# Dual Targeting of Tau Kinases and Autophagy by Abemaciclib Independent of CDK4/6 Inhibition

## TL;DR

Abemaciclib, a cancer drug, shows promise for treating Alzheimer's by targeting tau proteins and boosting brain cell cleanup, unrelated to its original use.

## Contribution

Abemaciclib's novel dual action on tau kinases and autophagy in Alzheimer's is revealed, independent of its CDK4/6 inhibition mechanism.

## Key findings

- Abemaciclib improves cognition and reduces neurodegeneration in Alzheimer's models without affecting amyloid or glial activation.
- The drug inhibits tau kinases CaMKII and GSK3β and enhances autophagy to clear pathological tau proteins.
- Findings are validated in both mouse models and human-derived brain organoids, supporting drug repurposing for Alzheimer's.

## Abstract

Alzheimer's disease (AD) is marked by progressive cognitive decline driven largely by tau pathology, yet disease‐modifying therapies targeting tau remain limited. In this study, we re‐evaluated abemaciclib, a clinically approved CDK4/6 inhibitor for breast cancer and uncovered its previously unrecognized therapeutic potential in AD via CDK4/6‐independent mechanisms. Using the APPNL−F/MAPT double knock‐in mouse model (dKI) and AD patient‐derived brain organoids, we found that abemaciclib robustly ameliorates cognitive deficits and reduces neurodegeneration without altering amyloid burden or glial activation. Mechanistically, abemaciclib selectively inhibited key tau kinases, particularly Ca2⁺/calmodulin‐dependent protein kinase II (CaMKII) and glycogen synthase kinase 3β (GSK3β), independent of CDK4/6 inhibition, as confirmed by lentiviral knockdown experiments. Furthermore, abemaciclib enhanced autophagic flux and lysosomal activity, promoting clearance of pathological tau proteins. This dual modulation—suppression of tau phosphorylation and facilitation of degradation—highlights abemaciclib as a promising repurposed therapeutic for AD. Our findings establish a novel pharmacological profile for abemaciclib beyond its canonical role in cell cycle control, offering immediate translational potential for tau‐targeted AD therapy.

Abemaciclib rescues cognitive function and attenuates tau pathology in Alzheimer's disease models, but not through its known cancer‐fighting mechanism. This study demonstrates that abemaciclib operates independently of CDK4/6 inhibition, instead directly targeting tau kinases CaMKII and GSK3β while simultaneously promoting autophagic clearance of pathological tau. Validation across physiologically relevant mouse models and human patient‐derived brain organoids provides compelling evidence for repurposing this FDA‐approved drug with established safety profiles.