Gene Description
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Alzheimer's Disease is the leading cause of dementia worldwide. Clinically, it is characterized by the presence of extracellular amyloid plaques and intracellular neurofibrillary tangles, which result in neuronal dysfunction and cell death. Genome-wide association studies have identified a cohort of risk genes associated with late-onset AD, including, but not limited to, APOE, BIN1, SORL1, TREM2, EphA1, MEF2C, CLU, and HLA-DRB1. APOE has three allele variants: ApoE2, ApoE3, and ApoE4. ApoE4 is associated with an increased risk of AD. Evidence suggests that this risk occurs through promotion of amyloid-beta plaque aggregation. ApoE4 is also associated with impaired microglial response, lipid transport, synaptic integrity and plasticity, glucose metabolism, and cerebrovascular integrity. Mutations in BIN1, primarily involved in endocytosis and maintaining cytoskeletal integrity in the brain, are suggested to play a role in the aggravation of tau pathology. Increased levels of BIN1 have been seen in AD postmortem brain tissue. SORL1 expression is decreased in the brain of AD patients. Studies have demonstrated a role for SORL1 as a neuronal sorting receptor that binds amyloid precursor protein and regulates its trafficking and proteolytic processing, thus regulating β-amyloid peptide production. The triggering receptor expressed on myeloid cells 2 is an innate immune receptor that is expressed on the cell surface of microglia, macrophages, osteoclasts, and immature dendritic cells. Research studies using AD mouse models indicate that deficiency and haploinsufficiency of TREM2 can lead to increased Aβ accumulation due to dysfunctional microglia response. EphA1 is a member of the ephrin family of receptor tyrosine kinases responsible for regulating cell morphology and motility. In the central nervous system, EphA1 plays a role in synaptic plasticity and axon guidance. EphA1 is involved in inflammatory signaling pathways, which may mean it plays a role in regulation of neuroinflammatory processes in AD. MEF2C is a member of the myocyte enhancer factor 2 family of transcription factors shown to play a role in learning and memory formation through regulation of synaptic plasticity. Studies have shown that MEF2C may play a role in age-related microglial activation through IFN-I associated MEF2C deregulation. MEF2C may also act as a modulator for APP proteolytic processing of Aβ. Clusterin is a multifunctional glycoprotein shown to play a protective role in AD by sequestering Aβ40 peptides to form long-lived, stable complexes, which prevent amyloid fibril formation. Major histocompatibility complex class II molecules are transmembrane glycoproteins expressed on the surface of antigen-presenting cells that bind exogenous peptide antigens derived from endocytosed extracellular proteins digested in the lysosome. Increases in MHC class II-expressing microglia have been shown in AD brain. |