Page 147 - AN-3-4

Advanced Neurology Drosophila Sirtuin 1 and Alzheimer’s disease

of proapoptotic genes (Figure 5H), and the increased anti- Laser Scanning Confocal Microscope facility supported
apoptotic activity of Drosophila IAP1 (diap1) (Figure 5I) by Department of Biotechnology (DBT), India at IAR and
when Bsk was downregulated (in both heterozygous in both financial support from Science and Engineering Research
and homozygous conditions) and with Sirt1 overexpression Board (SERB), New Delhi, India (No. EMR/2016/006911/
alongside Bsk downregulation in AD model flies. This finding HS), to AKT, is duly acknowledged. The authors are also
supports prior studies indicating that Aβ accumulation thankful to the Puri Foundation for Education in India for
42
activatesJNK-induced cell death in Drosophila. 61 Infrastructure support at IAR Gandhinagar. IAR reference

We also observed a significant increase in Sirt1 no. IAR/2022-23/RO/Research/090 is duly acknowledged.
expression levels when Bsk was downregulated in the AD Funding
model flies genetic background (Figure 6). Furthermore,
we found that AD-related pathologies improved when None.
Notch was downregulated along with Sirt1 overexpression
in AD model flies genetic background (Figure 7C‑G). Conflict of interest
To further confirm these findings, we analyzed Delta The authors declare that they have no competing interests.
protein expression in AD model flies. We observed that
Notch downregulation along with Sirt1 overexpression Author contributions
led to decreased Delta expression in AD model flies Conceptualization: All authors
(Figure 8). We further observed that Sirt1 overexpression Investigation: All authors
decreased, while Sirt1 downregulation increased, the Methodology: Vidhi Bhatt
expression of JNK and Notch signaling in Drosophila Writing – original draft: All authors
(Figures 9 and 10). Thus, our study indicates that Sirt1 Writing – review & editing: All authors
possesses neuroprotective role by regulating the JNK and
Notch signaling in Drosophila. Ethics approval and consent to participate

Between 2010 and 2023, several therapeutic The study involves use of invertebrate model organism
strategies targeting AD have been attempted, including Drosophila melanogaster and was approved by Institutional
the identification of early biomarkers, anti-amyloid Biosafety Committee (IBSC) Meeting, Agenda Item
immunotherapy, Aβ aggregation inhibitors, BACE No 1.1.1, dated January 18, 2021.
inhibitors, tau aggregation inhibitors, Selective Aβ42
lowering agents, α-secretase enhancers, anti-tau Consent for publication
60
immunotherapy, and anti-inflammatory agents. The Not applicable.
current study is a small step toward identifying therapeutic
targets for AD using Drosophila as a model organism. Availability of data
5. Conclusion The data supporting the present study’s findings are
available from the corresponding author upon reasonable
Our study demonstrated that overexpression of Sirt1 in request.
Drosophila affects AD-related pathologies by improving
the rough eye phenotype, correcting behavioral defects, References
increasing the phototaxis response, and reducing apoptosis
in the Drosophila model of AD. Furthermore, these 1. Donmez G, Guarente L. Aging and disease: Connections to
improvements were associated with reduced JNK/Notch sirtuins. Aging Cell. 2010;9(2):285-290.
activity in the Sirt1 overexpression genetic background, doi: 10.1111/j.1474-9726.2010.00548.x
which reduced neurodegeneration in AD model flies. The 2. Anekonda TS, Reddy PH. Neuronal protection by sirtuins in
present study also showed that Sirt1 genetically interacts with Alzheimer’s disease. J Neurochem. 2006;96(2):305-313.
AD-associated genes (Appl, Aβ , and Tau) in Drosophila and doi: 10.1111/j.1471-4159.2005.03492.x
42
could be a potential therapeutic intervention for NDDs. Thus,
based on our observations, we concluded the neuroprotective 3. Donmez G, Outeiro TF. SIRT1 and SIRT2: Emerging targets
potential associated with Sirt1 in Drosophila. in neurodegeneration. EMBO Mol Med. 2013;5(3):344-352.
doi: 10.1002/emmm.201302451
Acknowledgments
4. Wood JG, Schwer B, Wickremesinghe PC, et al. Sirt4 is
The authors are grateful to the Fly Daakia facility, IISER a mitochondrial regulator of metabolism and lifespan
Pune, Maharashtra, India for providing the fly stocks. The in Drosophila melanogaster. Proc Natl Acad Sci U S A.

Volume 3 Issue 4 (2024) 16 doi: 10.36922/an.4291