Alzheimer's disease and Down's syndrome: roles of APP, trophic factors and ACh.
Recent therapeutic investigations of Alzheimer's disease (AD) have been guided by two seemingly opposed hypotheses: the amyloid cascade theory, which favors the amyloid plaques as the cause of AD; and the cholinergic theory, which favors cholinergic neuron loss as the cause. New investigations indicate that the synthesis and processing of the amyloid precursor protein (APP) is linked to the trophic actions of nerve growth factor. A pathological cascade in both AD- and Down's syndrome-related memory loss could be triggered by alterations in APP processing or ACh-mediated neuronal function, or both, which in turn trigger the overexpression of amyloid beta, synaptic malfunction and trophic factor loss in target regions. This eventually leads to synaptic and dendritic loss with age.
Isacson
Ole
O
Neuroregeneration Laboratory, McLean Hospital, Program in Neuroscience and Dept of Neurology, Harvard Medical School, Belmont, MA 02478-9106, USA. isacson@helix.mgh.harvard.edu
Seo
Hyemyung
H
Lin
Ling
L
Albeck
David
D
Granholm
Ann Charlotte
AC
D000109:Acetylcholine / Q000172:deficiency / Q000378:metabolism*; D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D004314:Down Syndrome / Q000209:etiology / Q000378:metabolism*; D006133:Growth Substances / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D017774:Long-Term Potentiation; D011950:Receptors, Cholinergic / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D006133:Growth Substances; D011950:Receptors, Cholinergic; D000109:Acetylcholine