onizing radiation, often confusingly abbreviated as IR, consists of X-rays
or gamma rays. The safe assumption was that ionizing radiation was always
harmful—there is no threshold below which it is safe. This was
never scientifically established, and it was always acknowledged that
alternatives were possible. We are now starting to discover that those
alternatives do indeed exist.
When a gamma ray hits a cell, it disrupts the electronic bonds that bind molecules together. It also splits water into hydroxyl radicals, which react with anything, including proteins and DNA. This causes single-strand breaks and double-strand breaks in DNA. Repairing a single-strand break is fairly routine for the cell. Repairing a double-strand DNA (dsDNA) break is not so easy, and it often leads to cell death.
The goal of oncologists since the 1940s has always been to find clever new ways of killing cells. Lots of effort has been made to find ways to make radiation therapy for cancer more effective. One way is to block DNA repair by inhibiting ATR or ATM, the proteins that orchestrate single- and double-strand repair. Then, the theory goes, when the cell is blasted with radiation, it can't repair its DNA and so it dies. ATM works by activating tumor suppressor protein p53, which is the protein that decides the fate of the cell. p53 can cause apoptosis (programmed cell death), or it can permanently halt the cell cycle, preventing the cell from ever dividing again (called cellular senescence). If p53 is inactive, the cell stays alive. So it's not surprising that half of all cancers are associated with a cellular mutation that inactivates p53.
Naively, one might think that blocking apoptosis would protect against radiation. But the interior of a cell contains molecules that powerfully activate the immune system. In apoptosis, the cell destroys these molecules before dying. If apoptosis is blocked, the cell either starts secreting inflammatory molecules or dies in a very messy way and these molecules are released into the body, causing inflammation.
Radiation activates the immune system
Nature has devised a clever way for letting the adaptive immune system see what's happening inside your cells. In the cell, a giant protein complex called the proteasome grinds up old or unwanted proteins and turns them into peptides. MHC class I molecules (also known as HLA class I — the proteins that cause rejection of transplanted tissue) take these peptides and bring them to the surface, “presenting” them to the cytotoxic CD8+ T cells (called CTLs or cytotoxic T lymphocytes), as if showing them their papers. If the T cell doesn't like what it sees, it kills the cell. In this way, a virally infected cell is stopped from producing more viruses.
Researchers have found that when cells are exposed to radiation, they produce unique peptides called radiation-associated peptides. These peptides activate the MHC system, making cells more susceptible to cytotoxic T cells.[1] This works through a series of protein reactions known as the cGAS-STING pathway.[2] When the cell detects double-stranded DNA (which is never supposed to be in the cytosol), the cell produces a small molecule called cGAMP or cyclic GMP-AMP. cGAMP causes the cell to manufacture type I interferons, which are potent inflammatory cytokines.[3] In this way, radiation not only produces an anti-cancer response, it can also strengthen the cell's resistance to viruses and bacteria. The cGAS-STING pathway isn't always beneficial: it can also mediate autoimmune disorders, some of which are caused by the accumulation of bits of dsDNA in the cytosol.
Incidentally, this is why we'll probably never see dsDNA used in vaccines: it would cause a strong immune response that could do more harm than good. Cells use different pathways, such as MAVS, or mitochondrial antiviral signaling protein (which also causes the cell to make interferon), to detect dsRNA.
The cyclic dinucleotides made by the dsDNA sensing protein can also exit the cell to warn nearby cells (including dendritic cells, which are immune cells that act as tiny rat finks to warn the T cells that something is amiss) that they should start manufacturing interferons as well. Dendritic cells can also acquire bits of dsDNA from irradiated cells, and then manufacture lots of interferon themselves. But some researchers think this isn't important, and the dendritic cells are responding to cGAMP instead, which they detect by direct contact with irradiated cells.
In senescent cells, cytoplasmic chromatin fragments (CCFs) and bits of oxidized mitochondrial DNA trigger the cGAS pathway mentioned above, and so we get unstoppable chronic inflammation. Indeed, radiation creates chunks of mitochondrial DNA that float around in the cytosol, and this is thought that this also makes the radiotherapy more effective.
