Apolipoprotein D acts as a chaperone of Aβ peptide delaying its assembly into amyloid aggregates.

The accumulation of amyloid-β (Aβ) peptides is at the root of Alzheimer's disease (AD), where oligomeric forms of Aβ disrupt brain physiology before any sign of dementia. Intense research has been directed to extrinsic molecules that modulate Aβ aggregation. However, more knowledge is needed about endogenous mechanisms maintaining Aβ homeostasis in a healthy brain. The Lipocalin Apolipoprotein D (ApoD) displays neuroprotective functions, many of which rely on managing lipids in cell membranes or lipoprotein particles. ApoD is upregulated in the aging brain and AD and is present in amyloid-β plaques. However, the functional relationship of ApoD with Aβ peptides aggregation needs to be studied. Using aggregation and ligand binding assays guided by molecular dynamics modeling, in this work we demonstrate that human ApoD is able to interact with Aβ, both in monomeric or aggregated states. Multiple binding sites in ApoD, including its hydrophobic ligand-binding pocket, are demonstrated between ApoD and Aβ by fluorescence titration, and these diverse interactions delay the aggregation process and reduce the number of large aggregates. Modeling the dynamics of interactions in sub-stoichiometric ApoD/Aβ ratios predicts that ApoD decreases the probability of switching to the β-stranded structure required for Aβ oligomerization. Our findings reveal Aβ as a novel ligand category for ApoD and therefore place this Lipocalin as an important element of the endogenous control of Aβ. ApoD is able to chaperon Aβ monomers from their origin in cellular membranes, preventing their progression towards amyloid plaques.