Cranial irradiation significantly reduces beta amyloid plaques in the brain and improves cognition in a murine model of Alzheimer's Disease (AD)

Brian Marples, Mackenzie McGee, Sean Callan, Scott E. Bowen, Bryan J. Thibodeau, Daniel B. Michael, George D. Wilson, Michael E. Maddens, James Fontanesi, Alvaro A. Martinez

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background and purpose To investigate if cranial X-irradiation reduces amyloid-β (Aβ) plaques and influences cognitive function in a transgenic mouse model of AD. Methods and materials B6.Cg-Tg (APPswePSEN1dE9)85Dbo/J AD-prone mice were given cranial X-irradiation. The number of Aβ plaques, along with expression of AD specific genes (84 genes: Mouse Alzheimer's Disease RT2 Profiler™), radiation-associated cytokines (Milliplex® MAP Mouse Cytokine Chemokine Immunoassay) and immunohistochemistry (IL10, IL-1β, Iba1 CD45) was assessed. Behavioral testing was performed to relate changes in Aβ burden to cognitive function using a Morris water-maze task. Results Single X-ray doses reduced the number (p = 0.002) and size (p = 0.01) of Aβ plaques. Low-dose fractionation produced greater 50.6% (1 Gy × 10), 72% (2 Gy × 5) and 78% (2 Gy × 10) reductions. Irradiation was associated with gene (Pkp4, 1.5-fold, p = 0.004) and proteomic (MIP-2, 8-fold, p = 0.0024) changes at 24-48 h. Microglia increased at 4 weeks post-irradiation (p = 0.001). The reduction in Aβ burden (2 Gy × 5) was associated with cognitive improvement (p = 0.012). Conclusion This is the first report that a clinically relevant course of external beam irradiation (2 Gy × 5) produces a significant reduction in AD-associated amyloid-β plaques with a subsequent improvement in cognitive function. However, longer-term studies are needed to define the precise underlying mechanism and longevity of this response.

Original languageEnglish (US)
Pages (from-to)43-51
Number of pages9
JournalRadiotherapy and Oncology
Volume118
Issue number1
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Fingerprint

Cranial Irradiation
Amyloid Plaques
Cognition
Alzheimer Disease
Brain
Dose Fractionation
Cytokines
Genes
Microglia
Interleukin-1
Chemokines
Immunoassay
Interleukin-10
Proteomics
Transgenic Mice
Immunohistochemistry
X-Rays
Radiation
Water

Keywords

  • Amyloid-β
  • Murine model
  • Plaque clearance
  • Radiation

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Radiology Nuclear Medicine and imaging

Cite this

Cranial irradiation significantly reduces beta amyloid plaques in the brain and improves cognition in a murine model of Alzheimer's Disease (AD). / Marples, Brian; McGee, Mackenzie; Callan, Sean; Bowen, Scott E.; Thibodeau, Bryan J.; Michael, Daniel B.; Wilson, George D.; Maddens, Michael E.; Fontanesi, James; Martinez, Alvaro A.

In: Radiotherapy and Oncology, Vol. 118, No. 1, 01.01.2016, p. 43-51.

Research output: Contribution to journalArticle

Marples, B, McGee, M, Callan, S, Bowen, SE, Thibodeau, BJ, Michael, DB, Wilson, GD, Maddens, ME, Fontanesi, J & Martinez, AA 2016, 'Cranial irradiation significantly reduces beta amyloid plaques in the brain and improves cognition in a murine model of Alzheimer's Disease (AD)', Radiotherapy and Oncology, vol. 118, no. 1, pp. 43-51. https://doi.org/10.1016/j.radonc.2015.10.019
Marples, Brian ; McGee, Mackenzie ; Callan, Sean ; Bowen, Scott E. ; Thibodeau, Bryan J. ; Michael, Daniel B. ; Wilson, George D. ; Maddens, Michael E. ; Fontanesi, James ; Martinez, Alvaro A. / Cranial irradiation significantly reduces beta amyloid plaques in the brain and improves cognition in a murine model of Alzheimer's Disease (AD). In: Radiotherapy and Oncology. 2016 ; Vol. 118, No. 1. pp. 43-51.
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abstract = "Background and purpose To investigate if cranial X-irradiation reduces amyloid-β (Aβ) plaques and influences cognitive function in a transgenic mouse model of AD. Methods and materials B6.Cg-Tg (APPswePSEN1dE9)85Dbo/J AD-prone mice were given cranial X-irradiation. The number of Aβ plaques, along with expression of AD specific genes (84 genes: Mouse Alzheimer's Disease RT2 Profiler™), radiation-associated cytokines (Milliplex{\circledR} MAP Mouse Cytokine Chemokine Immunoassay) and immunohistochemistry (IL10, IL-1β, Iba1 CD45) was assessed. Behavioral testing was performed to relate changes in Aβ burden to cognitive function using a Morris water-maze task. Results Single X-ray doses reduced the number (p = 0.002) and size (p = 0.01) of Aβ plaques. Low-dose fractionation produced greater 50.6{\%} (1 Gy × 10), 72{\%} (2 Gy × 5) and 78{\%} (2 Gy × 10) reductions. Irradiation was associated with gene (Pkp4, 1.5-fold, p = 0.004) and proteomic (MIP-2, 8-fold, p = 0.0024) changes at 24-48 h. Microglia increased at 4 weeks post-irradiation (p = 0.001). The reduction in Aβ burden (2 Gy × 5) was associated with cognitive improvement (p = 0.012). Conclusion This is the first report that a clinically relevant course of external beam irradiation (2 Gy × 5) produces a significant reduction in AD-associated amyloid-β plaques with a subsequent improvement in cognitive function. However, longer-term studies are needed to define the precise underlying mechanism and longevity of this response.",
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T1 - Cranial irradiation significantly reduces beta amyloid plaques in the brain and improves cognition in a murine model of Alzheimer's Disease (AD)