In the olden days (i.e. two or three years ago), it was thought that apoptosis, or programmed cell death, was desirable in radiotherapy, as it would kill the tumor cells. But now, some scientists think that apoptosis does more harm than good because it inhibits immune signaling. Interferons aren't always helpful: they can protect cancer cells, and inflammation can promote metastasis. This means tumor cells co-opt the immune system to spread to distant organs.[4]
Did I mention this stuff is very complicated?
Alzheimer's disease
Well, you might say, this is all very interesting, but what does it have to do with Alzheimer's disease?
Irradiating the brain with gamma rays causes cell death. This is why we're constantly told that astronauts could never travel to Mars: their brain cells would get fried by solar radiation, beta-amyloid would be deposited, and they'd die of dementia.[5] We were even told that background radiation from radon in our houses is strongly statistically correlated with Alzheimer's.[6]
But now, some—but by no means all—researchers are suggesting using low-dose radiation to treat Alzheimer's. This is not to be confused with the claims of Mortazavi et al.[7,8] that 900 MHz GSM mobile phone radiofrequency enhances memory and protects against Alzheimer's. In one mouse study, a “low-moderate” dose (9 Grays) given to mice engineered to produce beta-amyloid was reported to reduce synaptic degeneration, neuronal loss, and neuroinflammation in the hippocampus and cerebral cortex.[9] The authors claimed that this was due to inhibition of NF-κB, which is a transcription factor that induces the cell to manufacture cytokines.
A dose of 9 Grays is fatal if given all at once to a human, but the time over which exposure occurs is the critical factor. The CDC says that 0.7 Grays delivered over a few minutes causes acute radiation syndrome, and a dose of 5 Grays is considered lethal. And of course it is well understood that ionizing radiation causes cancer. The US National Cancer Institute has a handy calculator that health physicists can use to estimate cancer risk from radiation.
But in 2016, one Alzheimer patient received five CAT scans, with a total exposure of 120 milliGray over a period of three months. The patient was said to have partially recovered cognition, memory, speech, movement and appetite.[10–12] A publicly available summary is available here.[13]
It should be noted that short-term responses like this often occur in Alzheimer patients given experimental treatments. I've seen it before: the patient gets a harsh experimental treatment and suddenly starts talking and asking questions, even asking to be discharged, as if the shock jolted the brain back into activity for a short time. After a few days the disease resumes its previous course. (Not just any shock: electroconvulsive therapy seems not to work, at least in animal models.) The questions are: is it real this time, and if so how long does the recovery last?
Maybe something important is going on. It's now clear that there really is an inverse relationship between cancer and Alzheimer's[14–16]. These claims kept cropping up, and there's now convincing evidence that they're real. But how to explain it? That's the next task.
1 Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, Camphausen K, Luiten RM, de Ru AH, Neijssen J, Griekspoor A, Mesman E, Verreck FA, Spits H, Schlom J, van Veelen P, Neefjes JJ. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006 May 15;203(5):1259–1271. doi: 10.1084/jem.20052494. PMID: 16636135; PMCID: PMC3212727. Link
2 Storozynsky Q, Hitt MM The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer Int J Mol Sci. 2020 Nov; 21(22): 8877. doi: 10.3390/ijms21228877 PMCID: PMC7700321 PMID: 33238631
3 Zitvogel L, Galluzzi L, Kepp O, Smyth MJ, Kroemer G. Type I interferons in anticancer immunity. Nat Rev Immunol. 2015 Jul;15(7):405–414. doi: 10.1038/nri3845. Epub 2015 Jun 1. PMID: 26027717.
4 Bakhoum SF, Ngo B, Laughney AM, Cavallo JA, Murphy CJ, Ly P, Shah P, Sriram RK, Watkins TBK, Taunk NK, Duran M, Pauli C, Shaw C, Chadalavada K, Rajasekhar VK, Genovese G, Venkatesan S, Birkbak NJ, McGranahan N, Lundquist M, LaPlant Q, Healey JH, Elemento O, Chung CH, Lee NY, Imielenski M, Nanjangud G, Pe'er D, Cleveland DW, Powell SN, Lammerding J, Swanton C, Cantley LC. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature. 2018 Jan 25;553(7689):467–472. doi: 10.1038/nature25432. PMID: 29342134; PMCID: PMC5785464.
