Distinct Filament Conformation for Receptor-Bound Amyloid-β from Alzheimers Disease Brain

Alzheimers disease is triggered by amyloid-{beta}, with symptoms linked to synapse loss. Oligomeric amyloid-{beta}, rather than monomeric or fibrillar amyloid-{beta}, has been proposed to be the proximate mechanistic cause, but the relevant molecular characteristics have remained unclear. Here, we define a distinct receptor-bound amyloid-{beta} pool in Alzheimers brain by release with a receptor antagonist and purification to homogeneity. Receptor-bound amyloid-{beta} is ten times more abundant than free unbound amyloid-{beta}. The amyloid-{beta} associated with receptor is composed of 65 nm long filaments with prion protein binding at its tips. There is no evidence for an oligomeric A{beta} state interacting with human brain receptors. Cryo-electron microscopy shows two symmetric S-shaped monomers per filament rung. The tilt between rung monomers, twist along the filament axis, amino terminal conformation and amyloid seeding properties distinguish this structure from plaque-associated amyloid-{beta} filaments of the same brain. High tip:length ratio is critical for prion protein receptor interaction and synaptic damage. Characterizing receptor-bound amyloid-{beta} filament provides insight into neuronal dysfunction separate from plaque aggregation.