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MST1 selective inhibitor Xmu-mp-1 ameliorates neuropathological changes in a rat model of sporadic Alzheimer’s Disease by modulating Hippo-Wnt signaling crosstalk

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Abstract

Alzheimer’s disease (AD), the most prevalent form of dementia, is characterized by progressive cognitive impairment accompanied by aberrant neuronal apoptosis. Reports suggest that the pro-apoptotic mammalian set20-like kinase 1/2 (MST1/2) instigates neuronal apoptosis via activating the Hippo signaling pathway under various stress conditions, including AD. However, whether inhibiting MST1/2 has any therapeutic benefits in AD remains unknown. Thus, we tested the therapeutic effects of intervening MST1/2 activation via the pharmacological inhibitor Xmu-mp-1 in a sporadic AD rat model. Sporadic AD was established in adult rats by intracerebroventricular streptozotocin (ICV-STZ) injection (3 mg/kg body weight). Xmu-mp-1 (0.5 mg/kg/body weight) was administered once every 48 h for two weeks, and Donepezil (5 mg/kg body weight) was used as a reference standard drug. The therapeutic effects of Xmu-mp-1 on ICV-STZ rats were determined through various behavioral, biochemical, histopathological, and molecular tests. At the behavioral level, Xmu-mp-1 improved cognitive deficits in sporadic AD rats. Further, Xmu-mp-1 treatment reduced STZ-associated tau phosphorylation, amyloid-beta deposition, oxidative stress, neurotoxicity, neuroinflammation, synaptic dysfunction, neuronal apoptosis, and neurodegeneration. Mechanistically, Xmu-mp-1 exerted these neuroprotective actions by inactivating the Hippo signaling while potentiating the Wnt/β-Catenin signaling in the AD rats. Together, the results of the present study provide compelling support that Xmu-mp-1 negated the neuronal dysregulation in the rat model of sporadic AD. Therefore, inhibiting MST/Hippo signaling and modulating its crosstalk with the Wnt/β-Catenin pathway can be a promising alternative treatment strategy against AD pathology. This is the first study providing novel mechanistic insights into the therapeutic use of Xmu-mp-1 in sporadic AD.

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Data availability

Data is provided in the masnucript and supplementary information file.

Abbreviations

AChE:

Acetylcholinesterase

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

Aβ:

Amyloid beta

Bace-1:

Beta secretase-1

BDNF:

Brain-derived neurotrophic factor

GFAP:

Glial fibrillary acidic protein

GSH:

Reduced glutathione

Iba-1:

Ionized calcium-binding adaptor molecule 1

ICV:

Intracerebroventricular

Il-6:

Interleukin-6

LATS:

Large tumor suppressor protein

LPO:

Lipid peroxidation

MAP-2:

Microtubule-associated protein – 2

MST:

Mammalian Ste20-like protein

MWM:

Morris water maze

NOR:

Novel object recognition

OFT:

Open field test

PCO:

Protein carbonyl

PMS:

Post-mitochondrial supernatant

PSD-95:

Post synaptic scaffolding protein-95

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

STZ:

Streptozotocin

ThT:

ThioflavinT

Tnf-α:

Tumour necrosis factor-α

Xmu-mp-1:

4-((5,10-Dimethyl-6-oxo-6,10-dihydro-5H- pyrimido[5,4-b]thieno[3,2-e][1,4]diazepin-2-yl)amino)benzenesulfonamide

YAP:

Yes-associated protein

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Acknowledgements

We acknowledge the central laboratory animal resources (CLAR) facility of Jawaharlal Nehru University for facilitating the animal experiments. We are thankful to Prof. Birendra Nath Mallick, School of Life Sciences (SLS), Jawaharlal Nehru University (JNU) for facilitating the stereotaxic surgery apparatus and ANY-Maze integrated behavioral setup.

Funding

This study was supported by the Department of Biotechnology (DBT), Govt. of India (BT/PR32907/MED/122/227/2019), (BT/PR38493/TRM/120/465/2020), and (BT/PR47726/CMD/150/26/2023), DBT- BUILDER-Level-III (BT/INF/22/SP45382/2022), and Department of Science & Technology, Govt. of India (DST-FIST-II) to the School of Life Sciences, JNU, India. Manas Ranjan Sahu acknowledges financial support from DST INSPIRE (DST/INSPIRE Fellowship/2018/IF180507).

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Authors and Affiliations

  1. Laboratory of Cellular and Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India

    Manas Ranjan Sahu, Mir Hilal Ahmad & Amal Chandra Mondal

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  1. Manas Ranjan Sahu
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  2. Mir Hilal Ahmad
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  3. Amal Chandra Mondal
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The study was conceptualized, designed, and supervised by Amal Chandra Mondal. Manas Ranjan Sahu carried out the experiments, analyzed the data, and wrote the manuscript. Mir Hilal Ahmad contributed to the experiments and manuscript editing. All authors reviewed the results and contributed to the final manuscript.

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Correspondence to Amal Chandra Mondal.

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Sahu, M.R., Ahmad, M.H. & Mondal, A.C. MST1 selective inhibitor Xmu-mp-1 ameliorates neuropathological changes in a rat model of sporadic Alzheimer’s Disease by modulating Hippo-Wnt signaling crosstalk. Apoptosis (2024). https://doi.org/10.1007/s10495-024-01975-0

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