Abstract Body

BIOMARKERS OF NEUROINFLAMMATION: FOCUS ON MONOCYTE CHEMOTAXIS 

Background and aims:

According to the amyloid cascade hypothesis, beta-amyloid (Abeta) aggregation represents the core pathogenic mechanism in Alzheimer’s disease (AD). Neuroinflammation, as an inflammatory process confined to the CNS, plays a key role as well, fueling a response against Abeta, and eventually further damaging the surrounding neurons.

Research currently points out at microglia cells as the central players of this game. However, an important role for periphery should be advocated, since peripheral blood monocytes cross the blood-brain barrier (BBB) attracted by Abeta and chemokines, and contribute to neuroinflammation by transforming into blood-born macrophages.

Interestingly, this process of “neuroinvasion” from periphery represents the afferent arc of the inflammatory reflex, regulating a response against protein aggregates. The efferent arc is represented by a vagal cholinergic pathway projecting onto alpha7nAChR expressed by spleen mononuclear cells for shutting off the inflammasome and so modulating the process.

In this talk we will focus on the role of peripheral monocytes, and in particular on the process of chemotaxis and neuroinvasion. Attention will be also given to the expression of the monocyte chemotactic systems, and among them, in particular, to the TSPO receptor (marker of activated microglia) and of the cognate biological ligand, the Diazepam Binding Inhibitor (DBI).

Conclusions:

Peripheral blood monocytes should be considered as real key players in AD pathogenesis and may represent a very interesting therapeutic target, since potentially able to be pharmacologically modified even by drugs unable to cross the BBB.

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Alzheimer’s disease (AD) is an incurable neurodegenerative disorder in which neuroinflammation plays a critical function. Yet, little is known about the contribution of the adaptive immune response in AD. Here we used integrated analyses of multiple cohorts to identify peripheral and central adaptive immune changes in AD. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of AD consisting of increased numbers of CD8⁺ T effector memory CD45RA⁺ (T_EMRA) cells. In a second cohort, we found that CD8⁺ T_EMRA cells were negatively associated with cognition. Furthermore, single cell RNA sequencing revealed their enhanced T cell receptor (TCR) signaling. Notably, by utilizing multiple single cell TCR sequencing strategies on a third cohort, we discovered clonally expanded CD8⁺ T_EMRA cells in patient cerebrospinal fluid (CSF). Finally, we used machine learning, cloning, and peptide screens to demonstrate specificity of clonally expanded AD CSF TCRs to two separate Epstein-Barr virus antigens. These results reveal a novel blood-CSF adaptive immune response in AD and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.

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Parkinson's disease is a progressive and debilitating disorder that has so far eluded attempts to develop disease-modifying treatment. Both epidemiological and genetic studies support a role of neuroinflammation in the pathophysiology of Parkinson's disease. Postmortem studies and experimental analyses suggest the involvement of both innate and adaptive immunity in the degenerative process. There is also some circumstantial evidence for effects of immune therapies on the disease. In this presentation, I will review 10 unanswered questions related to neuroinflammatory processes in Parkinson's disease with the goal of stimulating research in the field and accelerating the clinical development of neuroprotective therapies based on anti-inflammatory strategies.