Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes.
Genetic causes of Alzheimer's disease (AD) include mutations in the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) genes. The mutant APP(K670N,M671L) transgenic line, Tg2576, shows markedly elevated amyloid beta-protein (A beta) levels at an early age and, by 9-12 months, develops extracellular AD-type A beta deposits in the cortex and hippocampus. Mutant PS1 transgenic mice do not show abnormal pathology, but do display subtly elevated levels of the highly amyloidogenic 42- or 43-amino acid peptide A beta42(43). Here we demonstrate that the doubly transgenic progeny from a cross between line Tg2576 and a mutant PS1M146L transgenic line develop large numbers of fibrillar A beta deposits in cerebral cortex and hippocampus far earlier than their singly transgenic Tg2576 littermates. In the period preceding overt A beta deposition, the doubly transgenic mice show a selective 41% increase in A beta42(43) in their brains. Thus, the development of AD-like pathology is substantially enhanced when a PS1 mutation, which causes a modest increase in A beta42(43), is introduced into Tg2576-derived mice. Remarkably, both doubly and singly transgenic mice showed reduced spontaneous alternation performance in a "Y" maze before substantial A beta deposition was apparent. This suggests that some aspects of the behavioral phenotype in these mice may be related to an event that precedes plaque formation.
Holcomb
L
L
Department of Pharmacology, University of South Florida, Tampa 33612, USA.
Gordon
M N
MN
McGowan
E
E
Yu
X
X
Benkovic
S
S
Jantzen
P
P
Wright
K
K
Saad
I
I
Mueller
R
R
Morgan
D
D
Sanders
S
S
Zehr
C
C
O'Campo
K
K
Hardy
J
J
Prada
C M
CM
Eckman
C
C
Younkin
S
S
Hsiao
K
K
Duff
K
K
D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology; D003433:Crosses, Genetic; D005838:Genotype; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D011187:Posture; D053764:Presenilin-1; D011597:Psychomotor Performance; D012018:Reflex; D012640:Seizures
D016564:Amyloid beta-Protein Precursor; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1