ACS Chem. Biol. doi:10.1021/cb5008663

Credit: AMERICAN CHEMICAL SOCIETY

The assembly of amyloid-β peptides (Aβ) into oligomers and fibrils is a hallmark of Alzheimer's disease (AD) pathology. It is thought that the toxic species, which include oligomers and protofibrils, are soluble aggregates rather than the end product of aggregation, which are fibrils found in extracellular plaques in diseased brain. The toxicity of these intermediates is most likely due to their interactions with other biomolecules, including proteins and cell membranes. Indeed, several essential proteins have been shown to coaggregate with Aβ, leading to cytotoxicity due to loss of function. Other Aβ-binding proteins could cause toxicity by initiating aberrant signaling processes or by targeting the various Aβ species (and any coassociated proteins) for internalization, thereby mislocalizing them. Binding events may also reflect protective mechanisms to limit Aβ toxicity. To characterize Aβ protofibril interactions at a global level, Rahman et al. performed pulldown experiments with an Aβ variant that forms stable protofibrils that are indistinguishable in structure and function from those generated from wild-type Aβ. They identified proteins that bind the protofibrils in serum and in cerebrospinal fluid, where Aβ levels are known to reflect brain amyloid load. The authors identified 101 proteins, including known Aβ-binding proteins and proteins involved in the complement system, inflammation and hemostasis as well as lipid transport and metabolism. Among the known binders, apolipoproteins apolipoprotein E (ApoE) and clusterin as well as immunoglobulins were identified. ApoE, the Aβ binder that they found at the greatest abundance and that binds at high affinity (KD = 3 nM, as measured by surface plasmon resonance), is a major genetic risk factor associated with AD that has been shown to modulate Aβ aggregation and promote its clearance from the brain. Further study will be required to dissect the rich collection of interactions revealed here to define potential new mechanisms for modulating Aβ structure and function.