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Neural circuit mechanisms underlying aberrantly prolonged functional hyperemia in young Alzheimer’s disease mice

Molecular Psychiatry (2024)Cite this article

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Abstract

Neurovascular defects are one of the most common alterations in Alzheimer’s disease (AD) pathogenesis, but whether these deficits develop before the onset of amyloid beta (Aβ) accumulation remains to be determined. Using in vivo optical imaging in freely moving mice, we explored activity-induced hippocampal microvascular blood flow dynamics in AppSAA knock-in and J20 mouse models of AD at early stages of disease progression. We found that prior to the onset of Aβ accumulation, there was a pathologically elevated blood flow response to context exploration, termed functional hyperemia. After the onset of Aβ accumulation, this context exploration-induced hyperemia declined rapidly relative to that in control mice. Using in vivo electrophysiology recordings to explore the neural circuit mechanism underlying this blood flow alteration, we found that hippocampal interneurons before the onset of Aβ accumulation were hyperactive during context exploration. Chemogenetic tests suggest that hyperactive activation of inhibitory neurons accounted for the elevated functional hyperemia. The suppression of nitric oxide (NO) produced from hippocampal interneurons in young AD mice decreased the accumulation of Aβ. Together, these findings reveal that neurovascular coupling is aberrantly elevated before Aβ deposition, and this hyperactive functional hyperemia declines rapidly upon Aβ accumulation.

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Fig. 1: Aβ accumulation in the hippocampus of AppKI mice during aging.
Fig. 2: Context exploration induced hyperemia in the hippocampus of 3-month-old WT and AppKI mice.
Fig. 3: Context exploration induced hyperemia in the hippocampus of WT and AppKI mice during aging.
Fig. 4: Chemogenetic activation of hippocampal interneurons induced hyperemia in 3- and 6-month-old AppKI mice.
Fig. 5: Context exploration induced activation of hippocampal interneurons in 3-month-old AppKI mice.
Fig. 6: Effect of EE and suppression of hippocampal neurovascular coupling on Aβ accumulation in 4-month-old AppKI mice.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials. Raw flow dynamics images were acquired and directly processed using Inscopix Inc. software. All relevant data have been presented in this article. There was no data excluded from the analysis.

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Acknowledgements

We thank Professor Donghui Zhu for critical feedback on the manuscript and Yanyi Mai for assistance with figure illustrations. We also thank all other members of the Ge and Xiong laboratories for their valuable comments. This work was supported by grants R01AG066912 to SG and QX; R21AG065864 to SG; and R01AG0821471 and P01AG073082 to JJP.

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Authors and Affiliations

  1. Medical Scientist Training Program (MSTP), Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA

    Thomas A. Kim

  2. Program in Neuroscience, Stony Brook University, Stony Brook, NY, 11794, USA

    Thomas A. Kim & George Cruz

  3. Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY, 11794, USA

    Michelle D. Syty, Faye Wang, Xinxing Wang, Alexandra Duan, Qiaojie Xiong & Shaoyu Ge

  4. Department of Neurology, Stony Brook University, Stony Brook, NY, 11794, USA

    Marc Halterman

  5. Gladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA

    Jorge J. Palop

  6. Department of Neurology, University of California, San Francisco, CA, 94158, USA

    Jorge J. Palop

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Conceptualization: TAK and SG; Methodology: TAK and SG; Formal analysis: TAK, GC, MDS, and FW; Investigation: TAK, GC, MDS, XW, and FW; Writing: TAK and SG produced the initial manuscript, and all others reviewed and commented on the manuscript; Supervision: QX and SG; Funding Acquisition, SG, JJP, QX.

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Correspondence to Qiaojie Xiong, Jorge J. Palop or Shaoyu Ge.

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Kim, T.A., Cruz, G., Syty, M.D. et al. Neural circuit mechanisms underlying aberrantly prolonged functional hyperemia in young Alzheimer’s disease mice. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02680-9

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