Inter-individual variability in the expression of the mutated form of hPS1M146L determined the production of Abeta peptides in the PS1xAPP transgenic mice.
The detection of the early phenotypic modifications of Alzheimer's disease (AD) models is fundamental to understand the progression and identify pharmacologic targets of this pathology. However, a large variability within different models and between age-matched mice from the same model has been observed. This variability could be due to heterogeneity in the Abeta production. Present results showed the existence of a large variability in the Abeta deposition in both hippocampus and cortex in 6-month-old PS1xAPP mice. This variability was not due to the expression of hAPP751SL, however, linear relationship between hPS1M146L mRNA and Abeta production was identified. The Abeta content was related to the incorporation of the hPS1M146L into functional gamma-secretase complexes, detected by the presence of the corresponding human or endogenous PS1-CTFs. Animals expressing low amount of hPS1M146L mRNA, displayed low hPS1-CTF incorporation and produced a low amount of Abeta peptides. Conversely, mice with relatively high hPS1 mRNA expression displayed high hPS1-CTF and high Abeta deposition. Furthermore, the Abeta total and Abeta1-42 content was increased dramatically by the expression of hPS1M146L (as compared with transgenic APPsl littermates). Therefore, variations in the expression of transgenic form of hPS1M146L in this model, or even between different models, influenced strongly the incorporation of the mutated PS1 into functional gamma-secretase complexes, the production of Abeta peptides and, in consequence, the detrimental effects of Abeta peptides. These data might implicate an "apparent gain-of-function" of the gamma-secretase complex by the expression of the mutated PS1M146L.
Caballero
Cristina
C
Departmento de Bioquimica, Bromatologia, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
Jimenez
Sebastian
S
Moreno-Gonzalez
Ines
I
Baglietto-Vargas
David
D
Sanchez-Varo
Raquel
R
Gavilan
M Paz
MP
Ramos
Blanca
B
Del Rio
Juan Carlos
JC
Vizuete
Marisa
M
Gutierrez
Antonia
A
Ruano
Diego
D
Vitorica
Javier
J
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D015870:Gene Expression / Q000235:genetics*; D047468:Immunoprecipitation / Q000379:methods; D007930:Leucine / Q000235:genetics*; D008715:Methionine / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D053764:Presenilin-1 / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D012333:RNA, Messenger; D008715:Methionine; D007930:Leucine