A Hypothesis About Alzheimer’s Disease, Its Cause and a Possible Method of Treatment, and Experimental Support for the Hypothesis
by Sandy Shaw
One hypothesis shared by me and probably some others about AD is that it is the ultimate dissociative disorder, with the connections between various areas of the brain being destroyed, leaving behind the originally connected material (memories, stored data, etc.), in a state where it cannot be accessed by other brain areas (some scientists including myself wonder whether it might theoretically be possible to reconstruct the connections and retrieve this material. If that is possible, it is likely, I think, to be limited to a certain critical period of time as neurons die when they are not active.)
If the hypothesis is correct, then one prediction is that the restoration of connections in a model of cholinergic denervation might be a reasonable model for Alzheimer’s disease and a possible correction. Thus, a 2010 paper (Kampen and Eckman, 2010) is right on point. Here, the researchers studied the use of cholinergic agonists to restore hippocampal neurogenesis and improve cognition in a model of cholinergic denervation (the very connections the hypothesis would suggest are missing or damaged). The authors report “the effects of various cholinergic compounds on indices of hippocampal neurogenesis, demonstrating a significant induction following pharmacological activation of [cholinergic] muscarinic M1 receptors, located on hippocampal progenitors in the adult brain [of female Sprague-Dawley rats].” The chemicals studied included nicotine (which is an agonist, that is, it activates, nicotinic-cholinergic receptors and the cholinesterase inhibitor physostigmine, the nonselective cholinergic agonist carbachol, the muscarinic agonist oxotremorine, or their vehicle.
Results showed that the maximal induction was observed following the highest dose of oxotremorine, the muscarinic agonist. Only lower doses of carbachol elevated cell proliferation in the dentate gyrus (an area of neurogenesis), and the CHOLINESTERASE INHIBITOR physostigmine triggered a modest, but significant, elevation in the production of new neurons from progenitors. As the authors explain, “…we have shown that selective activation of muscarinic receptors is capable of triggering an induction of cell proliferation not only in the DG [dentate gyrus], but also the CA1 region of the hippocampus, an area of severe neuronal loss in AD [Alzheimer’s disease].” “…oxotremorine-induced increases in BrdU-positive cell counts [neurogenic cells] are likely to reflect an effect on cell proliferation rather than an indirect effect on cell survival.” “…impairments in cell proliferation, in a model of basal forebrain cholinergic cell loss are counteracted by chronic muscarinic activation. This restoration of cell proliferation is accompanied by a time dependent increase in the number of newly generated cells expressing neuronal markers and by a reversal of cognitive deficits characteristic of this model.”
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