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Direct AT2R Stimulation Slows Post-stroke Cognitive Decline in the 5XFAD Alzheimer’s Disease Mice

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Abstract

Alzheimer’s disease (AD), currently the single leading cause of death still on the rise, almost always coexists alongside vascular cognitive impairment (VCI). In fact, the ischemic disease affects up to 90% of AD patients, with strokes and major infarctions representing over a third of vascular lesions. Studies also confirmed that amyloid plaques, typical of AD, are much more likely to cause dementia if strokes or cerebrovascular damage also exist, leading to the term “mixed pathology” cognitive impairment. Although its incidence is expected to grow, there are no satisfactory treatments. There is hence an urgent need for safe and effective therapies that preserve cognition, maintain function, and prevent the clinical deterioration that results from the progression of this irreversible, neurodegenerative disease. To our knowledge, this is the first study to investigate the effects of long-term treatment with C21, a novel angiotensin II type 2 receptor (AT2R) agonist, on the development of “mixed pathology” cognitive impairment. This was accomplished using a unique model that employs the fundamental elements of both AD and VCI. Treatment with C21/vehicle was started 1 h post-stroke and continued for 5 weeks in mice with concurrent AD pathology. Efficacy was established through a series of functional tests assessing various aspects of cognition, including spatial learning, short-term/working memory, long-term/reference memory, and cognitive flexibility, in addition to the molecular markers characteristic of AD. Our findings demonstrate that C21 treatment preserves cognitive function, maintains cerebral blood flow, and reduces Aβ accumulation and toxic tau phosphorylation in AD animals post-stroke.

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Data Availability

The data generated and analyzed in this study will be made available from the corresponding author upon reasonable request.

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Acknowledgements

We acknowledge to Dr. Michael P. McDonald at UTHSC for providing a breeding pair for 5XFAD mice.

Funding

This work was supported by startup funds from the UTHSC Department of Anatomy and Neurobiology (TI) and by grants R01-NS097800 (TI), 1R01-AG058467-03 (FL), and 1R01 NS120327-01 (FL). This study was also supported by the National Institute of Health [R01-NS097800 (TI)].

Author information

Authors and Affiliations

  1. Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA

    Heba A. Ahmed, Saifudeen Ismael, Mohd. Salman, Patrick Devlin, Michael P. McDonald & Tauheed Ishrat

  2. Department of Neurology, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Michael P. McDonald

  3. Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Michael P. McDonald, Francesca-Fang Liao & Tauheed Ishrat

  4. Department of Pharmacology, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Francesca-Fang Liao

  5. Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Tauheed Ishrat

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  1. Heba A. Ahmed
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Contributions

HA conducted the research, analyzed the data, prepared the figures, and drafted the manuscript. SI performed the stroke surgeries and cerebral blood flow determinations. MS performed the western blots. PD sectioned the brains and prepared the slides for immunostaining. MM and FFL also helped in experimental design and reviewed the manuscript. TI designed and oversaw the whole project including experimental design, randomization, data analysis, and managing of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Tauheed Ishrat.

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Compliance with Ethical Standards

All procedures performed in studies involving animals were approved by the Institutional Animal Care and Use Committee (IACUC) at UTHSC in full accordance with the ethical guidelines of the National Institutes of Health for the care and use of laboratory animals.

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The authors declare no competing interests.

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Ahmed, H.A., Ismael, S., Salman, M. et al. Direct AT2R Stimulation Slows Post-stroke Cognitive Decline in the 5XFAD Alzheimer’s Disease Mice. Mol Neurobiol 59, 4124–4140 (2022). https://doi.org/10.1007/s12035-022-02839-x

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