Accelerated plaque accumulation, associative learning deficits, and up-regulation of alpha 7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteins.
Familial Alzheimer's disease-associated mutations in presenilin 1 or 2 or amyloid precursor protein result in elevated beta-amyloid, beta-amyloid accumulation, and plaque formation in the brains of affected individuals. By crossing presenilin 1 transgenic mice carrying the A246E mutation with plaque-producing amyloid precursor protein K670N/M671L transgenic mice (Tg2576), we show that co-expression of both mutant transgenes results in acceleration of amyloid accumulation and associative learning deficits. At 5 months of age with no detectable plaque pathology, amyloid precursor protein transgenic animals are impaired in contextual fear learning following two pairings of conditioned and unconditioned stimuli but appear normal following a more robust five-pairing training. At 9 months of age when beta-amyloid deposition is evident, these mice are impaired following both two-pairing and five-pairing protocols. Mice carrying both transgenes are impaired in contextual fear conditioning at either age. All transgenic animal groups performed as well as controls in cued fear conditioning, indicating that the contextual fear learning deficits are hippocampus-specific. The associative learning impairments are coincident with elevated alpha 7 nicotinic acetylcholine receptor protein in the dentate gyrus. These findings provide two robust and rapid assays for beta-amyloid-associated effects that can be performed on young animals: impaired contextual fear learning and up-regulation of alpha 7 nicotinic receptors.
Dineley
Kelly T
KT
Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
Xia
Xuefeng
X
Bui
Duy
D
Sweatt
J David
JD
Zheng
Hui
H
D000367:Age Factors; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D005239:Fear; D006624:Hippocampus / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D007858:Learning; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D053764:Presenilin-1; D011485:Protein Binding; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012769:Shock; D013997:Time Factors; D019076:Transgenes; D015854:Up-Regulation; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016564:Amyloid beta-Protein Precursor; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor