Immune landscape of the enteric nervous system differentiates Parkinson's disease patients from controls: The PADUA-CESNE cohort.

BACKGROUND: Gastrointestinal dysfunction has emerged as a prominent early feature of Parkinson's Disease, shedding new light on the pivotal role of the enteric nervous system in its pathophysiology. However, the role of immune-cell clusters and inflammatory and glial markers in the gut pathogenetic process needs further elucidation. OBJECTIVES: We aimed to study duodenum tissue samples to characterize PD's enteric nervous system pathology further. Twenty patients with advanced PD, six with early PD, and 18 matched controls were included in the PADUA-CESNE cohort. METHODS: Duodenal biopsies from 26 patients with early to advanced stage PD and 18 age-matched HCs were evaluated for the presence of surface markers (CD3+, CD4+, CD8+, CD20+, CD68+, HLA-DR), presence of misfolded alpha-synuclein and enteric glial alteration (GFAP). Correlation of immulogic pattern and clinical characteristic were analyzed. RESULTS: The findings validate that in patients with Parkinson's Disease, the activation and reactive gliosis are linked to the neurodegeneration triggered by the presence of misfolded alpha-synuclein in the enteric nervous system. This process intensifies from the initial to the advanced stages of the disease. The clusters of T- and B-lymphocytes in the enteric system, along with the overall expression of HLA-DR in antigen-presenting cells, exceeded those in the control group. Conversely, no differences in terms of macrophage populations were found. CONCLUSIONS: These findings broaden our understanding of the mechanisms underlying the enteric nervous system's involvement in PD and point to the gastrointestinal system as a potential therapeutic target, especially in the early stages of the disease. Moreover, our results propose a role of T- and B-lymphocytes in maintaining inflammation and ultimately influencing alpha-synuclein misfolding and aggregation.

Carotid body plastic behavior: evidence for D2-H3 receptor-receptor interactions.

Dopamine and histamine receptors D2R and H3R are G protein-coupled receptors (GPCRs) which can establish physical receptor-receptor interactions (RRIs), leading to homo/hetero-complexes in a dynamic equilibrium. Although D2R and H3R expression has been detected within the carotid body (CB), their possible heterodimerization has never been demonstrated. The aim of this work was to verify D2R and H3R colocalization in the CB, thus suggesting a possible interplay that, in turn, may be responsible of specific D2R-H3R antagonistic functional implications. The CBs of both Sprague-Dawley rats (n = 5) and human donors (n = 5) were dissected, and immunolocalization of D2R and H3R was performed; thereafter, in situ proximity ligation assay (PLA) was developed. According to experimental evidence (immunohistochemistry and double immunofluorescence), all the samples displayed positive D2R/H3R elements; hence, PLA assay followed by confocal microscopy analysis was positive for D2R-H3R RRIs. Additionally, D2R-H3R heterodimers were mainly detected in type I cells (ßIII-tubulin-positive cells), but type II cells' involvement cannot be excluded. RRIs may play a role in functional modulation of CB cells; investigating RRIs in the CB may guide toward the comprehension of its plastic changes and fine regulatory role while also unveiling their possible clinical implications.

ACE2 Receptor and TMPRSS2 Protein Expression Patterns in the Human Brainstem Reveal Anatomical Regions Potentially Vulnerable to SARS-CoV-2 Infection.

Angiotensin-converting enzyme 2 receptor (ACE2R) is a transmembrane protein expressed in various tissues throughout the body that plays a key role in the regulation of blood pressure. Recently, ACE2R has gained significant attention due to its involvement in the pathogenesis of COVID-19, the disease caused by the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2). While ACE2 receptors serve as entry points for the novel coronavirus, Transmembrane Serine Protease 2 (TMPRSS2), an enzyme located on the cell membrane, is required for SARS-CoV-2 S protein priming. Even though numerous studies have assessed the effects of COVID-19 on the brain, very little information is available concerning the distribution of ACE2R and TMPRSS2 in the human brain, with particular regard to their topographical expression in the brainstem. In this study, we investigated the expression of ACE2R and TMPRSS2 in the brainstem of 18 adult subjects who died due to pneumonia/respiratory insufficiency. Our findings indicate that ACE2R and TMPRSS2 are expressed in neuronal and glial cells of the brainstem, particularly at the level of the vagal nuclei of the medulla and the midbrain tegmentum, thus confirming the expression and anatomical localization of these proteins within specific human brainstem nuclei. Furthermore, our findings help to define anatomically susceptible regions to SARS-CoV-2 infection in the brainstem, advancing knowledge on the neuropathological underpinnings of neurological manifestations in COVID-19.