scholarly journals Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer’s disease

2018 ◽  
Author(s):  
Nisha Rathore ◽  
Sree Ranjani Ramani ◽  
Homer Pantua ◽  
Jian Payandeh ◽  
Tushar Bhangale ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Cell ◽  
Disease Risk ◽  
Missense Variant ◽  
Cell Types ◽  
Glycoprotein B ◽  
Receptor Alpha ◽  
Hsv 1

AbstractPaired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) is a cell surface inhibitory receptor that recognizes specific O-glycosylated proteins and is expressed on various innate immune cell types including microglia. We show here that a common missense variant (G78R, rs1859788) of PILRA is the likely causal allele for the confirmed Alzheimer’s disease risk locus at 7q21 (rs1476679). The G78R variant alters the interaction of residues essential for sialic acid engagement, resulting in >50% reduced binding for several PILRA ligands including a novel ligand, complement component 4A, and herpes simplex virus 1 (HSV-1) glycoprotein B. PILRA is an entry receptor for HSV-1 via glycoprotein B, and macrophages derived from R78 homozygous donors showed significantly decreased levels of HSV-1 infection at several multiplicities of infection compared to homozygous G78 macrophages. We propose that PILRA G78R protects individuals from Alzheimer’s disease risk via reduced inhibitory signaling in microglia and reduced microglial infection during HSV-1 recurrence.

scholarly journals Genetic meta-analysis identifies 9 novel loci and functional pathways for Alzheimer’s disease risk

2018 ◽  
Author(s):  
Iris E Jansen ◽  
Jeanne E Savage ◽  
Kyoko Watanabe ◽  
Julien Bryois ◽  
Dylan M Williams ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Late Onset ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
Cell Types ◽  
Mendelian Randomisation ◽  
Genome Wide

AbstractLate onset Alzheimer’s disease (AD) is the most common form of dementia with more than 35 million people affected worldwide, and no curative treatment available. AD is highly heritable and recent genome-wide meta-analyses have identified over 20 genomic loci associated with AD, yet only explaining a small proportion of the genetic variance indicating that undiscovered loci exist. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 AD cases, 383,378 controls). AD-by-proxy status is based on parental AD diagnosis, and showed strong genetic correlation with AD (rg=0.81). Genetic meta analysis identified 29 risk loci, of which 9 are novel, and implicating 215 potential causative genes. Independent replication further supports these novel loci in AD. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Furthermore, gene-set analyses indicate the genetic contribution of biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying more of the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD to guide new drug development.

Inhibitory Fcγ Receptor and Paired Immunoglobulin Type 2 Receptor Alpha Genotypes in Alzheimer’s Disease

2021 ◽  
pp. 1-4
Author(s):  
Janardan P. Pandey ◽  
Aryan M. Namboodiri ◽  
Paul J. Nietert ◽  
Lisa L. Barnes ◽  
David A. Bennett
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
African American ◽  
European American ◽  
Fcγ Receptor ◽  
Receptor Alpha

We investigated whether FCGRIIB (rs1050501 C/T) and PILRA (rs1859788 A/G) genotypes contributed to the development of Alzheimer’s disease (AD). We genotyped 209 African American (AA) and 638 European American participants for the FCGRIIB and PILRA alleles. In the AA cohort, subjects homozygous for the C allele of FCGRIIB were more than 4 times as likely to develop AD as those homozygous for the alternative T allele. This SNP also interacted with PILRA: participants who were the carriers of the FCGRIIB C allele and PILRA A allele were 3 times as likely to develop AD as those who lacked these alleles.

scholarly journals Vascular Dysfunction in Alzheimer’s Disease: A Prelude to the Pathological Process or a Consequence of It?

2019 ◽  
Vol 8 (5) ◽  
pp. 651 ◽  
Author(s):  
Karan Govindpani ◽  
Laura G McNamara ◽  
Nicholas R Smith ◽  
Chitra Vinnakota ◽  
Henry J Waldvogel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Function ◽  
Immune Cell ◽  
Vascular Dysfunction ◽  
Apoe Genotype ◽  
Cell Types ◽  
Pathological Process ◽  
Vascular Pathology ◽  
Amyloid Toxicity

