Genetic variability associated withOAS1expression in myeloid cells increases the risk of Alzheimer’s disease and severe COVID-19 outcomes

Abstract

Genome-wide association studies of late-onset Alzheimer’s disease (AD) have highlighted the importance of variants associated with genes expressed by the innate immune system in determining risk for AD. Recently, we and others have shown that genes associated with variants that confer risk for AD are significantly enriched in transcriptional networks expressed by amyloid-responsive microglia. This allowed us to predict new risk genes for AD, including the interferon-responsive oligoadenylate synthetase 1 (OAS1). However, the function of OAS1 within microglia and its genetic pathway are not known. Using genotyping from 1,313 individuals with sporadic AD and 1,234 control individuals, we confirm that the OAS1 variant, rs1131454, is associated with increased risk for AD and decreased OAS1 expression. Moreover, we note that the same locus was recently associated with critical illness in response to COVID-19, linking variants that are associated with AD and a severe response to COVID-19. By analysing single-cell RNA-sequencing (scRNA-seq) data of isolated microglia from APPNL-G-F knock-in and wild-type C57BL/6J mice, we identify a transcriptional network that is significantly upregulated with age and amyloid deposition, and contains the mouse orthologue Oas1a, providing evidence that Oas1a plays an age-dependent function in the innate immune system. We identify a similar interferon-related transcriptional network containing OAS1 by analysing scRNA-seq data from human microglia isolated from individuals with AD. Finally, using human iPSC-derived microglial cells (h-iPSC-Mg), we see that OAS1 is required to limit the pro-inflammatory response of microglia. When stimulated with interferon-gamma (IFN-γ), we note that cells with lower OAS1 expression show an exaggerated pro-inflammatory response, with increased expression and secretion of TNF-α. Collectively, our data support a link between genetic risk for AD and susceptibility to critical illness with COVID-19 centred on OAS1 and interferon signalling, a finding with potential implications for future treatments of both AD and COVID-19, and the development of biomarkers to track disease progression.

SARS-CoV-2-Induced Type I Interferon Signaling Dysregulation in Olfactory Networks Implications for Alzheimer’s Disease

“…A growing body of research posits that infections, particularly viral, increase the risk for Alzheimer's and related dementias [72]. Aside from our own study [2], others have also compared Alzheimer's disease and COVID-19 transcriptomes and found shared dysregulations in innate immune pathways, including IFITM and OAS family genes both in neuropathological studies and murine models [18,73]. IFITM3 is of particular note as its expression has been shown to be modulated by cGAS-STING, a pathway that is critical for SARS-CoV-2 infection [74] as it is for resilience against tau [62] and Aβ [75] induced neuroinflammation-with IFITM3 itself being an amyloidogenic gamma secretase modulator [14].…”

“…Rather, we aimed to identify IFN-I in gene expression data that had previously been generated. The main idea behind attempting this synthesis and the comparisons described herein is to examine the plausibility of an IFN-I centric model for SARS-CoV-2's effect on the CNS and its overlap with Alzheimer's disease as described in previous works from our group [2,17,21]; notably, aside from our work or the transolfactory concept explored herein, independent studies have provided further support to this concept [18][19][20].…”

“…IFITM3 functions as an antiviral protein that may be subverted by SARS-CoV-2 and enhance rather than restrict infection [15,16]. Furthermore, several studies, including those from our group have outlined IFITM3 pathways as overlapping networks between Alzheimer's disease and COVID-19 [2,[17][18][19][20][21]. IFITM3 was recently shown to modulate amyloidogenic APP processing by gamma secretase [14], and partake in IFN-I responsive circuits following microglial uptake of Aβ and Aβ-Nucleic Acid complexes [10].…”

The relationship of early- and late-onset Alzheimer’s disease genes with COVID-19

“…When bound, sialic acid activates CD33 and causes monocyte inhibition via cytosolic immunotyrosine inhibitory motif domains (Malik et al 2013 ). According to the findings provided by some genetic studies, CD33 gene variant is an important factor modifying Alzheimer’s disease risk and are expressed by the innate immune system (Magusali et al 2021 ). rs3865444 is located in the proximal promoter of CD33 and considered one of the SNPs linked to Alzheimer’s disease (Liu and Jiang 2016 ) .…”

“…rs3865444 is located in the proximal promoter of CD33 and considered one of the SNPs linked to Alzheimer’s disease (Liu and Jiang 2016 ) . CD33 gene variant plays a role in a related pathway so that it enables microglia to react to amyloid beta deposition, abnormal synaptic activity or damaged phospholipid membranes and to activate the complement system to induce phagocytosis (Magusali et al 2021 ).…”