Transcriptomic and epigenomic landscapes of Alzheimer's disease evidence mitochondrial-related pathways.

Alzheimers disease (AD) is the main cause of dementia and it is defined by cognitive decline coupled to extracellular deposit of amyloid-beta protein and intracellular hyperphosphorylation of tau protein. Historically, efforts to target such hallmarks have failed in numerous clinical trials. In addition to these hallmark-targeted approaches, several clinical trials focus on other AD pathological processes, such as inflammation, mitochondrial dysfunction, and oxidative stress. Mitochondria and mitochondrial-related mechanisms have become an attractive target for disease-modifying strategies, as mitochondrial dysfunction prior to clinical onset has been widely described in AD patients and AD animal models. Mitochondrial function relies on both the nuclear and mitochondrial genome. Findings from omics technologies have shed light on AD pathophysiology at different levels (e.g., epigenome, transcriptome and proteome). Most of these studies have focused on the nuclear-encoded components. The first part of this review provides an updated overview of the mechanisms that regulate mitochondrial gene expression and function. The second part of this review focuses on evidence of mitochondrial dysfunction in AD. We have focused on published findings and datasets that study AD. We analyzed published data and provide examples for mitochondrial-related pathways. These pathways are strikingly dysregulated in AD neurons and glia in sex-, cell- and disease stage-specific manners. Analysis of mitochondrial omics data highlights the involvement of mitochondria in AD, providing a rationale for further disease modeling and drug targeting.

Cladribine Treatment for MS Preserves the Differentiative Capacity of Subsequently Generated Monocytes, Whereas Its Administration In Vitro Acutely Influences Monocyte Differentiation but Not Microglial Activation.

Cladribine (2-chlorodeoxyadenosine, 2CdA) is one of the most effective disease-modifying drugs for multiple sclerosis (MS). Cladribine is a synthetic purine nucleoside analog that induces cell death of lymphocytes and oral cladribine treatment leads to a long-lasting disease stabilization, potentially attributable to immune reconstitution. In addition to its effects on lymphocytes, cladribine has been shown to have immunomodulatory effects on innate immune cells, including dendritic cells and monocytes, which could also contribute to its therapeutic efficacy. However, whether cladribine can modulate human macrophage/microglial activation or monocyte differentiation is currently unknown. The aim of this study was to determine the immunomodulatory effects of cladribine upon monocytes, monocyte-derived macrophages (MDMs) and microglia. We analyzed the phenotype and differentiation of monocytes from MS patients receiving their first course of oral cladribine both before and three weeks after the start of treatment. Flow cytometric analysis of monocytes from MS patients undergoing cladribine treatment revealed that the number and composition of CD14/CD16 monocyte subsets remained unchanged after treatment. Furthermore, after differentiation with M-CSF, such MDMs from treated MS patients showed no difference in gene expression of the inflammatory markers compared to baseline. We further investigated the direct effects of cladribine in vitro using human adult primary MDMs and microglia. GM-CSF-derived MDMs were more sensitive to cell death than M-CSF-derived MDMs. In addition, MDMs treated with cladribine showed increased expression of costimulatory molecules CD80 and CD40, as well as expression of anti-inflammatory, pro-trophic genes IL10 and MERTK, depending on the differentiation condition. Cladribine treatment in vitro did not modulate the expression of activation markers in human microglia. Our study shows that cladribine treatment in vitro affects the differentiation of monocytes into macrophages by modulating the expression of activation markers, which might occur similarly in tissue after their infiltration in the CNS during MS.

VISTA regulates microglia homeostasis and myelin phagocytosis, and is associated with MS lesion pathology.

V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) is a negative checkpoint regulator (NCR) that is involved in T-cell quiescence, inhibition of T-cell activation, and in myeloid cells regulates cytokine production, chemotaxis, phagocytosis, and tolerance induction. In the central nervous system (CNS), VISTA is expressed by microglia, the resident macrophage of the parenchyma, and expression is decreased during neuroinflammation; however, the function of VISTA in microglia is unknown. Here, we extensively analyzed VISTA expression in different MS lesion stages and characterized the function of VISTA in the CNS by deleting VISTA in microglia. VISTA is differentially expressed in distinct MS lesion stages. In mice, VISTA deletion in Cx3Cr1-expressing cells induced a more amoeboid microglia morphology, indicating an immune-activated phenotype. Expression of genes associated with cell cycle and immune-activation was increased in VISTA KO microglia. In response to LPS and during experimental autoimmune encephalomyelitis (EAE), VISTA KO and WT microglia shared similar transcriptional profiles and VISTA deletion did not affect EAE disease progression or microglia responses. VISTA KO in microglia in vitro decreased the uptake of myelin. This study demonstrates that VISTA is involved in microglia function, which likely affects healthy CNS homeostasis and neuroinflammation.