Although there is still no known effective preventative treatment or cure for Alzheimers disease (AD), the development of new drugs that target pathological features that appear early in the course of this disease and alleviate some of the early cognitive and memory symptoms is a laudable goal that may be one step closer. To date, the acetylcholinesterase inhibitors have been the most widely used AD drugs and have been somewhat successful in slowing loss of cognition. In the last few years, a number of studies have demonstrated that amyloid beta (1-42) (Aβ42), the predominant Aβ peptide species in amyloid plaques, first accumulates in vulnerable neurons prior to plaque formation. Recently, we have shown that many (if not most) amyloid plaques in the entorhinal cortex of AD brains are actually the lysis remnants of degenerated, Aβ42-overburdened neurons. Furthermore, the most vulnerable neurons appear to be those that abundantly express the alpha7 nicotinic acetylcholine receptor (α7nAChR), and internalization of Aβ42 appears to be facilitated by the high-affinity binding of Aβ42 to the α7nAChR on neuronal cell surfaces, followed by endocytosis of the resulting complex and its accumulation within the lysosomal compartment. This mechanism provides a reasonable explanation for the selective vulnerability of cholinergic and cholinoceptive neurons in AD brains and for the fact that Aβ42 is the dominant Aβ peptide species in both intraneuronal accumulations and amyloid plaques. In view of the pathophysiological consequences of Aβ42 binding to α7nAChR on neuronal surfaces that stem from excessive intraneuronal Aβ42 accumulation, the α7nAChR could be an important therapeutic target for treatment of AD. In addition, it further emphasizes the potential merits of new and effective therapeutic strategies pointed towards the goal of lowering of Aβ42 levels in the blood and cerebrospinal fluid as well as blocking Aβ42 in the blood from penetrating the blood-brain barrier and entering into the brain parenchyma.
Johnson & Johnson Pharmaceutical Research and Development, Drug Discovery, Welsh and McKean Rds., Spring House, Pennsylvania, 19477.