Adenylate kinase 5, a novel genetic risk factor for Alzheimer's disease, regulates microglial inflammatory activation

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive decline and neuroinflammation, with microglia playing a central role.
• Microglial dysfunction contributes significantly to AD pathogenesis.
• Understanding novel regulators of microglial function is crucial for AD research.

Purpose of the Study:

• To investigate the role of adenylate kinase 5 (AK5) in microglial function and its association with Alzheimer's disease (AD) pathology.
• To explore AK5's impact on microglial immune and metabolic responses.
• To examine the genetic association of AK5 variants with AD risk and brain structure.

Main Methods:

• Analysis of AK5 expression in human AD brain tissues and AD model mice.
• In vitro studies involving AK5 knockdown in microglial cells to assess inflammatory and phagocytic responses.
• Metabolic profiling of AK5-silenced microglial cells.
• Genome-wide association studies (GWAS) to identify AK5 single nucleotide polymorphisms (SNPs) associated with AD.

Main Results:

• Significantly reduced AK5 expression was observed in AD brains.
• AK5 knockdown in microglia attenuated pro-inflammatory responses (e.g., nitric oxide, TNF-alpha) and enhanced phagocytosis.
• AK5 silencing led to metabolic reprogramming, including altered lipid metabolism and increased FXR expression.
• Two AK5 SNPs (rs59556669, rs75224576) were significantly associated with hippocampal/amygdala atrophy and increased AD risk, independent of APOE.

Conclusions:

• AK5 is a key regulator of microglial immune and metabolic functions relevant to AD.
• AK5 variants represent potential independent genetic risk factors for AD susceptibility.
• AK5 expression and genetic status may serve as biomarkers for early AD risk assessment.
• Targeting AK5 offers potential therapeutic strategies for AD prevention and treatment.