Plasma Rich in Growth Factors (PRGF) Disrupt the Blood-Brain Barrier Integrity and Elevate Amyloid Pathology in the Brains of 5XFAD Mice.

Quoc-Viet Duong,Andrew Brannen,Ihab Abdallah,Amal Kaddoumi,William Kintzing,Margia Kintzing

doi:10.3390/ijms20061489

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder affecting 5.4 million people in the United States. Currently approved pharmacologic interventions for AD are limited to symptomatic improvement, not affecting the underlying pathology. Therefore, the search for novel therapeutic strategies is ongoing. A hallmark of AD is the compromised blood-brain barrier (BBB); thus, developing drugs that target the BBB to enhance its integrity and function could be a novel approach to prevent and/or treat AD. Previous evidence has shown the beneficial effects of growth factors in the treatment of AD pathology. Based on reported positive results obtained with the product Endoret®, the objective of this study was to investigate the effect of plasma rich in growth factors (PRGF) on the BBB integrity and function, initially in a cell-based BBB model and in 5x Familial Alzheimer’s Disease (5xFAD) mice. Our results showed that while PRGF demonstrated a positive effect in the cell-based BBB model with the enhanced integrity and function of the model, the in-vivo findings showed that PRGF exacerbated amyloid pathology in 5xFAD brains. At 10 and 100% doses, PRGF increased amyloid deposition associated with increased apoptosis and neuroinflammation. In conclusion, our results suggest PRGF may not provide beneficial effects against AD and the consideration to utilize growth factors should further be investigated.

Highlights

Alzheimer’s disease (AD) is the most common neurodegenerative disorder affecting the elderly population [1]
Results from this study indicate that while plasma rich in growth factors (PRGF) enhanced the functionality of our in-vitro cell-based blood-brain barrier (BBB) model, it worsened the in vivo BBB integrity and may have led to the exacerbated Aβ pathology observed in 5x Familial Alzheimer’s Disease (5xFAD) mice brains
The concentrations of growth factors selected for analysis, including vascular endothelial growth factor (VEGF), insulin like growth factor-1 (IGF-1) and TGF-β1, were determined in activated platelets-rich plasma by ELISA

Summary

Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disorder affecting the elderly population [1]. According to the 2018 Alzheimer’s Disease Facts and Figures, an estimated 5.4 million Americans have AD. This number includes an estimated 5.3 million people that are 65 and older and another 200,000 individuals under the age of 65 [2]. While the etiology of AD remains unknown, it is believed to be a combination of environmental and genetic factors affecting many cellular and molecular processes in the brain [3]. The pathogenesis of AD is complex and involves neuropathological lesions that remain incompletely understood. The accumulation of extracellular amyloid plaques, neurofibrillary tangles and a dysfunctional blood-brain barrier (BBB) are major hallmarks found in the brains of AD patients [4,5,6,7,8,9]

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