Growth Hormone-Releasing Hormone Modulation of Neuronal Exosome Biomarkers in Mild Cognitive Impairment (original) (raw)

Article type: Research Article

Authors: Winston, Charisse N.a | Goetzl, Edward J.c; d | Baker, Laura D.e | Vitiello, Michael V.f | Rissman, Robert A.a; b; *

Correspondence: [*] Correspondence to: Robert A. Rissman, PhD, Department of Neurosciences, UCSD School of Medicine, 9500 Gilman Drive, MTF 314 M/C 0624, La Jolla, CA 92093-0624, USA. Tel.: +1 858 246 0140; Fax: +1 858 246 0139; E-mail: [email protected].

Abstract: Age-related changes in cognition are linked to decreased expression of somatotropins, GHRH and IGF-1. Mild cognitive impairment (MCI) and Alzheimer’s disease (AD) are heterogeneous conditions. The loss of GHRH signaling in the brain may be mechanistically involved in AD pathogenesis. The consequent need to identify AD at an early and perhaps more treatable stage has fueled research into blood-based, exosome biomarkers. Plasma exosomes from participants enrolled in a randomized, double-blind, placebo-controlled 20-week trial of GHRH administration, were isolated, precipitated, and enriched by immuno-absorption with anti-L1CAM antibody (neural adhesion protein) from adults with MCI and age-matched, cognitively normal controls (CNC). Extracted protein cargo from neuronally-derived exosomes (NDEs) were assessed by ELISAs for protein levels implicated in AD neuropathology and for synaptic proteins altered by AD. Plasma NDE concentrations of Aβ1-42 were significantly increased while plasma NDE concentrations of NRGN, synaptophysin, synaptotagmin, and synaptopodin were significantly decreased in patients with MCI, independent of GHRH treatment. Plasma NDE concentrations of ptau-S396 and GAP43 were not affected by cognitive status (CNC versus MCI) or by GHRH treatment. Aβ1-42, neurogranin (NRGN), synaptophysin, synaptotagmin, and synaptopodin demonstrated the highest diagnostic accuracy for distinguishing between CNC and MCI patients, while synaptophysin and synaptotagmin demonstrated moderate accuracy in distinguishing between placebo-treated and GHRH-treated, MCI patients.

Keywords: Amyloid, biomarker, GHRH, growth hormone, mild cognitive impairment, neuronal exosomes, synapse, tau

DOI: 10.3233/JAD-180302

Journal: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 971-981, 2018

Accepted 10 September 2018

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Published: 23 November 2018