AU - Marples, Brian

AU - McGee, Mackenzie

AU - Callan, Sean

AU - Bowen, Scott E.

AU - Thibodeau, Bryan J.

AU - Michael, Daniel B.

AU - Wilson, George D.

AU - Maddens, Michael E.

AU - Fontanesi, James

AU - Martinez, Alvaro A.

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N2 - Background and purpose To investigate if cranial X-irradiation reduces amyloid-β (Aβ) plaques and influences cognitive function in a transgenic mouse model of AD. Methods and materials B6.Cg-Tg (APPswePSEN1dE9)85Dbo/J AD-prone mice were given cranial X-irradiation. The number of Aβ plaques, along with expression of AD specific genes (84 genes: Mouse Alzheimer's Disease RT2 Profiler™), radiation-associated cytokines (Milliplex® MAP Mouse Cytokine Chemokine Immunoassay) and immunohistochemistry (IL10, IL-1β, Iba1 CD45) was assessed. Behavioral testing was performed to relate changes in Aβ burden to cognitive function using a Morris water-maze task. Results Single X-ray doses reduced the number (p = 0.002) and size (p = 0.01) of Aβ plaques. Low-dose fractionation produced greater 50.6% (1 Gy × 10), 72% (2 Gy × 5) and 78% (2 Gy × 10) reductions. Irradiation was associated with gene (Pkp4, 1.5-fold, p = 0.004) and proteomic (MIP-2, 8-fold, p = 0.0024) changes at 24-48 h. Microglia increased at 4 weeks post-irradiation (p = 0.001). The reduction in Aβ burden (2 Gy × 5) was associated with cognitive improvement (p = 0.012). Conclusion This is the first report that a clinically relevant course of external beam irradiation (2 Gy × 5) produces a significant reduction in AD-associated amyloid-β plaques with a subsequent improvement in cognitive function. However, longer-term studies are needed to define the precise underlying mechanism and longevity of this response.

AB - Background and purpose To investigate if cranial X-irradiation reduces amyloid-β (Aβ) plaques and influences cognitive function in a transgenic mouse model of AD. Methods and materials B6.Cg-Tg (APPswePSEN1dE9)85Dbo/J AD-prone mice were given cranial X-irradiation. The number of Aβ plaques, along with expression of AD specific genes (84 genes: Mouse Alzheimer's Disease RT2 Profiler™), radiation-associated cytokines (Milliplex® MAP Mouse Cytokine Chemokine Immunoassay) and immunohistochemistry (IL10, IL-1β, Iba1 CD45) was assessed. Behavioral testing was performed to relate changes in Aβ burden to cognitive function using a Morris water-maze task. Results Single X-ray doses reduced the number (p = 0.002) and size (p = 0.01) of Aβ plaques. Low-dose fractionation produced greater 50.6% (1 Gy × 10), 72% (2 Gy × 5) and 78% (2 Gy × 10) reductions. Irradiation was associated with gene (Pkp4, 1.5-fold, p = 0.004) and proteomic (MIP-2, 8-fold, p = 0.0024) changes at 24-48 h. Microglia increased at 4 weeks post-irradiation (p = 0.001). The reduction in Aβ burden (2 Gy × 5) was associated with cognitive improvement (p = 0.012). Conclusion This is the first report that a clinically relevant course of external beam irradiation (2 Gy × 5) produces a significant reduction in AD-associated amyloid-β plaques with a subsequent improvement in cognitive function. However, longer-term studies are needed to define the precise underlying mechanism and longevity of this response.

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