Object recognition memory and cholinergic parameters in mice expressing human presenilin 1 transgenes.
Most autosomal dominant forms of Alzheimer disease (AD) are related to missense mutations in the human presenilin (PS) 1 gene. Although the underlying mechanisms associated with pathophysiology of AD have yet to be clearly established, pathogenic mutations in the PS1 gene influence the processing of beta-amyloid precursor protein, leading to increased production and deposition of highly fibrillogenic amyloid beta(1-42) peptide in the brains of AD patients. As cognitive dysfunction in AD is associated with a dramatic loss of cholinergic innervation particularly in the hippocampus and neocortex, we investigated learning and cholinergic neurochemistry in transgenic mice expressing pathogenic mutant L286V or wild-type(wt) human PS1 transgenes. Relative to wt, the L286V PS1 transgenic mice exhibited reduced sensorimotor activity and marked deterioration of object memory between 3 and 5 h after the first encounter. Activity of the biosynthetic enzyme choline acetyltransferase was not altered in the hippocampus, frontoparietal cortex, or striatum of mutant transgenic mice relative to wt transgenic or littermate nontransgenic controls. No differences in the densities of M1/[3H]pirenzepine, M2/[3H]AF-DX 384, or alpha(7) nicotinic/125I-alpha-bungarotoxin receptor binding sites were evident in any brain regions among L286V PS1 transgenic, wt PS1 transgenic, and littermate nontransgenic controls. These results suggest that overexpression of a mutated PS1 gene induces a subtle alteration in object memory without affecting cholinergic neurochemistry.
Vaucher
E
E
Douglas Hospital Research Center, Department of Psychiatry, McGill University, Verdun, Québec H4H 1R3, Canada.
Fluit
P
P
Chishti
M A
MA
Westaway
D
D
Mount
H T J
HT
Kar
S
S
D000109:Acetylcholine / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D015870:Gene Expression; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics*; D011939:Mental Recall / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D004856:Postural Balance / Q000502:physiology; D053764:Presenilin-1; D011976:Receptors, Muscarinic / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D021641:Recognition, Psychology / Q000502:physiology*; D019076:Transgenes
D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine