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

J M Krivinko, P Fan, Z Sui, C Happe, C Hensler, J Gilardi, M D Ikonomovic, B C McKinney, J Newman, Y Ding, L Wang, R A Sweet, M L MacDonald

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · pubmed

Paper

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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Research summary

The paper investigates the age-related loss of dendritic spines in the precuneus and identifies proteins that mediate this effect, which could have implications for cognitive decline and Alzheimer's disease. While it addresses a mechanism related to aging and cognitive impairment, it primarily focuses on correlational findings and potential drug targets rather than directly addressing the root causes of aging or lifespan extension. Thus, it contributes solid research but has limited impact on the broader field of longevity research.

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