Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Abstract

Alzheimer's disease (AD) is a complex agerelated neurodegenerative disorder of the central nervous system. Since the first description of AD in 1907, many hypotheses have been established to explain its causes. The inflammation theory is one of them. Pathological and biochemical studies of brains from AD individuals have provided solid evidence of the activation of inflammatory pathways. Furthermore, people with long-term medication of anti-inflammatory drugs have shown a reduced risk to develop the disease. After three decades of genetic study in AD, dozens of loci harboring genetic variants influencing inflammatory pathways in AD patients has been identified through genome-wide association studies (GWAS). The most well-known GWAS risk factor that is responsible for immune response and inflammation in AD development should be APOE e4 allele. However, a growing number of other GWAS risk AD candidate genes in inflammation have recently been discovered. In the present study, we try to review the inflammation in AD and immunity-associated GWAS risk genes like HLA-DRB5/DRB1, INPP5D, MEF2C, CR1, CLU and TREM2.

INPP5D rs35349669 polymorphism with late-onset Alzheimer's disease: A replication study and meta-analysis

“…INPP5D , as a member of the inositol polyphosphate-5-phosphatase (INPP5) family, is located on chromosome 2q37.1 [8, 11], it was implicated in AD pathogenesis through microglia-mediated inflammatory process and immune response [8, 12, 13]. Our study replicated the association between the rs35349669 polymorphism within INPP5D and LOAD risk in Northern Han Chinese.…”

The Receptor for Advanced Glycation Endproducts (RAGE) and Mediation of Inflammatory Neurodegeneration

“…While the primary risk factor for AD is advanced age, recent insights from genomic technology implicate inflammatory lipid and cytokine signaling in microglia, the myeloid cells of the CNS, as a prominent correlate of disease. Specifically, human GWAS suggest a powerful link between inflammatory pathways, including complement, chemokines and influential lipid and cholesterol molecules, such as Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), ABCA7, Apolipoprotein E variant 4 (APOE4) and others with AD susceptibility [14,20,[41][42][43][44][45][46][47][48][49]. Additional analyses within animal models have illuminated various molecules critical to the innate immune system as major contributors to increased or decreased rate of AD progression, such as Chemokine Receptor Type 2 (CCR2), Chemokine Receptor 1 (CX3CR1 or GPR1), complement components (C1q and C3) and Chemokine Ligand 8 (CXCL8) [43,[50][51][52][53][54][55][56][57][58][59][60][61][62][63].…”

“…DN-RAGE is composed of the extracellular RAGE domains and the transmembrane domain; hence, although ligand binding to this construct is intact and it is tethered to the cell membrane, signaling is abrogated on account of deletion of the cytoplasmic domain. These DN-RAGE studies have indicated that RAGE signal abrogation confers a benefit for AD progression and suggest a role for RAGE in myeloid cells during AD [10,12,47,74]. However, there are possible caveats to these studies, particularly since it is plausible that DN-RAGE may also act as a decoy receptor and "ligand sink", much like sRAGE, and mice devoid of Ager or expressing DN-RAGE constitutively from birth may develop differently than a wild-type animal.…”

MEF2C rs190982 polymorphism with late-onset Alzheimer's disease in Han Chinese: A replication study and meta-analyses

“…A recent work revealed that the overexpression of MEF2 function impeded the learning-induced increases in spine density and impaired memory formation via an Arc-mediated reduction in the surface expression of the GluA2-AMPA-type glutamate receptor [10]. In brain, MEF2C is highly expressed in the regions which are closely related with learning and memory such as dentate gyrus, frontal cortex, entorhinal cortex, and amygdala [11]. On the other hand, MEF2C may be involved in the inflammatory process altered in AD via the regulation of microglia proliferation [11].…”

“…In brain, MEF2C is highly expressed in the regions which are closely related with learning and memory such as dentate gyrus, frontal cortex, entorhinal cortex, and amygdala [11]. On the other hand, MEF2C may be involved in the inflammatory process altered in AD via the regulation of microglia proliferation [11]. In addition, MEF2 seems to play an important role in APP-mediated anti-apoptotic neuroprotection [12], and MEF2C is identified as a regulator of APP proteolytic process in which Amyloid-β (Aβ), one central factor to initiate AD pathogenesis, is produced [13].…”