Metabolic and Growth Rate Alterations in Lymphoblastic Cell Lines Discriminate Between Down Syndrome and Alzheimer’s Disease

Article type: Research Article

Authors: Coskun, Pinar^{a; *} | Helguera, Pablo^{a; b} | Nemati, Zahra^a | Bohannan, Ryan C.^a | Thomas, Jean^a | Samuel, Schriner E.^c | Argueta, Jocelyn^a | Doran, Eric^d | Wallace, Douglas C.^e | Lott, Ira T.^d | Busciglio, Jorge^{a; *}

Affiliations: [a] Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders (iMIND), and Center for the Neurobiology of Learning and Memory (CNLM), University of California, Irvine, CA, USA | [b] Instituto de Investigación Médica Mercedes y Martin Ferreyra, Córdoba, Argentina, USA | [c] Department of Pharmaceutical Science, University of California, Irvine, CA, USA | [d] Department of Pediatrics, University of California, Irvine, CA, USA | [e] Center for Mitochondrial and Epigenomic Medicine (CMEM), Children’s Hospital of Philadelphia, and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

Correspondence: [*] Correspondence to: Pinar Coskun, MD, and Jorge Busciglio, PhD, Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders (iMIND), University of California, Irvine, 3400C Biological Sciences III, Irvine, CA 92617, USA. Tel.: +1 949 824 9075; Fax: +1 949 824 2447; E-mail: [email protected] (Pinar Coskun) and Tel.: +1 949 824 4820; Fax: +1 949 824 2447; E-mail: [email protected](Jorge Busciglio).

Abstract: Background: Deficits in mitochondrial function and oxidative stress play pivotal roles in Down syndrome (DS) and Alzheimer’s disease (AD) and these alterations in mitochondria occur systemically in both conditions. Objective: We hypothesized that peripheral cells of elder subjects with DS exhibit disease-specific and dementia-specific metabolic features. To test this, we performed a comprehensive analysis of energy metabolism in lymphoblastic-cell-lines (LCLs) derived from subjects belonging to four groups: DS-with-dementia (DSAD), DS-without-dementia (DS), sporadic AD, and age-matched controls. Methods: LCLs were studied under regular or minimal feeding regimes with galactose or glucose as primary carbohydrate sources. We assessed metabolism under glycolysis or oxidative phosphorylation by quantifying cell viability, oxidative stress, ATP levels, mitochondrial membrane potential (MMP), mitochondrial calcium uptake, and autophagy. Results: DS and DSAD LCLs showed slower growth rates under minimal feeding. DS LCLs mainly dependent on mitochondrial respiration exhibited significantly slower growth and higher levels of oxidative stress compared to other groups. While ATP levels (under mitochondrial inhibitors) and mitochondrial calcium uptake were significantly reduced in DSAD and AD cells, MMP was decreased in DS, DSAD, and AD LCLs. Finally, DS LCLs showed markedly reduced levels of the autophagy marker LC3-II, underscoring the close association between metabolic dysfunction and impaired autophagy in DS. Conclusion: There are significant mitochondrial functional changes in LCLs derived from DS, DSAD, and AD patients. Several parameters analyzed were consistently different between DS, DSAD, and AD lines suggesting that metabolic indicators between LCL groups may be utilized as biomarkers of disease progression and/or treatment outcomes.

Keywords: Alzheimer’s disease, autophagy, dementia, Down syndrome, growth retardation, lymphoblastoid cell lines, metabolic alterations, mitochondrial dysfunction, oxidative stress

DOI: 10.3233/JAD-160278

Journal: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 737-748, 2017