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Age-related loss of large dendritic spines in the precuneus is statistically mediated by proteins which are predicted targets of existing drugs

Molecular Psychiatry volume 30, pages 2059–2067 (2025)Cite this article

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Abstract

Preservation of dendritic spines is a putative mechanism of protection against cognitive impairment despite development of Alzheimer Disease (AD)-related pathologies. Aging, the chief late-onset AD risk factor, is associated with dendritic spine loss in select brain areas. However, no study to our knowledge has observed this effect in precuneus, an area selectively vulnerable to early accumulation of AD-related pathology. We therefore quantified dendritic spine density in precuneus from 98 subjects without evidence of neurocognitive decline, spanning ages 20–96, and found a significant negative correlation between age and large dendritic spine density. In these same subjects, we conducted liquid chromatography–tandem mass spectrometry of >5000 proteins and identified 203 proteins which statistically mediate the effect of age on large dendritic spine density. Using computational pharmacology, we identified ten drugs which are predicted to target these mediators, informing future studies designed to test their effects on age-related dendritic spine loss and cognitive decline.

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Fig. 1: Correlations of age and density of small, medium, and large dendritic spines within the precuneus.
Fig. 2: Correlations of age and density of large dendritic spines with protein abundances within homogenate and synaptosome fractions.
Fig. 3: Homogenate and synaptosome fraction protein network modules generated by weighted correlation network analysis (WGCNA).
Fig. 4: Identification of existing pharmacotherapies which target protein mediators of age-related dendritic spine density loss using computational pharmacology.

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Data availability

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [45] partner repository with the dataset identifier PXD057115 and 10.6019/PXD057115. All other data are available from the corresponding author (or other sources, as applicable) on reasonable request.

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Acknowledgements

Subject tissue was obtained from the University of Pittsburgh Brain Tissue Donation Program and the NIH NeuroBioBank at the University of Pittsburgh Brain Tissue Donation Program.

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Author notes

  1. These authors contributed equally: R. A. Sweet, M. L. MacDonald.

Authors and Affiliations

  1. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    J. M. Krivinko, C. Happe, C. Hensler, J. Gilardi, B. C. McKinney, J. Newman, R. A. Sweet & M. L. MacDonald

  2. Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

    P. Fan & L. Wang

  3. Department of Biostatistics, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA

    Z. Sui & Y. Ding

  4. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    M. D. Ikonomovic & R. A. Sweet

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Contributions

All authors reviewed and approved the manuscript. Specific contributions are as follows: JMK—manuscript writing, study conceptualization and design, data analyses and interpretation; PF and LW—study design, computational pharmacology studies and analyses, manuscript writing; ZS and YD—study design, statistical analyses, manuscript writing; CaH—identification of precuneus, proteomics studies and analyses; CH and JN—IHC and microscopy studies, data analyses; JG—data analyses. MDI—study design, identification of precuneus; BCM—study conceptualization and design, postmortem cohort assembly, identification of precuneus; RAS—project conceptualization and design, data analyses and interpretation, manuscript writing; MLM—project conceptualization and design, data analyses and interpretation, manuscript writing.

Corresponding author

Correspondence to R. A. Sweet.

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Competing interests

The University of Pittsburgh holds a Physician-Scientist Institutional Award from the Burroughs Wellcome Fund (JMK). This work was supported in part by NIH grants: AG027224 and MH116046 (RAS), MH125235 and MH118497 (MLM), and P01AG14449 (MDI). RAS, JMK, PF, BCM, LW, and MLM are listed inventors on pending patent 63404994 filed by the University of Pittsburgh Innovation Institute. The methods of treating, preventing, or reducing dendritic spine density loss in a subject by administering one or a combination of the ten drugs listed in Fig. 4, or a pharmaceutically acceptable salt, prodrug, or derivative thereof, are protected by the patent.

Ethics approval and consent to participate

All methods were conducted in accordance with the University of Pittsburgh’s Committee for Oversight in Research Involving Decedents (ID 474) and the International Review Board for Biomedical Research (ID 19080015). Consent was obtained for all subjects from next of kin.

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Krivinko, J.M., Fan, P., Sui, Z. et al. Age-related loss of large dendritic spines in the precuneus is statistically mediated by proteins which are predicted targets of existing drugs. Mol Psychiatry 30, 2059–2067 (2025). https://doi.org/10.1038/s41380-024-02817-w

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