We have previously reported that low doses of external beam ionizing irradiation reduced amyloid-β (Aβ) plaques and improved cognition in APP/PS1 mice. In this study we investigated the effects of radiation in an age-matched series of 3xTg-AD mice. Mice were hemibrain-irradiated with 5 fractions of 2 Gy and sacrificed 8 weeks after the end of treatment. Aβ and tau were assessed using immunohistochemistry and quantified using image analysis with Definiens Tissue Studio. We observed a significant reduction in Aβ plaque burden and tau staining; these two parameters were significantly correlated. This preliminary data is further support that low doses of radiation may be beneficial in Alzheimer’s disease.
LongJM, HoltzmanDM (2019) Alzheimer disease: An update on pathobiology and treatment strategies. Cell179, 312–339.
2.
MarplesB, McGeeM, CallanS, BowenSE, ThibodeauBJ, MichaelDB, WilsonGD, MaddensME, FontanesiJ, MartinezAA (2016) Cranial irradiation significantly reduces beta amyloid plaques in the brain and improves cognition in a murine model of Alzheimer’s disease (AD). Radiother Oncol118, 579–580.
3.
MarplesB, McGeeM, CallanS, BowenSE, ThibodeauBJ, MichaelDB, WilsonGD, MaddensME, FontanesiJ, MartinezAA (2016) Cranial irradiation significantly reduces beta amyloid plaques in the brain and improves cognition in a murine model of Alzheimer’s disease (AD). Radiother Oncol118, 43–51.
PoovaneswaranS, RazakAR, LockmanH, BoneM, PollardK, MazdaiG (2008) Tracheobronchial amyloidosis: Utilization of radiotherapy as a treatment modality. Medscape J Med10, 42.
6.
MonroeAT, WaliaR, ZloteckiRA, JantzMA (2004) Tracheobronchial amyloidosis: A case report of successful treatment with external beam radiation therapy. Chest125, 784–789.
7.
ShelineGE, WaraWM, SmithV (1980) Therapeutic irradiation and brain injury. Int J Radiat Oncol Biol Phys6, 1215–1228.
8.
HuangZ, JiangJ, BelikovaNA, StoyanovskyDA, KaganVE, MintzAH (2010) Protection of normal brain cells from gamma-irradiation-induced apoptosis by a mitochondria-targeted triphenyl-phosphonium-nitroxide: A possible utility in glioblastoma therapy. J Neurooncol100, 1–8.
9.
RaberJ, RolaR, LeFevourA, MorhardtD, CurleyJ, MizumatsuS, VandenBergSR, FikeJR (2004) Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiat Res162, 39–47.
10.
RamananS, KooshkiM, ZhaoW, HsuFC, RiddleDR, RobbinsME (2009) The PPARalpha agonist fenofibrate preserves hippocampal neurogenesis and inhibits microglial activation after whole-brain irradiation. Int J Radiat Oncol Biol Phys75, 870–877.
11.
RolaR, RaberJ, RizkA, OtsukaS, Vanden BergSR, MorhardtDR, FikeJR (2004) Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp Neurol188, 316–330.
MarshJC, GieldaBT, HerskovicAM, AbramsRA (2010) Cognitive sparing during the administration of whole brain radiotherapy and prophylactic cranial irradiation: Current concepts and approaches. J Oncol2010, 198–208.
14.
PuiCH, ChengC, LeungW, RaiSN, RiveraGK, SandlundJT, RibeiroRC, RellingMV, KunLE, EvansWE, HudsonMM (2003) Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med349, 640–649.
15.
WaberDP, TurekJ, CataniaL, StevensonK, RobaeyP, RomeroI, AdamsH, AlymanC, Jandet-BrunetC, NeubergDS, SallanSE, SilvermanLB (2007) Neuropsychological outcomes from a randomized trial of triple intrathecal chemotherapy compared with 18Gy cranial radiation as CNS treatment in acute lymphoblastic leukemia: Findings from Dana-Farber Cancer Institute ALL Consortium Protocol 95-01. J Clin Oncol25, 4914–4921.
16.
KomakiR, MeyersCA, ShinDM, GardenAS, ByrneK, NickensJA, CoxJD (1995) Evaluation of cognitive function in patients with limited small cell lung cancer prior to and shortly following prophylactic cranial irradiation. Int J Radiat Oncol Biol Phys33, 179–182.
17.
EdelsteinK, D’AgostinoN, BernsteinLJ, NathanPC, GreenbergML, HodgsonDC, MillarBA, LaperriereN, SpieglerBJ (2011) Long-term neurocognitive outcomes in young adult survivors of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol33, 450–458.
18.
SlotmanBJ, MauerME, BottomleyA, Faivre-FinnC, KramerGW, RankinEM, SneeM, HattonM, PostmusPE, ColletteL, SenanS (2009) Prophylactic cranial irradiation in extensive disease small-cell lung cancer: Short-term health-related quality of life and patient reported symptoms: Results of an international Phase III randomized controlled trial by the EORTC Radiation Oncology and Lung Cancer Groups. J Clin Oncol27, 78–84.
19.
SpieglerBJ, KennedyK, MazeR, GreenbergML, WeitzmanS, HitzlerJK, NathanPC (2006) Comparison of long-term neurocognitive outcomes in young children with acute lymphoblastic leukemia treated with cranial radiation or high-dose or very high-dose intravenous methotrexate. J Clin Oncol24, 3858–3864.
20.
OddoS, CaccamoA, ShepherdJD, MurphyMP, GoldeTE, KayedR, MetherateR, MattsonMP, AkbariY, LaFerlaFM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction. Neuron39, 409–421.
21.
JohnsonGV, SeubertP, CoxTM, MotterR, BrownJP, GalaskoD (1997) The tau protein in human cerebrospinal fluid in Alzheimer’s disease consists of proteolytically derived fragments. J Neurochem68, 430–433.
22.
MastrangeloMA, BowersWJ (2008) Detailed immunohistochemical characterization of temporal and spatial progression of Alzheimer’s disease-related pathologies in male triple-transgenic mice. BMC Neurosci9, 81.
23.
DaiCL, TungYC, LiuF, GongCX, IqbalK (2017) Tau passive immunization inhibits not only tau but also Abeta pathology. Alzheimers Res Ther9, 1.
24.
Rabinovich-NikitinI, RakoverIS, BeckerM, SolomonB (2012) Beneficial effect of antibodies against beta- secretase cleavage site of APP on Alzheimer’s-like pathology in triple-transgenic mice. PLoS One7, e46650.
25.
RajamohamedsaitH, RasoolS, RajamohamedsaitW, LinY, SigurdssonEM (2017) Prophylactic active tau immunization leads to sustained reduction in both tau and amyloid-beta pathologies in 3xTg mice. Sci Rep7, 17034.
26.
RosenbergRN, FuM, Lambracht-WashingtonD (2018) Active full-length DNA Abeta42 immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology. Alzheimers Res Ther10, 115.
27.
JanczuraKJ, VolmarCH, SartorGC, RaoSJ, RicciardiNR, LambertG, BrothersSP, WahlestedtC (2018) Inhibition of HDAC3 reverses Alzheimer’s disease-related pathologies in vitro and in the 3xTg-AD mouse model. Proc Natl Acad Sci U S A115, E11148–E11157.
28.
Baglietto-VargasD, MedeirosR, Martinez-CoriaH, LaFerlaFM, GreenKN (2013) Mifepristone alters amyloid precursor protein processing to preclude amyloid beta and also reduces tau pathology. Biol Psychiatry74, 357–366.
29.
YangL, YangJ, LiG, LiY, WuR, ChengJ, TangY (2017) Pathophysiological responses in rat and mouse models of radiation-induced brain injury. Mol Neurobiol54, 1022–1032.
RajuU, GuminGJ, TofilonPJ (2000) Radiation-induced transcription factor activation in the rat cerebral cortex. Int J Radiat Biol76, 1045–1053.
32.
ParentJM, TadaE, FikeJR, LowensteinDH (1999) Inhibition of dentate granule cell neurogenesis with brain irradiation does not prevent seizure-induced mossy fiber synaptic reorganization in the rat. J Neurosci19, 4508–4519.
33.
TadaE, ParentJM, LowensteinDH, FikeJR (2000) X-irradiation causes a prolonged reduction in cell proliferation in the dentate gyrus of adult rats. Neuroscience99, 33–41.
34.
MuY, GageFH (2011) Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Mol Neurodegener6, 85.
35.
DietrichJ, BaryawnoN, NayyarN, ValtisYK, YangB, LyI, BesnardA, SevereN, GustafssonKU, AndronesiOC, BatchelorTT, SahayA, ScaddenDT (2018) Bone marrow drives central nervous system regeneration after radiation injury. J Clin Invest128, 2651.
36.
TsaiKJ, TsaiYC, ShenCK (2007) G-CSF rescues the memory impairment of animal models of Alzheimer’s disease. J Exp Med204, 1273–1280.
37.
ShinJW, LeeJK, LeeJE, MinWK, SchuchmanEH, JinHK, BaeJS (2011) Combined effects of hematopoietic progenitor cell mobilization from bone marrow by granulocyte colony stimulating factor and AMD3100 and chemotaxis into the brain using stromal cell-derived factor-1alpha in an Alzheimer’s disease mouse model. Stem Cells29, 1075–1089.
