# Radiation-Induced Neurodegeneration

**Authors:** Marialuisa Zedde, Rosario Pascarella

PMC · DOI: 10.3390/biomedicines14020357 · Biomedicines · 2026-02-03

## TL;DR

This review explores how radiation therapy for brain tumors can cause neurodegeneration and cognitive decline, and discusses potential ways to prevent or treat these effects.

## Contribution

The paper provides a comprehensive analysis of the mechanisms and clinical implications of radiation-induced neurodegeneration, highlighting potential therapeutic strategies.

## Key findings

- Radiation causes vascular injury, microglial activation, and impaired neurogenesis, leading to cognitive decline.
- Patient age, treatment regimens, and genetic factors influence the severity of radiation-induced neurotoxicity.
- Emerging biomarkers in cerebrospinal fluid may help identify individual susceptibility to radiation-induced cognitive impairments.

## Abstract

Background: Radiation therapy is a critical treatment modality for craniofacial tumors and metastatic lesions, particularly gliomas. While effective, it poses significant risks of neurotoxicity, which adversely affects patient quality of life. This review aims to explore the mechanisms underlying radiation-induced neurodegeneration (RIN) and its clinical implications, focusing on the interplay between radiation exposure, cognitive decline, and potential therapeutic strategies. Methods: A comprehensive literature review was conducted, analyzing studies on radiation effects on the central nervous system (CNS), including mechanisms of injury, clinical outcomes, and emerging therapeutic approaches. Key areas of interest included the role of inflammation, vascular damage, neurogenesis impairment, and genetic predispositions in the context of radiation therapy. Results: The findings indicate that radiation induces a complex cascade of neurobiological changes, including vascular injury, microglial activation, and neurogenesis dysfunction, leading to cognitive impairments. The severity of these effects is influenced by patient age, treatment regimens, and individual genetic factors. Additionally, emerging biomarkers in cerebrospinal fluid may provide insights into individual susceptibility to radiation-induced neurotoxicity. Therapeutic strategies such as neuroprotective agents, anti-inflammatory treatments, and advanced radiation techniques show promise in mitigating cognitive decline. Conclusions: Radiation-induced neurodegeneration is a multifaceted process with significant implications for patients undergoing radiation therapy. The underlying mechanisms include endothelial cell apoptosis leading to blood–brain barrier breakdown, chronic inflammation, and the destruction of neural progenitor cells in the hippocampus, which collectively trigger cognitive decline and progressive degeneration. A better understanding of these mechanisms is crucial for developing effective preventative and therapeutic strategies. Future research should focus on identifying high-risk patients and exploring innovative approaches to minimize cognitive impacts while maximizing the efficacy of radiation treatment.

