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.
Casas
Caty
C
Department of Central Nervous System/Alzheimer Disease, Aventis-Pharma Paris Research Center, Vitry sur Seine, France.
Sergeant
Nicolas
N
Itier
Jean-Michel
JM
Blanchard
Véronique
V
Wirths
Oliver
O
van der Kolk
Nicolien
N
Vingtdeux
Valérie
V
van de Steeg
Evita
E
Ret
Gwenaëlle
G
Canton
Thierry
T
Drobecq
Hervé
H
Clark
Allan
A
Bonici
Bruno
B
Delacourte
André
A
Benavides
Jesús
J
Schmitz
Christoph
C
Tremp
Günter
G
Bayer
Thomas A
TA
Benoit
Patrick
P
Pradier
Laurent
L
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)