Memory deficits correlating with acetylcholinesterase splice shift and amyloid burden in doubly transgenic mice.
Current mouse models of Alzheimer's disease show brain pathology that correlates to a degree with memory impairment, but underlying molecular mechanisms remained unknown. Here we report studies with three lines of transgenic mice: animals that doubly express mutated human amyloid precursor protein (APPswe) and human acetylcholinesterase (hAChE); and animals transgenic for only the APPswe or the hAChE. Among these genotypes, variations were observed in expression of mRNA for presenilin-1, which was highest in singly transgenic hAChE mice, and the stress-inducible form of AChE, which was elevated when both transgenes were present. At the age of nine months, both double and single transgenic mice displayed working memory impairment in a radial arm water maze. However, as compared with mice expressing amyloid alone, the double transgenic animals exhibited more numerous plaques and greater amyloid burden in brain (both by histochemistry and by ELISA of amyloid protein). Moreover, the amyloid burden in double transgenics was tightly correlated with memory impairment as measured by total maze errors (r2= 0.78, p = .002). This correlation was markedly stronger than observed in mice with amyloid alone. These new findings support the notion of cholinergic-amyloid interrelationships and highlight the double transgenic mice as a promising alternative for testing Alzheimer's therapies.
Rees
Tina M
TM
Department of Molecular Pharmacology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
Berson
Amit
A
Sklan
Ella H
EH
Younkin
Linda
L
Younkin
Steven
S
Brimijoin
Stephen
S
Soreq
Hermona
H
D000110:Acetylcholinesterase / Q000235:genetics*; D000682:Amyloid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004274:DNA, Recombinant; D004797:Enzyme-Linked Immunosorbent Assay; D014644:Genetic Variation; D008297:Male; D018782:Maze Learning; D008565:Membrane Proteins / Q000378:metabolism; D008569:Memory Disorders / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D058225:Plaque, Amyloid; D053764:Presenilin-1; D012333:RNA, Messenger / Q000378:metabolism; D013550:Swimming
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D004274:DNA, Recombinant; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D012333:RNA, Messenger; D000110:Acetylcholinesterase