# Sex-dependent effects of ultra-low-dose-THC preventive treatment on neuroinflammation and cognitive decline in 5xFAD mice

## TL;DR

This study shows that ultra-low-dose THC may help prevent Alzheimer’s-related brain inflammation and cognitive decline, with different effects in male and female mice.

## Contribution

The study reveals sex-specific neuroprotective effects of ULD-THC in preventing AD-related neuroinflammation.

## Key findings

- ULD-THC reduced astrocytic and microglial activation in AD-affected brain regions.
- Male mice showed reduced hippocampal inflammation, while females showed reduced prefrontal cortex inflammation.
- Early ULD-THC treatment before pathology onset successfully mitigated AD-related neuroinflammation.

## Abstract

Alzheimer’s disease (AD) remains the most prevalent cause of dementia, yet no existing treatment effectively prevents its onset. Current therapies primarily aim to slow disease progression or manage symptoms, leaving a critical gap in preventive strategies. Recent findings suggest that ultra-low-dose tetrahydrocannabinol (ULD-THC) may exert neuroprotective effects without the adverse consequences associated with chronic THC use. This study investigates whether preventive ULD-THC treatment can mitigate neuroinflammation and early cognitive decline in the 5xFAD mouse model of AD, with a specific focus on sex differences in treatment response.

Male and female 5xFAD mice received monthly ULD-THC injections from 3 to 5 months of age, before significant pathology emerged. At 6 months, behavioral assessments were conducted, followed by molecular analyses of hippocampal and prefrontal cortex (PFC) tissue.

Results indicated that ULD-THC attuned AD-related cognitive decline in both males and females, with sex-specific neuroinflammatory responses. Males exhibited reduced hippocampal inflammation, whereas females showed reduced inflammation in the PFC, suggesting distinct neuroprotective mechanisms across sexes.

These findings highlight ULD-THC’s potential as a preventive strategy for AD, emphasizing the importance of sex-dependent therapeutic approaches. By attenuating neuroinflammatory processes before cognitive deficits fully manifest, ULD-THC offers a novel, biologically targeted approach to AD prevention. Future research should explore its long-term efficacy and translational potential in clinical settings.

The online version contains supplementary material available at 10.1186/s13293-025-00815-3.

ULD-THC modulates neuroinflammationand glial activity: Treatment reduced astrocytic (GFAP) and microglial (AIF1) activation, alongside changes in additional inflammation-related markers, demonstrating a targeted biological response in key AD-affected brain regions.Sex-specific neuroinflammatory effects: Males exhibited reduced hippocampal inflammation, while females showed a decrease in PFC inflammation, indicating distinct region-dependent responses.Preventive potential of ULD-THC: Early administration of ULD-THC, before significant pathology emerged, successfully reduced AD-related neuroinflammation.

ULD-THC modulates neuroinflammationand glial activity: Treatment reduced astrocytic (GFAP) and microglial (AIF1) activation, alongside changes in additional inflammation-related markers, demonstrating a targeted biological response in key AD-affected brain regions.

Sex-specific neuroinflammatory effects: Males exhibited reduced hippocampal inflammation, while females showed a decrease in PFC inflammation, indicating distinct region-dependent responses.

Preventive potential of ULD-THC: Early administration of ULD-THC, before significant pathology emerged, successfully reduced AD-related neuroinflammation.

The online version contains supplementary material available at 10.1186/s13293-025-00815-3.