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Advanced Neurology Drosophila Sirtuin 1 and Alzheimer’s disease

flies were driven by pan-retinal GAL4 “GMR-GAL4” and weights of 17.04, 15.46, and 14.56 mg, respectively
pan-neuronal GAL4 “elav-GAL4.” Sirt1 overexpression in (Figure 1K). Sirt1 overexpression in elav-Gal4/+;UAS-
control flies (GMR-GAL4/UAS-Sirt1;+/+) did not show Sirt1/+;UAS-ArcAβ /+ flies significantly increased body
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observable changes in the eye compared to that in control weights to 15.24, 14, and 11.82 mg, respectively,
GMR-GAL4/+;+/+ flies (Figure 1A and A’), whereas compared to elav-Gal4/+;+/+;UAS-ArcAβ /+ flies
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slight degeneration in ommatidia and abnormal bristle (Figure 1K).
arrangement was observed in the Sirt1 downregulation
flies driven by GMR-GAL4 (GMR-GAL4/+;UAS- 3.2. Overexpressing Sirt1 modulates the lifespan of
Sirt1 RNAi /+) (Figure 1E and E’). Further, we found AD model flies
that the rough eye phenotype, abnormal bristles, and We examined the impact of Sirt1 overexpression on the
ommatidial arrangement characteristic of AD model lifespan (survival) of AD model flies. Our results showed
flies were significantly improved by Sirt1 overexpression a significant decrease in the median survival (30 days)
(GMR-GAL4-UAS-Aβ (Human)/UAS-Sirt1;+/+, GMR- of AD model flies (elav-Gal4/+;+/+;UAS-ArcAβ /+)
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GAL4-UAS-Tau /UAS-Sirt1;+/+, and GMR-GAL4/UAS- compared to the median survival of 60 days for elav-
WT
Sirt1;UAS-Appl RNAi /+) (Figure 1B, B’‑C, C’‑D and D’), Gal4/+;+/+;+/+ flies and 56 days for w 1118 flies (Figure 2).
whereas Sirt1 downregulation in an AD genetic background Furthermore, we observed that AD model flies with Sirt1
(GMR-GAL4-UAS-Aβ (Human)/+;UAS-Sirt1 RNAi /+, overexpression (elav-Gal4/+;UAS-Sirt1/+;UAS-ArcAβ /+)
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GMR-GAL4-UAS-Tau /+;UAS-Sirt1 RNAi /+ and GMR- exhibited a significantly increased median survival of up to
WT
GAL4/+;UAS-ApplRNAi/UAS-Sirt1 RNAi ) slightly increased 48 days compared to control AD model flies (Figure 2). In
these AD-related pathologies (Figure 1F, F’‑G, G’‑H, and H’). contrast, AD model flies with Sirt1 downregulation (elav-
Further, we investigated the effect of Sirt1 on learning Gal4/+;UAS-ArcAβ /+;UAS-Sirt1 RNAi /+) showed a reduced
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and memory, as impairments in these areas directly impact median survival of 34 days.
behavioral activities in AD model flies. 39-41 We analyzed Table 2 shows the median survival (days) for all
the effect of Sirt1 overexpression on phototaxis activity genotypes.
in 10-day-old AD model flies using a phototaxis assay
(Figure 1I). 3.3. Overexpression of Sirt1 decreases the ectopic
expression of Aβ in third-instar larval brain of
As shown in Figure 1I, GMR-GAL4-UAS-Aβ 42 42
(Human)/+;+/+ flies had a light preference index of Drosophila.
7.56, which significantly improved to 15.61 with Sirt1 As demonstrated in Figure 3, elav-GAL4/+;+/+;UAS-
overexpression in GMR-GAL4-UAS-Aβ (Human)/UAS- ArcAβ /+ (AD model flies) exhibited increased expression of
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Sirt1;+/+ flies. Similarly, GMR-GAL4-UAS-Tau /+;+/+ Aβ in the third instar larval brain (Figure 3B and E) compared
WT
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flies had a light preference index of 9.19, which increased to the experimental control flies (elav-Gal4/+;+/+;+/+)
to 14.59 with Sirt1 overexpression in GMR-GAL4- (Figure 3A and E). Furthermore, overexpression of
UAS-Tau /UAS-Sirt1;+/+ flies. In GMR-GAL4/+;UAS- Sirt1 in elav-Gal4/+;UAS-Sirt1/+;UAS-ArcAβ /+ flies
WT
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Appl RNAi /+ flies, the light preference index was 8.80, which significantly decreased Aβ expression compared to that
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significantly increased to 15.3 with Sirt1 overexpression in in AD model flies (elav-GAL4/+;+/+;UAS-ArcAβ /+)
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GMR-GAL4/UAS-Sirt1;UAS-Appl RNAi /+ flies. (Figure 3C and E). In contrast, Sirt1 downregulation in elav-
We also examined the impact of Sirt1 on the climbing Gal4/+;UAS-ArcAβ /+;UAS-Sirt1 RNAi /+ flies significantly
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activity of arctic Aβ mutants in flies aged 10, 20, and increased Aβ expression compared to AD model flies
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30 days. Our results showed that Sirt1 overexpression (elav-GAL4/+;+/+;UAS-ArcAβ /+) (Figure 3D and E).
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in elav-Gal4/+;UAS-Sirt1/+;UAS-ArcAβ /+ flies These results indicate that Sirt1 overexpression has a
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significantly improved climbing activity to 77.4%,
71.6%, and 66%, respectively, compared to same-aged Table 2. The median survival (days) of control and
elav-Gal4/+;+/+;UAS-ArcAβ /+ AD model flies, which experimental group flies
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exhibited lower climbing activity at 52.2%, 46.6%, and Genotype (data comparison) Median survival (days)
35.4%, respectively (Figure 1J).
w 1118 56
We further investigated the effect of Sirt1 on body elav-Gal4/+;+/+;+/+ 60
weight in elav-GAL4-driven AD model flies. The body elav-Gal4/+;+/+;UAS-ArcAβ /+ 30
weights of 10-, 20-, and 30-day-old elav-Gal4/+;+/+;UAS- 42
ArcAβ /+ flies were 15.24, 9.8, and 6.48 mg, respectively, elav-Gal4/+;UAS-Sirt1/+;UAS-ArcAβ /+ 48
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compared to elav-Gal4/+;+/+;+/+ flies, which had body elav-Gal4/+;UAS-ArcAβ /+;UAS-Sirt1 RNAi /+ 34
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Volume 3 Issue 4 (2024) 5 doi: 10.36922/an.4291