5 Rudobeck E, Bellone JA, Szücs A, Bonnick K, Mehrotra-Carter S, Badaut J, Nelson GA, Hartman RE, Vlkolinský R. Low-dose proton radiation effects in a transgenic mouse model of Alzheimer's disease - Implications for space travel. PLoS One. 2017 Nov 29;12(11):e0186168. doi: 10.1371/journal.pone.0186168. PMID: 29186131; PMCID: PMC5706673.
6 Lehrer S, Rheinstein PH, Rosenzweig KE. Association of Radon Background and Total Background Ionizing Radiation with Alzheimer's Disease Deaths in U.S. States. J Alzheimers Dis. 2017;59(2):737–741. doi: 10.3233/JAD-170308. PMID: 28671130.
7 Mortazavi S, Shojaei-Fard M, Haghani M, Shokrpour N, Mortazavi S. Exposure to mobile phone radiation opens new horizons in Alzheimer's disease treatment. J Biomed Phys Eng. 2013 Sep 17;3(3):109–112. PMID: 25505755; PMCID: PMC4204502.
8 Mortazavi SA, Tavakkoli-Golpayegani A, Haghani M, Mortazavi SM. Looking at the other side of the coin: the search for possible biopositive cognitive effects of the exposure to 900 MHz GSM mobile phone radiofrequency radiation. J Environ Health Sci Eng. 2014 Apr 26;12:75. doi: 10.1186/2052-336X-12-75. PMID: 24843789; PMCID: PMC4004454.
9 Kim S, Nam Y, Kim C, Lee H, Hong S, Kim HS, Shin SJ, Park YH, Mai HN, Oh SM, Kim KS, Yoo DH, Chung WK, Chung H, Moon M. Neuroprotective and Anti-Inflammatory Effects of Low-Moderate Dose Ionizing Radiation in Models of Alzheimer's Disease. Int J Mol Sci. 2020 May 23;21(10):3678. doi: 10.3390/ijms21103678. PMID: 32456197; PMCID: PMC7279400.
10 Low Doses of Ionizing Radiation as a Treatment for Alzheimer's Disease: A Pilot Study. Cuttler JM, Abdellah E, Goldberg Y, Al-Shamaa S, Symons SP, Black SE, Freedman M. J Alzheimers Dis. 2021;80(3):1119–1128. doi: 10.3233/JAD-200620. PMID: 33646146
11 Cuttler JM, Moore ER, Hosfeld VD, Nadolski DL. Update on a patient with Alzheimer disease treated with CT scans. Dose-Response. 2017;15:1559325817693167. doi: 10.1177/1559325817693167.
12 Cuttler JM, Moore ER, Hosfeld VD, Nadolski DL. Treatment of Alzheimer Disease With CT Scans: A Case Report. Dose Response. 2016;14:1559325816640073. doi: 10.1177/1559325816640073.
13 Bevelacqua JJ, Mortazavi S. (2018). Alzheimer 's Disease: Possible Mechanisms Behind Neurohormesis Induced by Exposure to Low Doses of Ionizing Radiation. Journal of biomedical physics & engineering, 8(2), 153–156.
14 Lanni C, Masi M, Racchi M, Govoni S. Cancer and Alzheimer's disease inverse relationship: an age-associated diverging derailment of shared pathways. Mol Psychiatry. 2021;26(1):280–295. doi: 10.1038/s41380-020-0760-2. PMID: 32382138.
15 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. doi: 10.1136/bmj.e1442. PMID: 22411920; PMCID: PMC3647385
16 Frain L, Swanson D, Cho K, Gagnon D, Lu KP, Betensky RA, Driver J. Association of cancer and Alzheimer's disease risk in a national cohort of veterans. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2017;13(12):1364–1370. doi: 10.1016/j.jalz.2017.04.012. PMID: 28711346; PMCID: PMC5743228.
july 11 2021, 9:55 am
