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P4‐084: Suppression of TAU Increase in Cerebrospinal Fluid of App Transgenic Mice Provides Evidence for Downstream Effect of Bace1 Inhibition
Author(s) -
Kaeser Stephan A.,
Schelle Juliane,
Haesler Lisa,
Goepfert Jens C.,
Joos Thomas O.,
Vanderstichele Hugo Marcel,
Stoops Erik,
Neumann Ulf,
Shimshek Derya Robert,
Staufenbiel Matthias,
Jucker Mathias
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.2173
Subject(s) - cerebrospinal fluid , genetically modified mouse , transgene , chemistry , biomarker , amyloid beta , tau protein , pathology , amyloid (mycology) , amyloid precursor protein secretase , amyloid precursor protein , beta (programming language) , alzheimer's disease , medicine , disease , biochemistry , gene , computer science , programming language
SAMP8/SAMR1. Results: The level of cortical p-tau396 of 2months-old SAMP8 was significantly lower than SAMR1, while p-tau262 level of 2-months-old SAMP8 was comparable, and these levels increased upto 10 months-old SAMP8. The pattern of pGSK3b expression showed a negative correlation with p-tau396. In the hippocampus, p-tau396 and p-tau262 were observed to increase as SAMP8 aged, as compared to the levels of age-matched SAMR1. The early activation of cortical AMPK of 2-months-old SAMP8 disappeared in 5-monthsand 10-months-old mice, as compared to SAMR1; however, we could not observed the activation of AMPK in the hippocampus of SAMP8 across all ages. The level of Sirt1 in the cortex of 2-months-old SAMP8 was significantly lower than SAMR1, which persisted until 5-months-old and disappeared at 10-months-old, compared to the levels of SAMR1. The level of insulin receptor substrate-1 (IRS-1) expression in the cortex of SAMP8 was significantly lower than SAMR1 across all ages. In the hippocampus, the level of Sirt1, but not IRS-1, was lower in 2-months-old SAMP8 than SAMR1; however, the levels of Sirt1 in 10-months-old SAMP8 were comparable. However, when we treated metformin to activate AMPK, the AMPK-mediated regulation of p-tau396 in SAMP8 was not clear. Conclusions: Our data showed that the differential and possibly indirect regulation of tau phosphorylation by AMPK in cerebral cortex of SAMP8 ADmodel. However, further investigations to clarify precise mechanism of AMPK in tau phosphorylation and energy metabolism in the cerebral cortex are needed.