# Chronic oral administration of ibrutinib prevents long-term memory deficits and reduces AD pathology and neuroinflammatory responses in a mouse model of AD

## TL;DR

Long-term low-dose oral ibrutinib improves memory and reduces Alzheimer's disease (AD) pathology and brain inflammation in a mouse model.

## Contribution

Chronic low-dose oral ibrutinib is shown to reduce AD pathology and neuroinflammation without toxicity in 5xFAD mice.

## Key findings

- Ibrutinib improved cognitive function and reduced amyloid-beta (Aβ) pathology in 5xFAD mice.
- Ibrutinib decreased tau hyperphosphorylation and neuroinflammation markers like Iba-1, GFAP, and NLRP3.
- No hepatotoxicity was observed with long-term low-dose oral ibrutinib administration.

## Abstract

We previously demonstrated that ibrutinib has therapeutic efficacy against AD pathologies when injected intraperitoneally at a lower dosage (10 mg/kg, daily for 2 weeks) or orally at a higher dosage (30 mg/kg, daily for 1 month) in AD mice models. However, the effect of chronic lower dose of ibrutinib by oral administration on AD pathologies has not been investigated yet. Therefore, we investigated whether long-term oral administration of ibrutinib at a lower dose (1 or 10 mg/kg, daily for 5 months) on AD pathology and in vivo toxicity in 5xFAD mice. We found ibrutinib enhanced cognitive function and alleviated Aβ pathology in 5xFAD mice without hepatotoxicity. Furthermore, ibrutinib-treated 5xFAD mice decrease tau hyperphosphorylation, p-GSK3α/β levels, and markers of neuroinflammation such as Iba-1, GFAP, and NLRP3. Collectively, these translational studies indicate chronic oral administration of ibrutinib at low doses improves cognitive function and suppresses AD pathology/neuroinflammation in an AD mice model thereby having potential as an effective multitarget AD therapeutic in clinical application.

The online version contains supplementary material available at 10.1186/s13041-025-01225-7.