Letter to the Editor
Alzheimer disease controls cancer — Concerning the apoptogenic interaction of cell membrane-standing type-1 VDAC and amyloid peptides via GxxxG motifs

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Abstract

A hypothesis tries to explain why patients who suffer from Alzheimer Disease show less cancer development. Accordingly the interaction of amyloid peptides, cut from amyloid precursor protein and shed to cerebrospinal fluid and blood plasma, with N-terminal stretches of type-1 VDAC, the voltage sensor of the channel, is thought to show double effect: on the one hand, the peptides induce apoptosis thus increasing numbers of cell deaths at critical points of the brain over time and worsening

Note added in proof

According to an impressive recent study C-terminal parts of Bcl-xL, cut from the molecule by caspases, mediate ischemia-induced neuronal deaths in hippocampal CA1 pyramidal neurons, a process going with cognitive deficits [30]. This makes me ask if caspases after ichemia, by whatever mechanism, work as increased γ-secretase BACE1 does in hypo-metabolic neurons after sensory deprivation, here finally ending in Alzheimer Disease [22], [23].

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    • VDAC1, mitochondrial dysfunction, and Alzheimer's disease

      2018, Pharmacological Research
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      It is proposed that, on one hand, the peptides induce apoptosis in the brain, over time worsening the state of AD. However, on the other hand, the peptides may be using the same mechanism to eliminate cancerous cells and thus prevent the development of tumours [230]. Mitochondria play crucial roles in many of the vital processes in the cell from generation of energy to cell proliferation and differentiation.

    • Aβ promotes VDAC1 channel dephosphorylation in neuronal lipid rafts. Relevance to the mechanisms of neurotoxicity in Alzheimer's disease

      2014, Neuroscience
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      Binding to this domain is compatible with a GxxxG motif located in positions 20–24 at N-terminal of VDAC1 sequence, which is an aggregation/membrane perturbation motif also found in Aβ peptides at C-terminal. This sequence may be a consensus site of contact between VDAC and Aβ peptides (Thinnes 2012, 2013). Preservation of phosphorylation maintains the channel inactivated under normal physiological conditions, whereas its activation by the loss of phosphate group(s) has been related to initiation of toxic signal transduction, including brain ischemia and hypoxia (Sabirov and Merzlyak, 2012).

    • Lipid raft disarrangement as a result of neuropathological progresses: A novel strategy for early diagnosis?

      2013, Neuroscience
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      In this order or ideas, protein disassemblies of ER/IGF-1R/VDAC signalosome have been observed as a result of cortical raft lipid alterations, a phenomenon that may have important consequences in neuronal preservation against Aβ-induced toxicity (Ramirez et al., 2009). This may also affect Aβ generation since VDAC is also known to interact with γ-secretase in these domains (Hur et al., 2012), and probably to Aβ peptide (Thinnes, 2012). Furthermore, these protein rearrangements occurring in AD lipid rafts may profoundly affect signaling responses for neuronal integrity, which could be validated for future therapies of early diagnoses.

    • New findings concerning vertebrate porin II - On the relevance of glycine motifs of type-1 VDAC

      2013, Molecular Genetics and Metabolism
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      Thinking along this line I recently proposed explanations for systemic effects observed concerning Alzheimer's disease and cancer. A recent paper by Driver et al. (2012) [121] stimulated a synopsis of data from different laboratories that, at least formally, allows to understand why patients who suffer from Alzheimer's disease have a lower risk of cancer [122]. Accordingly, upcoming cancerous cells or cell islets can be expected to be cleaned off by apoptotic processes induced by free amyloid Aβ peptide cut from APP molecules of metabolically down-regulated neurons.

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