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Inverse association between cancer and Alzheimer’s disease: results from the Framingham Heart Study

BMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e1442 (Published 12 March 2012) Cite this as: BMJ 2012;344:e1442

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Re: Inverse association between cancer and Alzheimer’s disease: results from the Framingham Heart Study

Cell death, induced by several Amyloid Aß Peptides via Opening Plasma lemma-standing VDAC/porin over time
ends in Alzheimer´s Disease but may also hold up tumorgenesis

The expression of type-1 Voltage Dependent Anion Channel/vertebrate porin, the gene product of VDAC1, in the plasma lemma of cells is beyond reasonable doubt. Concerning its function it has been shown that the channel is involved in cell volume regulation and thus apoptosis.

After hypotonic stimulation of HeLa cells plasmalemmal VDAC opens to give way to anions of different seize in regulatory volume decrease (RVD) reactions.1 For a corresponding video recording see http://www.futhin.de. Mammalian type-1 porin also plays its role in the apoptotic volume decrease (AVD) of neuronal cells as shown by demonstrating that opening of VDAC precedes other apoptotic cell traits induced by staurosporine or synthetic amyloid Aß peptides, respectively.2,3 In either case a cell outside application of different anti-VDAC antibodies prevented cells to return to their starting volumes, while initial swelling was unaffected.

The primary structure of mammalian type-1 VDAC is known, so is its crystallographic arrangement. Its N-terminal mostly helical stretch of 26 amino acids, including a voltage sensor of the channel, is proximally attached to ß-pleated sheet 1 out of nineteen of the molecule, and from here traverses the lumen - in the plasma lemma towards the cell surface, in the outer mitochondrial membrane towards the cytosol. The 20GYGFG24 stretch found inside the N-terminal part has been shown to function as an aggregation/membrane perturbation motif; amyloid Aß1-42 includes several of those and thus may explain data on apoptogenic effects of Aß on neuronal cells mentioned above.3

According to the amyloid cascade hypothesis the Alzheimer's disease rests on pathological processing of APP by several secretases. Mild at the beginning AD symptoms steadily increase over worsening stages and thus point to a progressive process on the somatic level. First just few cells being affected, over time a burden of cell disturbances accumulate which – by Aß shedding and Tau processing - finally end in Alzheimer dementia and its cell biological correlates, free amyloid Aß peptides, brain senile plaques and neurofibrillary tangles.

In a synopsis of those data I recently proposed a model of interaction of ubiquitously expressed cell membrane-standing type-1 mammalian porin with amyloid Aß1-42, given in l.c.4 Accordingly, Alzheimer´s Disease is thought to result from increasing numbers of extrinsically induced apoptotic neuronal deaths over time. From here it appears obvious that patients with AD may have a lower risk of cancer, cancerous cells being cleaned away by amyloid Aß cut from neurons.

In conclusion, to look for interactions of amyloid Aß peptides on type-1 VDAC in cell membranes may help further define the molecular basis of data on an association of Alzheimer´s Disease and cancer, which were recently supported another time by the study under discussion here.5

The free N-terminus of VDAC, accessible at cell surfaces carries a single aggregation / membrane perturbation motif while amyloid Aß1-42 includes several of those. Experiments with neuronal cell lines have shown that anti-VDAC antibodies block canonical traits of the apoptotic process after stimulation by staurosporine or amyloid Aß peptides, respectively.2,3

Noteworthy, there are two differences concerning the primary structure of VDAC´s free N-terminal stretch comparing vertebrates and plants: first, the 20GYGFG24 is missing in plants6; second, the very N-terminus of the human molecule Ac-AVPPTYADL shows varying sequences in Arabidopsis thaliana, e.g. VDAC1: mvkgpglyte.

References
1 Thinnes FP, Hellmann KP, Hellmann T, Merker R, Brockhaus-Pruchniewicz U, Schwarzer C, et al. 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; 69:331-7.

2 Elinder F, Akanda N, Tofighi R, Shimizu S, Tsujimoto Y, Orrenius S, et al. Opening of plasma membrane voltage-dependent anion channels (VDAC) precedes caspase activation in neuronal apoptosis induced by toxic stimuli. Cell Death Differ 2005; 12:1134-40.

3 Marin R, Ramírez CM, González M, González-Muñoz E, Zorzano A, Camps M, et al.
Voltage-dependent anion channel (VDAC) participates in amyloid beta-induced toxicity and interacts with plasma membrane estrogen receptor alpha in septal and hippocampal neurons. Mol Membr Biol 2007; 24:148-60.

4 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;101:301-3.

5 Driver JA, Beiser A, Au R, Kreger BE, Splansky GL, Kurth T, et al. Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study. BMJ. 2012 Mar 12;344:e1442. doi: 10.1136/bmj.e1442.

6 Thinnes FP. On GxxxG in N-terminal stretches of type-1 VDAC/porin: critical in vertebrate apoptosis, missing in plants. Plant Mol Biol 2012 Mar 27. [Epub ahead of print]

Competing interests: No competing interests

22 April 2012
Friedrich P. Dr. Thinnes
Scientist
no
privat; retired from MPG Munich
Baumschulenweg 5 D-37083 Göttingen, Germany