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

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

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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: None declared

Friedrich P. Dr. Thinnes, Scientist

no

privat; retired from MPG Munich, Baumschulenweg 5 D-37083 Göttingen, Germany

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Inverse association between cancer and Alzheimer’s disease (AD). But, for all cancer types?

A recent Framingham study involving 1278 participants has shown an inverse association between cancer and AD (1,2). In other words, people who suffer from AD are likely to have reduced risk of develop age related cancer.
Driver et al correctly acknowledge that further insight will possibly be gained from analysis in large clinical database with the power to look at the relation between AD and individual types of cancer .
In particular, data reported in Table 5 showed a similar incidence between AD subjects and controls for colorectal tumors (2.0 vs 2.6%), whereas the incidence of other main tumors, namely lung, was 1/3 in AD patients 0.6 vs 2.2%; on the contrary, bladder and urinary cancer showed an increased incidence in AD patients vs controls (1.4 % vs 0.9 %)
Interestingly, in a completely different study, a cross-sectional survey of the prevalence of associated cancer among 1392 subjects, admitted with a diagnosis of AD to a geriatric institute during years 2004-2009, an overall diagnosis of previous of subsequent cancer, was made in 79 subjects (51 F, 28 M, mean age 83 years, range 62-97 y). Interestingly, in comparison with 25 breast and 15 colorectal cancers, in patients with AD there where only two cases of lung cancer, 0 with pancreas, or kidney cancer, whereas there were 6 patients with bladder and the urinary tract cancer (double that in the control population). Therefore, the results of two different approaches, which can be considered complementary and mutually supportive of each other, seem to suggest that the occurrence of most, but not all cancer types, is likely reduced in subjects with AD.
In our opinion, the striking similarity of AD associated cancers, which are not only less (less the 1/3 in our study) and then different in numbers, but also different for type (in particular they involve mainly some histotypes, and not others, with an increased incidence for some cancer sites) cannot be considered fortuitous. Obviously, the Driver’s study should be replicated by other longitudinal studies, maybe including a greater number of incident cases. But this will require long time.
Exploring possible causes of the inverse association, we suspect that, instead of a presumed cooperation (or mutually exclusion) concerning only a few genes (p53, PIN1), acting along the same molecular pathway, a more complex genetic signature, - including many genes, and also epigenetic and/or environmental factors (smoke can be one of these factors), maybe involving major complex functions, such as immune response or cancer susceptibility, - could facilitate, at the entire organism level, the mutually exclusive occurrence of AD and cancer, irrespective of the prior occurrence of cancer or AD. The observation that, whereas some of the most frequent cancer types are greatly reduced, other histotypes (bladder and urinary tract) are increased, suggests that further study is required, focusing selectively not only on cancer prevalence and incidence, but also on the inhomogeneous incidence of the various cancer types and sites.

References
(1) Driver JA, Beiser A, Au R, Kreger BE, Splansky GL, Kurth T, Kiel DP, Lu KP, Seshadri S, Wolf PA. Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study. BMJ 2012;344:e1442
(2) Gouguli M. A reduced risk of Alzheimer’s disease in those who survive cancer. BMJ 2012; 344:e1662

Competing interests: None declared

Francesco Cetta, Oncologistic Surgeon

Valentina Guercio, Cinzia Negri Chinaglia, Massimo Monti

IRCCS Multimedica, Milano, Italy

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Inverse association between cancer and Alzheimer’s disease: What is the cause?

A recent Framingham Study, involving 1278 participants, has shown an inverse association between cancer and Alzheimer’s disease (1, 2). In other words, people who suffer from Alzheimer’s disease (AD) are likely to have a reduced risk of developing age-related cancers.

Quite remarkably, exactly the same type of inverse association exists in Down syndrome (DS). Thus, people suffering from DS, characterised by an extra chromosome 21 (trisomy 21, T21), have an increased risk of developing AD but, on the other hand, they have a decreased risk for the development of solid cancers (3). Furthermore, in vitro culture of DS brain stem cells provides a model for the development of the characteristic features of AD brains (4).

The outstanding question here is what might be the cause for this type of inverse association? This is an exceedingly important question, not the least as we here might find leads for the development of improved therapeutic measures for solid cancers as well as for Alzheimer’s disease (1-3).

Driver et al (1) suggest that the reason may be related to an inappropriate activation of the cell cycle. A related, intriguing, possibility is the occurrence of T21 mosaicism in the specific tissues. Thus, it has been suggested that the relative proportion of T21 cells are of importance. An increased proportion in the cerebral cortex would underlie the development of AD but, when occurring in the different relevant tissues, provide protection against development of solid cancers (3).

Hopefully, the recent support for research into the origin of AD (5) will lead to additional studies along these lines, thus promoting the development of improved therapy, not only for AD but also for solid cancers.

References

(1) Driver JA, Beiser A, Au R, Kreger BE, Splansky GL, Kurth T, Kiel DP, Lu KP, Seshadri S, Wolf PA. Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study. BMJ 2012;344:e1442

(2) Gouguli M. A reduced risk of Alzheimer’s disease in those who survive cancer. BMJ 2012; 344:e1662

(3) Hultén MA, Jonasson J, Nordgren A, Iwarsson E. Germinal and Somatic Trisomy 21 Mosaicism: How Common is it, What are the Implications for Individual Carriers and How Does it Come About? Curr Genomics 2010, 6:409-19

(4) Shi Y, Kirwan P, Smith J, Maclean G, Orkin SH, Livesey FJ. A human stem cell model of early Alzheimer's disease pathology in down syndrome. Sci Transl Med. 2012, 4:124ra29

(5) Tanne JH: US scientists discuss early detection and treatment of Alzheimer's disease. BMJ 2012; 344:e1068

Competing interests: None declared

Maj A Hulten, Medical Geneticist

Warwick University, Karolinska Institutet, Stockholm, 22 Mayfield Road, Moseley, Birmingham B139HJ

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