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bioRxiv · 10.1101/2025.09.05.674491

Modeling interaction between focal cerebral ischemia and Alzheimer`s Disease Pathology in an APP/PS1 Mouse Model

Waits, P. K.·Otero, P. A.·Zimmerly, M. P.·Vedati, V. P.·Shah, K. J.·Orfila, J. E.·Herson, P. S.
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Abstract

Ischemic stroke is one of the leading causes of death and disability in the United States and is a known risk factor for Alzheimers Disease (AD) development. One of the characteristics of AD is the accumulation of {beta}-amyloid peptide due to the proteolysis of Amyloid Precursor Protein (APP) by the protein Presenilin 1 (PS1). The study of interaction between ischemia and AD has been limited due to lack of experimental models. The current study describes a novel model utilizing a brief transient ischemia (15 min MCAO) in an AD mouse model to assess mechanistic interaction. Here we investigate the effects of increased {beta}-amyloid peptide on motor coordination, behavioral and cellular memory, when subjected to brief focal ischemia. APP/PS1 or Wt male mice are initially subjected to either a 15-minute MCAO or Sham surgery. Injury volume using MRI is assessed at 3-days using T2 imaging and demonstrates that injury magnitude was not different between Wild-type and APP/PS1 mice. We observed that 15 min MCAO did not cause significant motor deficits in either WT or APP/PS1 mice, as measured by open field and tapered balance beam. Short-term memory was assessed 7 days after recovery from brief MCAO using the contextual fear conditioning task. APP/PS1 mice exhibited intact memory at 3 months of age and Wt mice also having intact memory 7 days after 15 min MCAO. In contrast, APP/PS1 + 15 min MCAO mice exhibited a significant reduction in freezing behavior suggesting impairment in short term memory. Consistent with our contextual fear conditioning, we observed impaired hippocampal long-term potentiation (LTP) in APP/PS1 + 15 min MCAO compared to their sham counterparts. Remarkably, we observed an additive effect of ischemia and AD, with cellular and behavior memory deficits observed in APP/PS1 mice exposed to brief ischemia that does not cause symptoms in WT mice. This study represents an important new model to be study the mechanistic link between ischemia and accelerated AD progression.

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Waits, P. K., Otero, P. A., Zimmerly, M. P., Vedati, V. P., Shah, K. J., Orfila, J. E., Herson, P. S.. 2025-09-11. Modeling interaction between focal cerebral ischemia and Alzheimer`s Disease Pathology in an APP/PS1 Mouse Model. https://doi.org/10.1101/2025.09.05.674491

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