## Full-text entities

- **Genes:** APOA1 (apolipoprotein A1) [NCBI Gene 335] {aka AMYLD3, HPALP2, apo(a)}, CCL8 (C-C motif chemokine ligand 8) [NCBI Gene 6355] {aka HC14, MCP-2, MCP2, SCYA10, SCYA8}, PTGS2 (prostaglandin-endoperoxide synthase 2) [NCBI Gene 5743] {aka COX-2, COX2, GRIPGHS, PGG/HS, PGHS-2, PHS-2}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, TLR4 (toll like receptor 4) [NCBI Gene 7099] {aka ARMD10, CD284, TLR-4, TOLL}, ACSM3 (acyl-CoA synthetase medium chain family member 3) [NCBI Gene 6296] {aka SA, SAH}, ATM (ATM serine/threonine kinase) [NCBI Gene 472] {aka AT1, ATA, ATC, ATD, ATDC, ATE}, IL1A (interleukin 1 alpha) [NCBI Gene 3552] {aka IL-1 alpha, IL-1A, IL1, IL1-ALPHA, IL1F1}, Mki67 (antigen identified by monoclonal antibody Ki 67) [NCBI Gene 17345] {aka D630048A14Rik, Ki-67, Ki67}, CEP128 (centrosomal protein 128) [NCBI Gene 145508] {aka C14orf145, C14orf61, LEDP/132}, GLB1 (galactosidase beta 1) [NCBI Gene 2720] {aka EBP, ELNR1, MPS4B}, ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase) [NCBI Gene 6098] {aka MCF3, ROS, c-ros-1}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, APP (amyloid beta precursor protein) [NCBI Gene 351] {aka AAA, ABETA, ABPP, AD1, APPI, CTFgamma}, NLRP3 (NLR family pyrin domain containing 3) [NCBI Gene 114548] {aka AGTAVPRL, AII, AVP, C1orf7, CIAS1, CLR1.1}, BCL2 (BCL2 apoptosis regulator) [NCBI Gene 596] {aka Bcl-2, PPP1R50}, HOMER1 (homer scaffold protein 1) [NCBI Gene 9456] {aka HOMER, HOMER1A, HOMER1B, HOMER1C, SYN47, Ves-1}, ALK (ALK receptor tyrosine kinase) [NCBI Gene 238] {aka ALK1, CD246, NBLST3}, CHI3L1 (chitinase 3 like 1) [NCBI Gene 1116] {aka ASRT7, CGP-39, GP-39, GP39, HC-gp39, HCGP-3P}, Psen1 (presenilin 1) [NCBI Gene 19164] {aka Ad3h, PS-1, PS1, S182}, CLU (clusterin) [NCBI Gene 1191] {aka AAG4, APO-J, APOJ, CLI, CLU1, CLU2}, COX2 (cytochrome c oxidase subunit II) [NCBI Gene 4513] {aka COII, MTCO2}, PRKCG (protein kinase C gamma) [NCBI Gene 5582] {aka PKC-gamma, PKCC, PKCG, PKCI(3), PKCgamma, SCA14}, APEX1 (apurinic/apyrimidinic endodeoxyribonuclease 1) [NCBI Gene 328] {aka APE, APE1, APEN, APEX, APX, HAP1}, CD8A (CD8 subunit alpha) [NCBI Gene 925] {aka CD8, CD8alpha, IMD116, Leu2, p32}, CCL2 (C-C motif chemokine ligand 2) [NCBI Gene 6347] {aka GDCF-2, HC11, HSMCR30, MCAF, MCP-1, MCP1}, GFAP (glial fibrillary acidic protein) [NCBI Gene 2670] {aka ALXDRD}, TMEM119 (transmembrane protein 119) [NCBI Gene 338773] {aka OBIF}, SOD1 (superoxide dismutase 1) [NCBI Gene 6647] {aka ALS, ALS1, HEL-S-44, IPOA, SOD, STAHP}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, H2AX (H2A.X variant histone) [NCBI Gene 3014] {aka H2A.X, H2A/X, H2AFX}, CGAS (cyclic GMP-AMP synthase) [NCBI Gene 115004] {aka C6orf150, D4, MB21D1, h-cGAS}, PGR (progesterone receptor) [NCBI Gene 5241] {aka NR3C3, PR}, SELE (selectin E) [NCBI Gene 6401] {aka CD62E, ELAM, ELAM1, ESEL, LECAM2, selectin-e}, APOE (apolipoprotein E) [NCBI Gene 348] {aka AD2, APO-E, ApoE4, LDLCQ5, LPG}, GSK3B (glycogen synthase kinase 3 beta) [NCBI Gene 2932], ERBB2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 2064] {aka CD340, HER-2, HER-2/neu, HER2, MLN 19, MLN-19}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, GRIA1 (glutamate ionotropic receptor AMPA type subunit 1) [NCBI Gene 2890] {aka GLUH1, GLUR1, GLURA, GluA1, HBGR1, MRD67}, App (amyloid beta precursor protein) [NCBI Gene 11820] {aka Abeta, Abpp, Adap, Ag, Cvap, E030013M08Rik}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, ICAM1 (intercellular adhesion molecule 1) [NCBI Gene 3383] {aka BB2, CD54, P3.58}, IDO1 (indoleamine 2,3-dioxygenase 1) [NCBI Gene 3620] {aka IDO, IDO-1, INDO}, BDNF (brain derived neurotrophic factor) [NCBI Gene 627] {aka ANON2, BULN2}, SNCA (synuclein alpha) [NCBI Gene 6622] {aka NACP, PARK1, PARK4, PD1}, HMGB1 (high mobility group box 1) [NCBI Gene 3146] {aka HMG-1, HMG1, HMG3, SBP-1}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, CDKN2A (cyclin dependent kinase inhibitor 2A) [NCBI Gene 1029] {aka ARF, CAI2, CDK4I, CDKN2, CMM2, INK4}, PPARD (peroxisome proliferator activated receptor delta) [NCBI Gene 5467] {aka FAAR, NR1C2, NUC1, NUCI, NUCII, PPARB}, EPO (erythropoietin) [NCBI Gene 2056] {aka DBAL, ECYT5, EP, MVCD2}, CDH5 (cadherin 5) [NCBI Gene 1003] {aka 7B4, CD144}, MAPT (microtubule associated protein tau) [NCBI Gene 4137] {aka DDPAC, FTD1, FTDP-17, MAPTL, MSTD, MTBT1}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, STING1 (stimulator of interferon response cGAMP interactor 1) [NCBI Gene 340061] {aka ERIS, MITA, MPYS, NET23, SAVI, STING}, TREM2 (triggering receptor expressed on myeloid cells 2) [NCBI Gene 54209] {aka AD17, PLOSL2, TREM-2, Trem2a, Trem2b, Trem2c}, NEFL (neurofilament light chain) [NCBI Gene 4747] {aka CMT1F, CMT2E, CMTDIG, NF-L, NF68, NFL}, BRAF (B-Raf proto-oncogene, serine/threonine kinase) [NCBI Gene 673] {aka B-RAF1, B-raf, BRAF-1, BRAF1, NS7, RAFB1}, HTT (huntingtin) [NCBI Gene 3064] {aka HD, IT15, LOMARS}, FUS (FUS RNA binding protein) [NCBI Gene 2521] {aka ALS6, ETM4, FUS1, HNRNPP2, POMP75, TLS}, GDNF (glial cell derived neurotrophic factor) [NCBI Gene 2668] {aka ATF, ATF1, ATF2, HFB1-GDNF, HSCR3}
- **Diseases:** astrocytosis (MESH:D005911), microvascular damage (MESH:D017566), Glioma (MESH:D005910), cerebral microbleeds (MESH:D002547), cerebral damage (MESH:D002539), Amyotrophic Lateral Sclerosis (MESH:D000690), thrombus (MESH:D013927), metastases (MESH:D009362), neurodegeneration (MESH:D019636), disease (MESH:D004194), injuries (MESH:D014947), headaches (MESH:D006261), Inflammatory (MESH:D007249), Brain Damage (MESH:D001925), PD (MESH:D010300), Mitochondrial damage (MESH:D028361), brain (MESH:D001927), brain injury (MESH:D001930), intellectual disability (MESH:D008607), vascular dementia (MESH:D015140), Demyelination (MESH:D003711), motor, intellectual, visual, and psychological dysfunctions (MESH:D014786), melanoma, breast, renal, and colorectal (MESH:D061325), SCLC (MESH:D055752), hypertrophy (MESH:D006984), astrocytic reactive hyperplasia (MESH:D019310), cerebral ischemia (MESH:D002545), lung, (MESH:D008171), microangiopathy (MESH:D014652), Dysbiosis (MESH:D064806), HD (MESH:D006816), psychosis (MESH:D011618), Tumor (MESH:D009369), ischemic strokes (MESH:D002544), Neurogenesis Dysfunction (MESH:D001750), AD (MESH:D000544), diminished memory (MESH:D015354), cognitive and neurological impairments (MESH:D060825), Neurogenic Coupling failure (MESH:D051437), mental disorders (MESH:D001523), brain atrophy (MESH:C566985), Neurocognitive impairment (MESH:D019965), infections (MESH:D007239), Neurotoxic (MESH:D020258), lung cancer (MESH:D008175), CNS injury (MESH:D002493), edema (MESH:D004487), Neuroinflammation (MESH:D000090862), anxiety (MESH:D001007), atrophy (MESH:D001284), neural loss (MESH:C537239), Tauopathy (MESH:D024801), Vascular Damage (MESH:D057772), vascular dysfunction (MESH:D002561), head and neck cancer (MESH:D006258), cytotoxic (MESH:D064420), autoimmune toxicity (MESH:D001327), organ dysfunction (MESH:D009102), infarcts (MESH:D007238), nausea (MESH:D009325)
- **Chemicals:** HA (-), pemetrexed (MESH:D000068437), Succinate (MESH:D019802), oxygen (MESH:D010100), thymoquinone (MESH:C003466), Quercetin (MESH:D011794), indomethacin (MESH:D007213), Idebenone (MESH:C036619), Lactate (MESH:D019344), Memantine (MESH:D008559), Dasatinib (MESH:D000069439), celecoxib (MESH:D000068579), Metformin (MESH:D008687), steroid (MESH:D013256), MPTP (MESH:D015632), lipids (MESH:D008055), iron (MESH:D007501), Kynurenine (MESH:D007737), hydrogen (MESH:D006859), glutamate (MESH:D018698), SCFA (MESH:D005232), ROS (MESH:D017382), Bevacizumab (MESH:D000068258), NO (MESH:D009569), GW501516 (MESH:C425931)
- **Species:** Mus musculus (house mouse, species) [taxon 10090], Escherichia coli Nissle 1917 (strain) [taxon 316435], Lactobacillus (genus) [taxon 1578], Bifidobacterium (genus) [taxon 1678], Homo sapiens (human, species) [taxon 9606]
- **Mutations:** rs17111237

## Full text

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## Figures

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## References

330 references — full list in the complete paper: https://tomesphere.com/paper/PMC12938431/full.md

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Source: https://tomesphere.com/paper/PMC12938431