Low-Dose Radiation Therapy Impacts Microglial Inflammatory Response without Modulating Amyloid Load in Female TgF344-AD Rats

Abstract

Background: Low-dose radiation therapy (LD-RT) has demonstrated in preclinical and clinical studies interesting properties in the perspective of targeting Alzheimer’s disease (AD), including anti-amyloid and anti-inflammatory effects. Nevertheless, studies were highly heterogenous with respect to total doses, fractionation protocols, sex, age at the time of treatment and delay post treatment. Recently, we demonstrated that LD-RT reduced amyloid peptides and inflammatory markers in 9-month-old TgF344-AD (TgAD) males. Objective: As multiple studies demonstrated a sex effect in AD, we wanted to validate that LD-RT benefits are also observed in TgAD females analyzed at the same age. Methods: Females were bilaterally treated with 2 Gy×5 daily fractions, 2 Gy×5 weekly fractions, or 10 fractions of 1 Gy delivered twice a week. The effect of each treatment on amyloid load and inflammation was evaluated using immunohistology and biochemistry. Results: A daily treatment did not affect amyloid and reduced only microglial-mediated inflammation markers, the opposite of the results obtained in our previous male study. Moreover, altered fractionations (2 Gy×5 weekly fractions or 10 fractions of 1 Gy delivered twice a week) did not influence the amyloid load or neuroinflammatory response in females. Conclusions: A daily treatment consequently appears to be the most efficient for AD. This study also shows that the anti-amyloid and anti-inflammatory response to LD-RT are, at least partly, two distinct mechanisms. It also emphasizes the necessity to assess the sex impact when evaluating responses in ongoing pilot clinical trials testing LD-RT against AD.

In a circuit necessary for cognition and emotional affect, Alzheimer's-like pathology associates with neuroinflammation, cognitive and motivational deficits in the young adult TgF344-AD rat

“…8 D). Consistent with one other study ( Ceyzériat et al, 2024 ), our results suggest brain inflammation in AD is non-uniform and is region-specific in early phases of AD, as expected given the time course of pathology spread in humans. Indeed, the BLA may be one of a few important hubs undergoing changes indicative of early pathology and inflammatory processes occurring in Alzheimer's disease.…”

“…There have been positive reports of inflammation in this rat model and two mouse models (the TgAPPsw and PS1/APPsw) at young adult and later ages in other structures, for example, the hippocampus ( Bac et al, 2023 ; Cohen et al, 2013 ; Patel et al, 2005 ; Wu et al, 2020 ). In our current study, and consistent with at least one other study ( Ceyzériat et al, 2024 ), we demonstrate specific markers of inflammation are not expressed uniformly across the brain at young ages, and furthermore, we highlight potentially important markers of inflammation that are strongly related to each other based on protein-protein interactions which could predict AD pathology early in life.…”

“…However, it is possible the null effect was due to the difficulty of the DNMTS task vs the DMTS task employed in our current study, as the WT rats were performing, on average, under 80 percent during what the authors considered short delays ( MuñozMoreno et al, 2018 ). Moreover, it was not clear if differences may have been driven by the longest delays, as the data were binned into delays less than or greater than 15 s. Another study did report memory impairments as assessed by a Y-maze task in young adult TgAD rats ( Anderson et al, 2023 ), although others found no impairment in a hippocampal dependent Y-maze task in young adults TgAD rats ( Ceyzériat et al, 2024 ). Here, we chose a task that isolated the functional output of the mPFC (executive function) and is not hippocampal dependent ( Sloan et al, 2006 ).…”

“…In addition to the characteristic pathology, several studies have described peripheral inflammation as co-occurring with AD ( Lai et al, 2017 ), particularly after disease onset. While markers of inflammation in the brain have been identified at later ages in AD patients ( Lue et al, 2001 ) and rodent models of AD ( Patel et al, 2005 ; Wu et al, 2020 ) in addition to early disease stages ( Belfiore et al, 2019 ; Ceyzériat et al, 2024 ; Liu et al, 2021 ; Pascoal et al, 2021 ; Wright et al, 2013 ), the degree to which individual variability in intracerebral inflammation influences individual variability in cognition at early stages remains unclear.…”