Blood-Based Biomarkers of Neuroinflammation in Alzheimer's Disease: A Central Role for Periphery?

Abstract

Neuroinflammation represents a central feature in the development of Alzheimer's disease (AD). The resident innate immune cells of the brain are the principal players in neuroinflammation, and their activation leads to a defensive response aimed at promoting β-amyloid (Aβ) clearance. However, it is now widely accepted that the peripheral immune system-by virtue of a dysfunctional blood-brain barrier (BBB)-is involved in the pathogenesis and progression of AD; microglial and astrocytic activation leads to the release of chemokines able to recruit peripheral immune cells into the central nervous system (CNS); at the same time, cytokines released by peripheral cells are able to cross the BBB and act upon glial cells, modifying their phenotype. To successfully fight this neurodegenerative disorder, accurate and sensitive biomarkers are required to be used for implementing an early diagnosis, monitoring the disease progression and treatment effectiveness. Interestingly, as a result of the bidirectional communication between the brain and the periphery, the blood compartment ends up reflecting several pathological changes occurring in the AD brain and can represent an accessible source for such biomarkers. In this review, we provide an overview on some of the most promising peripheral biomarkers of neuroinflammation, discussing their pathogenic role in AD.

Keywords: Alzheimer’s disease; TSPO; chemokines; cytokines; delirium; monocytes; neuroinflammation; peripheral markers.

Figure 1

(1) Beta-amyloid oligomers and their subsequent deposition in plaque fuel neuroinflammation, leading microglia to produce chemokines that lure monocytes into the brain. The chemotaxis process is regulated, among other players, by the TSPO, expressed by monocytes and well-known markers of activated microglia. (2) Besides entering the blood–brain barrier, peripheral monocytes produce proinflammatory cytokines that represent the afferent arm of the “inflammatory reflex”. (3) The efferent arm of this reflex is known as the “cholinergic anti-inflammatory pathway” (CAIP) and is represented by a vagal efflux indirectly stimulating the activation of the α7-nicotinic cholinergic receptor (α 7nAChR) expressed by peripheral monocytes and shutting off inflammasome and cytokine production. Created with BioRender.com.

Figure 2

(A) Mononucleate cells phagocytize beta-amyloid by TREM2 involvement (1). Due to the beta sheet-rich structure, the autophagy–lysosomal system (2) eventually results in incompetence for a full degradation and (3) leakage of the toxic peptide activates the inflammasome (4) with the secretion of proinflammatory cytokines (5), fueling downstream neuroinflammation. (B) In vitro phagocytosis assay; fluorescence micrograph showing beta-amyloid (in green) phagocytized by a THP-1 cell (acute monocytic leukemia line) (courtesy of Virginia Rodriguez-Menendez, UNIMIB, Italy). Created with BioRender.com.