Researchers here argue that the fine details of how and when amyloid-β is cleared from the brain matters greatly in the treatment of Alzheimer's disease. To make the point they use a form of antigen-binding protein known as an anticalin, a technology that produces similar outcomes to monoclonal antibodies but with fewer inflammatory side-effects. The researchers target forms of amyloid-β that arise prior to the formation of amyloid plaques, attacking the very earliest stages leading to pathology. It works in a mouse model of Alzheimer's disease, but it is worth bearing in mind that these models are very artificial and a great deal of what has worked in mice has failed in humans.
Until relatively recently, treatment strategies aiming at the scavenging of amyloid-β (Aβ) by passive immunization with antibodies have largely failed to show a significant deceleration of cognitive decline in clinical studies, in fact raising concerns about the amyloid hypothesis. Similar discouraging observations were made in Alzheimer's mouse models. There are several possible explanations for the general failure of these approaches, most prominently an inadequate timing of the therapeutic intervention after the brain has already undergone irreparable damage. Moreover, anti-Aβ treatment at very early stages of development had positive outcomes in mouse models of amyloidosis. Thus, before Aβ plaque formation, the prevention of extracellular Aβ accumulation involving the use of γ-secretase inhibitors can effectively abolish neuronal hyperactivity. This is relevant because a variety of studies in mice and humans have established that neuronal hyperactivity is probably the earliest form of neuronal dysfunction in the diseased brain. To untangle the conflicting results on the effectivity of Aβ removal obtained from previous mouse studies, we applied here an alternative approach based on the direct intracerebral application of Aβ-binding anticalins (Aβ-anticalins). Anticalins exhibit very high target affinities and, in contrast to antibodies, a low immunogenic potential. We demonstrate that an Aβ-anticalin can suppress early neuronal hyperactivity and synaptic glutamate accumulation in the APP23xPS45 mouse model of amyloidosis. Our results suggest that the sole targeting of Aβ monomers is sufficient for the hyperactivity-suppressing effect of the Aβ-anticalin at early disease stages.