Time sequence of maturation of dystrophic neurites associated with Abeta deposits in APP/PS1 transgenic mice.
Several novel transgenic mouse models expressing different mutant APPs in combination with mutant PS1 have been developed. These models have been analyzed to investigate the formation and progressive alterations of dystrophic neurites (DNs) in relation to Abeta deposits. In the most aggressive model, Abeta deposits appear as early as 2.5 months of age. Maturation of DNs was qualitatively quite similar among models and in some respect reminiscent of human AD pathology. From the onset of deposition, most if not all Abeta deposits were decorated with a high number of APP-, ubiquitin-, and MnSOD-immunoreactive DNs. Phosphorylated Tau DNs, however, appeared at a much slower rate and were more restricted. Mitochondrial dysfunction markers were observed in DNs: the frequency and the density per deposit of DNs accumulating cytochrome c, cytochrome oxidase 1, and Bax progressively increased with age. Later, the burden of reactive DNs was reduced around large compact/mature deposits. In addition, the previously described phenomenon of early intraneuronal Abeta accumulation in our models was associated with altered expression of APP protein as well as oxidative and mitochondrial stress markers occasionally in individual neurons. The present study demonstrates that oxidative and mitochondrial stress factors are present at several phases of Abeta pathology progression, confirming the neuronal dysfunction in APP transgenic mice.
Blanchard
Véronique
V
Neurodegenerative Disease Group, Centre de Recherche de Paris, Aventis Pharma 94403, Vitry sur Seine Cedex, France. veronique.blanchard@aventis.com
Moussaoui
Saliha
S
Czech
Christian
C
Touchet
Nathalie
N
Bonici
Bruno
B
Planche
Michel
M
Canton
Thierry
T
Jedidi
Iness
I
Gohin
Micheline
M
Wirths
Oliver
O
Bayer
Thomas A
TA
Langui
Dominique
D
Duyckaerts
Charles
C
Tremp
Günter
G
Pradier
Laurent
L
D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D006801:Humans; D007118:Immunoassay; D007150:Immunohistochemistry; D008163:Luminescent Measurements; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D016501:Neurites / Q000473:pathology*; D058225:Plaque, Amyloid / Q000235:genetics / Q000473:pathology*; D010957:Plasmids / Q000235:genetics; D053764:Presenilin-1; D013312:Stress, Physiological / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins; D013482:Superoxide Dismutase