Elucidating the relationship between TGF‐β signaling and Alzheimer’s disease

Abstract Background The TGF‐β signaling pathway represents a complex family and network of ligands and receptors. A body of evidence suggests that in Alzheimer’s Disease this signaling network may be perturbed and could contribute to disease development and progression. Other studies have shown a role for TGF‐β signaling in both Aβ clearance and deposition, as well as, in neuroprotection and neurotoxicity. It remains to be determined precisely the contributions of TGF‐β signaling to mechanisms underlying Alzheimer’s disease and other dementias and whether targeting TGF‐β may lead to suitable novel therapies. Methods To interrogate the contributions of TGF‐β signaling to Aβ and tau pathology in AD we developed several recombinant adeno‐associated virus (rAAV) constructs to express TGF‐β family ligands and decoy receptors. APP overexpressing (TgCRND8) mice were injected with rAAVs at postnatal day 0 or after 3 months of aging to examine contributions of the TGF‐β family prior to and during Aβ deposition. We also examined how TGF‐β family ligands and decoy receptors affect the development of tau pathology in tau brain slice culture (BSC) models. Results We have successfully expressed TGF‐β family ligands and decoy receptors to determine their contributions to Aβ clearance and deposition in vivo in APP overexpressing mice, as well as, effects on tau pathology in ex vivo tau BSC models. Stimulating and blocking TGF‐β signaling cascades appears to have opposing effects on AD‐relevant pathology. Using this rAAV approach we can rapidly dissect how complex signaling cascades may contribute to the progression and development of human AD and how targeting these pathways may be therapeutically rewarding. Conclusions These findings suggest that interventions targeting TGF‐β signaling may be a novel therapeutic approach to AD. This data also enforces that pathways involved in immune function can have significant effects on the healthy and diseased brain and should be explored further in order to understand the development and progression of AD. Using a systems approach (NIH U01AG046139) we identified perturbed networks regulating innate immunity in the AD brain and have now validated how intervening with TGF‐β signaling may provide therapeutic benefit.