Targeting the alpha 7 nicotinic acetylcholine receptor to reduce amyloid accumulation in Alzheimer's disease pyramidal neurons

Although there is still no known effective preventative treatment or cure for Alzheimer's 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) (A beta 42), the predominant A beta 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, A beta 42-overburdened neurons. Furthermore, the most vulnerable neurons appear to be those that abundantly express the alpha7 nicotinic acetylcholine receptor (alpha 7nAChR), and internalization of A beta 42 appears to be facilitated by the high-affinity binding of A beta 42 to the alpha 7nAChR 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 A beta 42 is the dominant A beta peptide species in both intraneuronal accumulations and amyloid plaques. In view of the pathophysio logical consequences of A beta 42 binding to alpha 7nAChR on neuronal surfaces that stem from excessive intrancuronal A beta 42 accumuiation, the alpha 7nAChR 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 A beta 42 levels in the blood and cerebrospinal fluid as well as blocking A beta 42 in the blood from penetrating the blood-brain barrier and entering into the brain parenchyma.