Investigating the effect of CD۳۳ and TREM۲ genes on the pathogenesis of Alzheimer's disease and their therapeutic targets

Alzheimer's disease (AD) is the leading cause of dementia worldwide, which presents great challenges for policy makers, health care professionals, and family members of AD patients. Symptoms of AD include progressive memory loss, impaired executive function, and inability to perform daily life activities. AD is histologically characterized by intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein in neurons and accumulation of extracellular plaques composed of amyloid beta peptide (Aβ) in the brain. These protein clumps are associated with the loss of synapses and neurons. In genome-wide association studies (GWAS), many Alzheimer's disease risk genes have been identified to be associated with the immune system response, particularly microglia, including the phagocytic receptors CD۳۳ and TREM۲. Impaired microglial phagocytosis leads to amyloid beta (Aβ) accumulation. This leads to neuroinflammation, which is the main cause of neurodegeneration. CD۳۳ and TREM۲ modulate Alzheimer's disease pathogenesis and neuroinflammation and have emerged as therapeutic targets in Alzheimer's disease. TREM۲ is essential for microglia recognition and response to signs of neurodegeneration, and TREM۲ expression correlates with phagocytosis rate. The CD۳۳ receptor, also called Siglec-۳, inhibits TREM۲ receptor-induced phagocytic activity of microglia. Targeting neuroinflammation through CD۳۳ inhibition or TREM۲ activation with gene therapy, small molecules, or immunotherapy may have important implications for neurodegeneration in Alzheimer's disease and may be complementary to anti-Aβ monoclonal antibody therapies that target plaques which removes plaques without reducing neuroinflammation. Advances have also been made in inhibiting CD۳۳ by gene therapy, small molecules or immunotherapy, and increasing TREM۲ activity by immunotherapy, which may reduce neuroinflammation in the brains of Alzheimer's patients.

Keywords:

Alzheimer's disease , AD , Gene Expression , CD۳۳ , TREM۲.