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. 2016 Mar;102:111-20.
doi: 10.1016/j.neuropharm.2015.11.002. Epub 2015 Nov 6.

Linalool Reverses Neuropathological and Behavioral Impairments in Old Triple Transgenic Alzheimer's Mice

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Free PMC article

Linalool Reverses Neuropathological and Behavioral Impairments in Old Triple Transgenic Alzheimer's Mice

Angélica Maria Sabogal-Guáqueta et al. Neuropharmacology. .
Free PMC article

Abstract

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder. Several types of treatments have been tested to block or delay the onset of the disease, but none have been completely successful. Diet, lifestyle and natural products are currently the main scientific focuses. Here, we evaluate the effects of oral administration of the monoterpene linalool (25 mg/kg), every 48 h for 3 months, on aged (21-24 months old) mice with a triple transgenic model of AD (3xTg-AD) mice. Linalool-treated 3xTg-AD mice showed improved learning and spatial memory and greater risk assessment behavior during the elevated plus maze. Hippocampi and amygdalae from linalool-treated 3xTg-AD mice exhibited a significant reduction in extracellular β-amyloidosis, tauopathy, astrogliosis and microgliosis as well as a significant reduction in the levels of the pro-inflammatory markers p38 MAPK, NOS2, COX2 and IL-1β. Together, our findings suggest that linalool reverses the histopathological hallmarks of AD and restores cognitive and emotional functions via an anti-inflammatory effect. Thus, linalool may be an AD prevention candidate for preclinical studies.

Keywords: Alzheimer's disease; Behavior function; Inflammation; Linalool.

Conflict of interest statement

Conflict of interest

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Experimental design
Linalool (25 mg/kg) or saline were administered orally by gavage to 18- to 21-month-old Non-Tg and 3xTg-AD mice for 3 months, every 48 hours. Learning and memory were evaluated in the Morris water maze test (five days, ten trials) at 21–24 months of age. Afterward, the elevated plus maze was performed over two days. Then, the mice were sacrificed for histological and biochemical analyses.
Figure 2
Figure 2. Linalool treatment prevented spatial memory impairment in 3xTg- AD mice
a) Mean latency to reach the hidden platform during the spatial learning task. b) Latency, c) number of crossings, d) time spent reaching the platform and e) distance to reach the platform in the retention test. f) Representative images of the route of travel during the retention test. g) No differences were detected between the experimental groups in the visual, motor or motivational skills of the animals during the visible test. The data are expressed as the means ± SEM. n=8–16. *Difference between the 3xTg-AD vehicle-treated group and the other groups *p<0.05.
Figure 3
Figure 3. Anxiolytic effect of linalool oral administration on 3xTg-AD mice
ab) Relative frequency of open arm entries and the time spent in the open arms. c–d) Number of grooming behaviors and the time spent grooming. e–f) Number of head-dipping behaviors and the time spent head-dipping. g–h) Number of rearing actions and the time spent rearing at the end of the EPM test performed two weeks after the final dose of vehicle or linalool. The data are expressed as the means ± SEM. n=4–5. *p<0.05.
Figure 4
Figure 4. 3xTg-AD linalool-treated mice show reduced β-amyloidosis
a) Representative images of βA (anti-βA 6E10) immunoreactivity in the CA1 area, the subiculum, the EC and the amygdala of vehicle- and linalool-treated 3xTg-AD and vehicle-treated Non-Tg mice at 21–24 months of age. Magnification: 10x; scale bar: 50 μm. b) The values in the bar graph are expressed in densitometric relative units (RU) of βA immunoreactivity in the CA1 area, c) he subiculum, d) the EC and e) the amygdala. f) The relative βA 1–40 and g) βA 1–42 fragment levels were analyzed in hippocampal lysates by ELISA. Veh: vehicle (Saline solution); Lin: Linalool; CA1 and S: subiculum of the hippocampus; EC: entorhinal cortex; Amyg: amygdala. The data are expressed as the means ± SEM. n=4–5. *p<0.05; **p<0.01; ***p<0.001.
Figure 5
Figure 5. Linalool treatment attenuated tau hyperphosphorylation in old 3xTg-AD mice
a) Representative images of AT8 (anti-tau pSer202/Thr205) immunoreactivity in the CA1 area, the subiculum, the EC and the amygdala of Non-Tg and 3xTg-AD mice treated with vehicle or linalool. Magnification: 10x; scale bar: 50 μm. b) The values in the bar graph are expressed in densitometric relative units (RU) of AT8 immunoreactivity in the CA1 area, c) the subiculum, d) the EC and e) the amygdala. f) Representative bands and densitometric intensities of PHF-1 in hippocampal lysates. Tubulin was used as a loading control. Veh: vehicle (Saline solution); Lin: Linalool; CA1 and S: subiculum of the hippocampus; EC: entorhinal cortex; Amyg: amygdala. The data are expressed as the means ± SEM. n=4. *p<0.05; **p<0.01; ***p<0.001.
Figure 6
Figure 6. Linalool decreased astrogliosis in old 3xTg-AD mice
a) Representative images of GFAP immunoreactivity in the CA1 area, the subiculum, the EC and the amygdala of Non-Tg and 3xTg-AD mice treated with vehicle or Linalool. Magnification: 40x. b) The values in the bar graphs are expressed in densitometric relative units (RU) of GFAP immunoreactivity in the CA1 area, c) the subiculum, d) the EC and e) the amygdala. Veh: vehicle (Saline solution); Lin: Linalool; CA1 and S: subiculum of the hippocampus; EC: entorhinal cortex; Amyg: amygdala. The data are expressed as the means ± SEM. n=3–4. **p<0.01; ***p<0.001.
Figure 7
Figure 7. Linalool ameliorated microgliosis in 3xTg-AD mice
a) Representative images of GFAP immunoreactivity in the CA1 area, the subiculum, the EC and the amygdala of Non-Tg and 3xTg-AD mice treated with vehicle or linalool. Magnification: 40x. b) The values in the bar graphs are expressed in densitometric relative units (RU) of Iba1 immunoreactivity in the CA1 area, c) the subiculum, d) the EC and e) the amygdala. Veh: vehicle (Saline solution); Lin: Linalool; CA1 and S: subiculum of the hippocampus; EC: entorhinal cortex; Amyg: amygdala. The data are expressed as the means ± SEM. n=3–4. *p<0.05 **p 0.01; ***p<0.001.
Figure 8
Figure 8. Linalool reduced the proinflammatory response in 3xTg-AD mice
Morphological characterization showing nuclei stained with Hoechst (blue), β-amyloid stained with Alexa Fluor 594 phalloidin dye (red) and microglia visualized with Iba1 (green). Magnification, 10x and 60x. a) Representative images of CA1, subiculum, EC, and the amygdala. b) Quantification of IL-1β in hippocampal lysates. Representative bands and densitometric intensities of c) COX-2, d) NOS2 and e) p38 MAPK in hippocampal lysates. Veh: vehicle (Saline solution); Lin: Linalool; CA1 and S: subiculum of the hippocampus; EC: entorhinal cortex; Amyg: amygdala. The data are expressed as the means ± SEM. n=4–5. *p<0.05; **p<0.01‚ ***p<0.001.

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