Protein Aggregates as Drivers of Receptor Clustering and Pathological Signaling: A Framework Linking Extracellular Amyloid-β to Tau Dysregulation

Abstract Extracellular protein aggregates have long been viewed primarily as toxic deposits, yet this framing fails to explain a critical clinical observation: removal of amyloid-β oligomers does not halt or reverse Alzheimer’s disease progression. Here, we propose that this paradox reflects the emergence of a self-sustaining intracellular signaling state, initiated by aggregate-driven receptor clustering but capable of persisting independently of the original extracellular trigger. We argue that oligomeric assemblies act as multivalent scaffolds that cross-link cell-surface receptors, inducing nanoscale clustering and the formation of signaling-competent membrane platforms. In Alzheimer’s disease, this mechanism links amyloid-β to a receptor complex involving PrPc and mGluR5, leading to Fyn activation and downstream tau hyperphosphorylation. Critically, redistributed tau enhances Fyn recruitment to postsynaptic compartments, establishing a positive feedback loop in which kinase activity and tau pathology become mutually reinforcing, and progressively decoupled from the initiating amyloid signal. This self-amplifying circuit provides a mechanistic basis for the limited efficacy of amyloid-targeted therapies and reframes the therapeutic window problem in neurodegeneration. Beyond Alzheimer’s disease, we propose that clustering-driven feedback loops may represent a generalizable principle in proteinopathies involving extracellular or membrane-associated aggregates─such as α-synuclein─though the applicability of this principle appears to depend on whether the aggregating protein directly engages cell-surface receptor systems. This framework shifts the focus from aggregate burden to membrane organization and feedback topology as determinants of disease progression, and identifies the tau–Fyn feedback loop as a candidate therapeutic target in proteinopathies.