Involvement of the Chemokine Prokineticin-2 (PROK2) in Alzheimer's Disease: From Animal Models to the Human Pathology.

Roberta Lattanzi,Giuseppe Sancesario,Cinzia Severini,Sergio Bernardini,Massimo Ralli,Roberta Possenti,Massimo Pieri,Carla Petrella,Antonio Greco,Tommaso Schirinzi,Giulia Sancesario,Daniela Maftei,Christian Barbato

doi:10.3390/cells8111430

Abstract

Among mediators of inflammation, chemokines play a pivotal role in the neuroinflammatory process related to Alzheimer’s disease (AD). The chemokine Bv8/prokineticin 2 (PROK2) is a critical player in inflammatory and neuroinflammatory diseases and has been demonstrated to be involved in Aβ toxicity. The aim of the present study was to extend the research to rats chronically intracerebroventricularly (i.c.v.) injected with Aβ, to an AD transgenic mouse model, and subsequently to AD patients, mainly with the aim of detecting a potential biomarker. Real-time PCR and immunofluorescence analysis were used to evaluate Prokineticin-2 (PROK2) mRNA and the corresponding protein levels in both animal and human AD brain extracts, and the ELISA test was used to measure the amount of PROK2 in the serum of AD patients. We demonstrated a significant upregulation of PROK2 levels in brain tissues of Aβ1–42 i.c.v. injected rats, transgenic AD mice (Tg2576), and in the hippocampus of AD patients. Additionally, through a pilot study, an approximate twofold increase of PROK2 levels has been proved in the serum of AD patients, compared to the control subjects, identifying a potential blood-based biomarker of the disease.

Highlights

Alzheimer’s disease (AD) is the widespread neurodegenerative disease, mainly characterized by the extracellular deposition of misfolded amyloid beta (Aβ) proteins in amyloid plaques and by intraneuronal tangles composed by the hyperphosphorylated tau protein [1].Over the past few decades, a role played by the immune system in AD has been highlighted, as demonstrated by the presence of activated microglia and astrocytes in the brains of affected patients [2,3]
Considering the involvement of prokineticin 2 (PROK2) and its receptors in Aβ toxicity, the present study aimed to extend our research to rats chronically i.c.v. injected with Aβ, to the AD transgenic mouse model
We investigated the long-term modulation of PROK2 expression induced by Aβ1–42 injection analyzing mRNA levels of PROK2 after 1, 7, 14, and 35 days in extracts of cortex and hippocampus of treated rats

Summary

Introduction

Over the past few decades, a role played by the immune system in AD has been highlighted, as demonstrated by the presence of activated microglia and astrocytes in the brains of affected patients [2,3]. Deposition of aberrant proteins is responsible for an immune reaction against. Chemokines play a pivotal role in the neuroinflammatory process due to their dual function as both chemoattractants for immune cells and molecular messengers in crosstalk among central nervous system (CNS)-resident cells. It has been demonstrated that chemokines play a critical role in the onset and progression of neuroinflammation, by affecting the functions of various cell populations, including resident glial cells, and by infiltrating immune cells [7,8,9]

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