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Amyloid \(\upbeta\) (1–42) peptide impairs mitochondrial respiration in primary human brain microvascular endothelial cells: impact of dysglycemia and pre-senescence

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Abstract

Diabetes increases the risk of Alzheimer’s disease (AD). We investigated the impact of glucose concentrations on the β-amyloid (Aβ)-induced alteration of mitochondrial/cellular energetics in primary human brain microvascular endothelial cells (HBMECs). HBMECs were grown and passaged in media containing 15 mmol/l glucose (normal) based on which the glucose levels in the media were designated as high (25 mmol/L) or low (5 mmol/L). HBMECs were treated with Aβ (1–42) (5 µmol/l) or a scrambled peptide for 24 h and mitochondrial respiratory parameters were measured using Seahorse Mito Stress Test. Aβ (1–42) decreased the mitochondrial ATP production at normal glucose levels and decreased spare respiratory capacity at high glucose levels. Aβ (1–42) diminished all mitochondrial respiratory parameters markedly at low glucose levels that were not completely recovered by restoring normal glucose levels in the media. The addition of mannitol (10 mmol/l) to low and normal glucose-containing media altered the Aβ (1–42)-induced bioenergetic defects. Even at normal glucose levels, pre-senescent HMBECs (passage 15) displayed greater Aβ (1–42)-induced mitochondrial respiratory impairments than young cells (passages 7–9). Thus, hypoglycemia, osmolarity changes, and senescence are stronger instigators of Aβ (1–42)-induced mitochondrial respiration and energetics in HBMECs and contributors to diabetes-related increased AD risk than hyperglycemia.

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Funding

This research project was supported by the National Institutes of Health: National Institute of Neurological Disorders and Stroke (NS094834 and NS114286—P.V. Katakam; NS114286 – R. Mostany; NS099539 – X. Wang) and National Institute on Aging (AG047296 – R. Mostany; AG074489 – P.V. Katakam and R. Mostany). In addition, the study was supported by American Heart Association (National Center Scientist Development Grant, 14SDG20490359—P.V. Katakam; Greater Southeast Affiliate Predoctoral Fellowship Award, 16PRE27790122—V.N. Sure).

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Authors and Affiliations

  1. Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA

    Siva S. V. P. Sakamuri, Venkata N. Sure, Vivian A. Fonseca, Ricardo Mostany & Prasad V. G. Katakam

  2. Department of Neurosurgery, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA

    Xiaoying Wang & Gregory Bix

  3. Tulane Brain Institute, Tulane University, 200 Flower Hall, LA, 70118, New Orleans, USA

    Xiaoying Wang, Gregory Bix, Ricardo Mostany & Prasad V. G. Katakam

  4. Clinical Neuroscience Research Center, 131 S. Robertson, Suite 1300, New Orleans, LA, 70112, USA

    Xiaoying Wang, Gregory Bix & Prasad V. G. Katakam

  5. Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA

    Vivian A. Fonseca

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  1. Siva S. V. P. Sakamuri
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Sakamuri, S.S.V.P., Sure, V.N., Wang, X. et al. Amyloid \(\upbeta\) (1–42) peptide impairs mitochondrial respiration in primary human brain microvascular endothelial cells: impact of dysglycemia and pre-senescence. GeroScience 44, 2721–2739 (2022). https://doi.org/10.1007/s11357-022-00644-x

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