Reduction BACE1 expression via suppressing NF-κB mediated signaling by Tamibarotene in a mouse model of Alzheimer's disease

Abstract

This present study examined the effect of Tamibarotene (AM80) in APP/PS1 mice, a well-established AD mouse model. AM80 was intraperitoneal administered to 3-month-old APP/PS1 mice at a dose of 5 mg/kg/day for 16 weeks. The results clearly showed that AM80 could reduce amyloid-β peptides through impact on APP processing and reduce microglia and astrocyte activation in APP/PS1 mice. The most notable finding in the present study was that inhibitory effect on BACE1 mediated by NF-κB pathway underlies the anti-inflammatory action of AM80. Moreover, AM80 could significantly decrease synaptic loss and enhance the expressions of Synapsin and Drebrin. Therefore, AM80 treatment may have the preclinical prevention of AD with new therapeutic strategies.

Keywords: AM80; Alzheimer’s disease; BACE1; Neuroinflammation; Synapse.

Fig. 1

Effect on Aβ level after AM80 treatment in AD mice. (A-B) Levels of total Aβ40 and Aβ42 are analyzed using the ELISA kits (n = 6). *P < 0.05 vs. APP/PS1-vehicle mice.

Fig. 2

AM80 reduced the production of APP-CTFs (C99 and C83) and Aβ oligomers. (A, C) Western blots of APP, APP-CTFs and Aβ oligomers (a mouse anti-Aβ monoclonal antibody 6E10) in the hippocampus and cerebral lysates of different groups of mice are shown. (B, D) Quantitative results of APP-CTFs and Aβ oligomers are shown (n = 8). *P < 0.05 vs. APP/PS1-vehicle mice, **P < 0.01 vs. APP/PS1-vehicle mice.

Fig. 3

AM80 reduced the expressions of BACE1 and p-NF-kB. (A, C) Western blots of BACE1, NEP, IDE, p-NF-kB and NF-kB in the whole brain lysates of four groups of mice are shown. (B, D) Quantification of p-NF-kB and BACE1 immunoblots are shown. Data are mean ±SD (n = 8). *P < 0.05 vs. APP/PS1-vehicle mice.

Fig. 4

AM80 attenuated microglial activation. (A-D) High-magnification (20×) images are showing Iba1-immunopositive microglia (Green) around Aβ (Red) in neocortex. Scale bars, 100 µm. (E) Quantification of microglial number in neocortex is shown (n = 8). *P < 0.05 vs. APP/PS1-vehicle mice. (For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)

Fig. 5

AM80 attenuated astrocyte activation. (A) Representative images (63×) of GFAP (Green) and Aβ plaques (Red) are shown in neocortex(. Scale bar, 100 µm. (B) Low magnification (4×) of GFAP (Green) and Aβ plaques (Red) are shown. (C) Quantification of astrocyte is shown. Data were mean ±SD (n = 8). **P < 0.01 vs. APP/PS1-vehicle mice. (For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)

Fig. 6

AM80 suppressed the production of TNF-α in APP/PS1 mice. The contents of TNF-α in AD mice or wild type mice treated without or with AM80 were determined by Elisa method. Data were mean ±SD (n = 6). **P < 0.01 vs. APP/PS1- vehicle mice.

Fig. 7

AM80 exhibited reduced synaptic loss compared with APP/PS1 littermates. (A) Representative images of SYN immunostaining in the CA3 zone of mouse brain are shown. (B) Brains slices are prepared for electron transmission microscopy. Arrows point to synapses. Scale bars, 200 nm. (C) Western blot of Drebrin in the hippocampus lysates of mouse brain is shown. (D) Quantification of synapse is showed in four groups of mice treated or untreated by AM80 (n = 6). *P < 0.05, compared with APP/PS1-vehicle mice.