Article: PubMed Central - PubMed

Affiliation: Max-Planck-Gesellschaft München, Göttingen Germany †

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

From my point of view the observations presented by Siemers et al. not only represent a therapeutic breakthrough... The effects observed also broaden the understanding of the pathogenesis of Alzheimer Disease, this by plainly pointing to induced neuronal cell death as basic in AD... The group meanwhile presented additional data to demonstrate that the interaction of VDAC and mERα in caveolae from human cortex is altered in Alzheimer disease (Ramírez et al., ; Marin, ), results which appear to be in line with an early 2D-electrophoresis report on differences in VDAC content of biopsies taken from normal or Alzheimer brains, respectively (Yoo et al., )... Finally, Reddy's laboratory elaborated relevant data on effects of amyloid Aß on VDAC-1, here mostly focussed on mitochondrial processes (Manczak et al., ; Manczak and Reddy, ; Reddy, )... Asking for a putative mechanism of interactions of cell membrane-standing type-1 VDAC and amyloid mono- and oligomers, it helps to notice that plasmalemmal VDAC-1 carries a critical GxxxG motif cell outside (Thinnes, ), while amyloid Aß40/42 includes several of them in series (Thinnes,, )... Given this background recent data on an enhancement of BACE1 expression of hypometabolic neurons (Zhang et al., ) made me ask if amyloid Aß, cut from ubiquitous amyloid precursor protein (APP) by ß-secretase BACE1 and γ-secretase, may spot wise induce neuronal cell death via opening ubiquitous VDAC-1 in cell membranes of critical brain regions - a process ending in Alzheimer Disease (Thinnes,, )... The authors, remembering cerebral hypometabolism and amyloid accumulation as prevailing neuropathological characteristics of Alzheimer 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 (Zhang et al., ; Xiao et al., )... Taking for granted that (1) neuronal cells having lost their balance show enhanced BACE1 expression and thus increased Aß production, (2) amyloid Aß mono- and/or oligomers dock to cell membrane-standing type-1 VDAC of neuronal cells via GxxxG motifs, (3) docking reactions result in plasmalemmal VDAC-1 channel opening followed by a form of extrinsic cell death, and (4) Solanezumab antibodies neutralize Aß oligomers by agonist scavenging, a revised version of the amyloid cascade hypothesis of Alzheimer pathogenesis comes up... However, my hope is that looking on Alzheimer pathogenesis in the context of induced cell death will stimulate the field, this the more as recent literature indicates that amyloid Aß may work this way in other places (Martí-Fàbregas et al., ; Kaffashian et al., ; Zetterberg, )... One of those called 6E10 a) in vitro disaggregates artificial amyloid fibrils and thus increases the number of Aß oligomers, while b) the injection of co-incubates into the lateral ventricle of 6-month-old C57 mice increased the neurotoxicity in vivo... However, 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.

No MeSH data available.