Outside-in induction of the IFITM3 trafficking system by infections, including SARS-CoV-2, in the pathobiology of Alzheimer’s disease

Abstract

Background IFITM3 is a viral restriction protein that enables sequestration of viral particles and subsequent trafficking to lysosomes. Recently, IFITM3 upregulation was found to induce gamma – secretase activity and the production of amyloid beta. The purpose of this study was to determine whether dysregulation of IFITM3-dependent pathways was present in neurons and peripheral immune cells donated by AD patients. As a secondary aim, we sought to determine whether these perturbations could be induced by viruses, including SARS-CoV-2. Methods Gene set enrichment analyses (GSEA) previously performed on publicly available transcriptomic data from tissues donated by AD patients were screened for enriched pathways containing IFITM3. Subsequently, signature containing IFITM3, derived from entorhinal cortex (EC) neurons containing neurofibrillary tangles (NFT) was screened for overlap with curated, publicly available, viral infection-induced gene signatures (including SARS-CoV-2). Results GSEA determined that IFITM3 gene networks are significantly enriched both in CNS sites (entorhinal and hippocampal cortices) and in peripheral blood mononuclear cells (PBMCs) donated by AD patients. Overlap screening revealed that IFITM3 signatures are induced by several viruses, including SARS-CoV, MERS-CoV, SARS-CoV-2 and HIV-1 (adjusted p-value <0.001; Enrichr Database). Discussion A data-driven analysis of AD tissues revealed IFITM3 gene signatures both in the CNS and in peripheral immune cells. GSEA revealed that an IFITM3 derived gene signature extracted from EC/NFT neurons overlapped with those extracted from publicly available viral infection datasets, including SARS-CoV-2. Our results are in line with currently emerging evidence on IFITM3’s role in AD, and SARS-CoV-2’s potential contribution in the setting of an expanded antimicrobial protection hypothesis.

BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia

“…Our results further show that Ifitm3 – one of the genes stimulated by type I interferons, as well as by proinflammatory cytokines that are critical mediators of the host innate immune response, including IL-1b, IL-6, and TNF [ 35 ] – is positively regulated by BIN1, both in vitro and in vivo. A recent publication found IFITM3 gene networks to be enriched in tau tangle-containing neurons and peripheral mononuclear cells from AD patients [ 38 ]. Expression of IFITM3 is also upregulated in microglia of a transgenic model of AD amyloid pathogenesis [ 33 , 94 ].…”

“…IFITM3 facilitates lysosome acidification [ 34 , 35 ] and limits immune-response cytokine production [ 36 , 37 ]. Notably, IFITM3 gene networks are enriched in brains and peripheral blood mononuclear cells of AD patients [ 38 ], suggesting that IFITM3 plays a role in microglial inflammatory responses to AD pathology. Collectively, these findings provide important insights into BIN1 expression and function in microglia, demonstrating the significance of microglial BIN1 expression in brain inflammatory response.…”

Type I interferon signaling in SARS-CoV-2 associated neurocognitive disorder (SAND): Mapping host-virus interactions to an etiopathogenesis

“…In recently published work by Vavougios and colleagues ( 46 ), disrupted proteostasis and trained immunity pathways were among overlapping molecular pathways that are common across different tissues in AD. This work suggested that IFN-1 has a specific relationship with unique signaling cascades, focusing on the IFN response to antiviral effectors, such as the interferon-inducible transmembrane (IFITM) and the 2′-5′-oligoadenylate synthase (OAS) family genes in both AD and COVID-19 ( 15 ). The specific relationship of perturbed IFN-I signaling to both AD and COVID-19, focuses on interferon responsive antiviral effectors, such as IFITMs and OASs, which are interferon stimulated (ISGs) gene families that provide cellular-level defense against intracellular pathogens.…”

“…Dysfunctions of IFITMs and OASs on a pathway level not only have the potential to abrogate antiviral activity, but several studies suggest this dysfunction enables these factors to act as pro-viral factors ( 47 – 49 ). Vavougios and colleagues found that IFN-I signatures containing members of these ISG families are common in neurons, peripheral immune cells, and microglia affected by COVID-19 or by AD ( 10 , 15 , 33 , 50 , 51 ).…”

“…Collectively, these studies point toward type I interferon signaling, a pathway contested by SARS-CoV-2 ( 13 ), as the potential culprit. Furthermore, interferon responsive genes such as those in the ISG, OAS, and IFITM families, dysregulated by SARS-CoV-2, have recently and independently emerged as key players in AD ( 9 , 14 , 15 ). To date, studies attempting to summarize the evidence on this overlap have not attempted to explore their synthesis towards an etiopathogenic mechanism emerging from host-virus interactions.…”