Microglial Dysfunction and Amyloid-Beta Pathology in Alzheimer's Disease and HIV-Associated Neurocognitive Disorders

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Chronic neuroinflammation and impaired protein clearance characterize neurodegenerative diseases like Alzheimer's disease (AD) and HIV-associated neurocognitive disorders (HAND).
• Microglia, the brain's immune cells, are crucial for maintaining homeostasis by clearing misfolded proteins like amyloid-beta (Aβ).
• Microglial dysfunction in AD and HAND exacerbates inflammation, hinders Aβ clearance, and leads to neuronal damage.

Purpose of the Study:

• To review how microglial pattern recognition receptors coordinate Aβ sensing, uptake, and inflammatory responses.
• To elucidate the mechanisms by which HIV infection and viral proteins disrupt these microglial pathways.
• To identify gaps in understanding HIV's impact on microglial function and its implications for HAND.

Main Methods:

• Synthesis of evidence from human and animal studies.
• Analysis of the roles of TREM2, TLRs, and scavenger receptors in Aβ processing.
• Examination of the effects of HIV proteins (Tat, gp120) on microglial receptor expression, lysosomal function, and metabolism.

Main Results:

• Key microglial receptors (TREM2, TLRs, SRs) are central to Aβ sensing, uptake, and inflammatory signaling.
• HIV infection and viral proteins disrupt these pathways by altering receptor expression and microglial function.
• This disruption creates a cycle of neurotoxicity and amyloid accumulation.

Conclusions:

• Microglial dysfunction and disrupted receptor signaling are critical in AD and HAND pathogenesis.
• HIV actively impairs microglial functions essential for brain homeostasis.
• Further research is needed to fully understand HIV's effects on microglia and develop targeted therapies for HAND.