Apomorphine and Alzheimer Aβ: Roles for Regulated α Cleavage, Autophagy, and Antioxidation?

In this issue, Himeno and colleagues1 describe a new, exciting – and potentially therapeutically important – regulatory event in the life cycle of the Alzheimer's amyloid precursor protein (APP) and the fragments of APP generated by proteolytic processing. At the outset, before diving deeply into the cell biology of APP and Aβ metabolism, it should be noted that, if confirmed, the effect identified by Himeno et al 1 would constitute an important addition to the experimental Aβ–lowering armamentarium currently being martialed against the cerebral amyloidosis of Alzheimer's disease (AD). About half of the over 65 population has measurable cerebral accumulation of fibrillar Aβ as defined by PET scans employing Pittsburgh compound B (PiB) as tracer2. By extension, at the time of diagnosis, patients with clinically apparent mild cognitive impairment (MCI) or early AD are bound to have a substantial cerebral burden of both fibrillar (detectable on PiB scan) and oligomeric Aβ (undetectable on PiB scan). All current experimental therapies are more effective as prophylaxis than as treatment3,4,5. The potential breakthrough from Himeno et al is the suggestion that something as simple and drug-like as apomorphine – through some pathway that is not immediately obvious – can activate clearance of Aβ from the brain. Because of this potential clinical implication, it is important to try to make sense of the new data in light of the current conventional wisdom about APP metabolism.