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) (Abeta42), the predominant Abeta 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, Abeta42-overburdened neurons. Furthermore, the most vulnerable neurons appear to be those that abundantly express the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), and internalization of Abeta42 appears to be facilitated by the high-affinity binding of Abeta42 to the alpha7nAChR 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 Abeta42 is the dominant Abeta peptide species in both intraneuronal accumulations and amyloid plaques. In view of the pathophysiological consequences of Abeta42 binding to alpha7nAChR on neuronal surfaces that stem from excessive intraneuronal Abeta42 accumulation, the alpha7nAChR 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 Abeta42 levels in the blood and cerebrospinal fluid as well as blocking Abeta42 in the blood from penetrating the blood-brain barrier and entering into the brain parenchyma.
D'Andrea
Michael R
MR
Johnson & Johnson Pharmaceutical Research and Development, Drug Discovery, Spring House, Pennsylvania, 19477, USA. mdandrea@prdus.jnj.com
Nagele
Robert G
RG
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D008854:Microscopy, Electron; D018733:Nicotinic Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000648:ultrastructure; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011978:Receptors, Nicotinic / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016229:Amyloid beta-Peptides; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C500437:amyloid beta-peptide (5-42)