Alzheimer’s disease (AD) is the most prevalent form of dementia. Despite decades of research following several theoretical and clinical lines, all existing treatments for the disorder are purely symptomatic. AD research has traditionally been focused on neuronal and glial dysfunction. Although there is a wealth of evidence pointing to a significant vascular component in the disease, this angle has been relatively poorly explored. In this review, we consider the various aspects of vascular dysfunction in AD, which has a significant impact on brain metabolism and homeostasis and the clearance of β-amyloid and other toxic metabolites. This may potentially precede the onset of the hallmark pathophysiological and cognitive symptoms of the disease. Pathological changes in vessel haemodynamics, angiogenesis, vascular cell function, vascular coverage, blood-brain barrier permeability and immune cell migration may be related to amyloid toxicity, oxidative stress and apolipoprotein E (APOE) genotype. These vascular deficits may in turn contribute to parenchymal amyloid deposition, neurotoxicity, glial activation and metabolic dysfunction in multiple cell types. A vicious feedback cycle ensues, with progressively worsening neuronal and vascular pathology through the course of the disease. Thus, a better appreciation for the importance of vascular dysfunction in AD may open new avenues for research and therapy.

scholarly journals Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer's disease

PLoS Genetics ◽  
2018 ◽  
Vol 14 (11) ◽  
pp. e1007427 ◽  
Author(s):  
Nisha Rathore ◽  
Sree Ranjani Ramani ◽  
Homer Pantua ◽  
Jian Payandeh ◽  
Tushar Bhangale ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ligand Binding ◽  
Receptor Alpha

scholarly journals PLCG2 as a Risk Factor for Alzheimer’s Disease

2020 ◽  
Author(s):  
Andy P. Tsai ◽  
Chuanpeng Dong ◽  
Christoph Preuss ◽  
Miguel Moutinho ◽  
Peter Bor-Chian Lin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Immune Cell ◽  
Missense Variant ◽  
Brain Regions ◽  
Disease Pathogenesis ◽  
Surface Receptors ◽  
The Brain ◽  
Brain Amyloid Deposition

AbstractAlzheimer’s disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Indeed, genetic variants in microglial genes are linked to risk for AD. Phospholipase C γ 2 (PLCG2) participates in the transduction of signals emanating from immune cell-surface receptors that regulate the inflammatory response and is selectively expressed by microglia in the brain. A rare variant in PLCG2 (P522R) was previously found to be protective against AD, indicating that PLCG2 may play a role in AD pathophysiology. Here, we report that a rare missense variant in PLCG2 confers increased AD risk (p=0.047; OR=1.164 [95% CI=1.002-1.351]). Additionally, we observed that PLCG2 expression levels are increased in several brain regions of AD patients, correlating with brain amyloid deposition. This provides further evidence that PLCG2 may play an important role in AD pathophysiology. Together, our findings indicate that PLCG2 is a potential new therapeutic target for AD.

P4-011: The Alzheimer's disease risk loci bin1 is associated with poorer episodic memory performance in cognitively normal type 2 diabetes elderly

2015 ◽  
Vol 11 (7S_Part_16) ◽  
pp. P769-P770
Author(s):  
Lior Greenbaum ◽  
Ramit Ravona-Springer ◽  
Irit Lubitz ◽  
James Schmeidler ◽  
Itzik Cooper ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Episodic Memory ◽  
Disease Risk ◽  
Memory Performance ◽  
Normal Type ◽  
Cognitively Normal

scholarly journals A human brain vascular atlas reveals diverse cell mediators of Alzheimer’s disease risk

2021 ◽  
Author(s):  
Andrew C. Yang ◽  
Ryan T. Vest ◽  
Fabian Kern ◽  
Davis P. Lee ◽  
Christina A. Maat ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Protein Transport ◽  
Disease Risk ◽  
Expression Patterns ◽  
Cell Types ◽  
Mural Cell ◽  
Perivascular Cell ◽  
Brain Vasculature

AbstractThe human brain vasculature is of vast medical importance: its dysfunction causes disability and death, and the specialized structure it forms—the blood-brain barrier—impedes treatment of nearly all brain disorders. Yet, no molecular atlas of the human brain vasculature exists. Here, we develop Vessel Isolation and Nuclei Extraction for Sequencing (VINE-seq) to profile the major human brain vascular and perivascular cell types through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 17 control and Alzheimer’s disease (AD) patients. We identify brain region-enriched pathways and genes divergent between humans and mice, including those involved in disease. We describe the principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum; but discover that many zonation and cell-type markers differ between species. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In AD, we observe a selective vulnerability of ECM-maintaining pericytes and gene expression patterns implicating dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 AD GWAS genes are expressed in the human brain vasculature, confirmedin situ. Vascular GWAS genes map to endothelial protein transport, adaptive immune, and ECM pathways. Many are microglia-specific in mice, suggesting an evolutionary transfer of AD risk to human vascular cells. Our work unravels the molecular basis of the human brain vasculature, informing our understanding of overall brain health, disease, and therapy.

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