Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model.
Alzheimer's disease (AD) is characterized by a substantial degeneration of pyramidal neurons and the appearance of neuritic plaques and neurofibrillary tangles. Here we present a novel transgenic mouse model, APP(SL)PS1KI that closely mimics the development of AD-related neuropathological features including a significant hippocampal neuronal loss. This transgenic mouse model carries M233T/L235P knocked-in mutations in presenilin-1 and overexpresses mutated human beta-amyloid (Abeta) precursor protein. Abeta(x-42) is the major form of Abeta species present in this model with progressive development of a complex pattern of N-truncated variants and dimers, similar to those observed in AD brain. At 10 months of age, an extensive neuronal loss (>50%) is present in the CA1/2 hippocampal pyramidal cell layer that correlates with strong accumulation of intraneuronal Abeta and thioflavine-S-positive intracellular material but not with extracellular Abeta deposits. A strong reactive astrogliosis develops together with the neuronal loss. This loss is already detectable at 6 months of age and is PS1KI gene dosage-dependent. Thus, APP(SL)PS1KI mice further confirm the critical role of intraneuronal Abeta(42) in neuronal loss and provide an excellent tool to investigate therapeutic strategies designed to prevent AD neurodegeneration.
Department of Central Nervous System/Alzheimer Disease, Aventis-Pharma Paris Research Center, Vitry sur Seine, France.
Caty
C
Casas
Nicolas
N
Sergeant
Jean-Michel
JM
Itier
Véronique
V
Blanchard
Oliver
O
Wirths
Nicolien
N
van der Kolk
Valérie
V
Vingtdeux
Evita
E
van de Steeg
Gwenaëlle
G
Ret
Thierry
T
Canton
Hervé
H
Drobecq
Allan
A
Clark
Bruno
B
Bonici
André
A
Delacourte
Jesús
J
Benavides
Christoph
C
Schmitz
Günter
G
Tremp
Thomas A
TA
Bayer
Patrick
P
Benoit
Laurent
L
Pradier
D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D018628:Gene Dosage; D005911:Gliosis / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007118:Immunoassay; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1; D017966:Pyramidal Cells / Q000473:pathology*
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42)