FGFR3 drives Aβ-induced tau uptake.

Area of Science:

• Neuroscience
• Cell Biology
• Pathology

Background:

• The amyloid cascade hypothesis posits amyloid beta (Aβ) initiates tau pathology in Alzheimer's disease (AD).
• Mechanisms of Aβ-mediated tau uptake and propagation are not fully understood.

Purpose of the Study:

• To elucidate how Aβ facilitates extracellular tau uptake into neurons.
• To identify novel molecular targets for mitigating tau pathology in AD.

Main Methods:

• Quantitative proteomic analysis of endocytic vesicles.
• Investigated fibroblast growth factor receptor 3 (FGFR3) and fibroblast growth factor 2 (FGF2) interactions with tau.
• Utilized knockdown of FGFR3 in hippocampus of AD model mice.

Main Results:

• Preexisting amyloid pathology enhances neuronal uptake of extracellular tau.
• Aβ induces FGFR3 internalization, mediating tau binding and uptake via FGF2.
• FGFR3 knockdown in AD mice reduced tau aggregation, decreased tau uptake, and improved memory.

Conclusions:

• Fibroblast growth factor receptor 3 (FGFR3) acts as a novel neuronal tau receptor.
• FGFR3 is a key mediator of Aβ-induced tau uptake in Alzheimer's disease.
• Targeting FGFR3 presents a potential therapeutic strategy for AD.