Amyloid-β aggregates activate peripheral monocytes in mild cognitive impairment

Area of Science:

• Neuroimmunology
• Neurodegenerative Diseases
• Molecular Biology

Background:

• The peripheral immune system's role in neurodegenerative diseases like Alzheimer's Disease (AD) is significant but poorly understood.
• AD is often preceded by a prodromal phase characterized by mild cognitive impairment (MCI).

Purpose of the Study:

• To investigate the presence and significance of amyloid-beta (Aβ) aggregates in the plasma of individuals with MCI.
• To elucidate the mechanisms by which peripheral immune cells interact with Aβ aggregates and influence brain pathology.

Main Methods:

• Detection and characterization of plasma Aβ aggregates in MCI patients using advanced imaging (¹¹C-PiB PET, ¹⁸F-FTP PET).
• Analysis of monocyte populations (CD18-rich) and their association with Aβ aggregates.
• In vitro studies using stem cell-derived microglia to assess the role of complement receptor 4 (CR4) in Aβ phagocytosis and lysosomal activity.
• Investigation of KIM127 integrin activation in monocytes for size-selective Aβ phagocytosis.
• Hydrodynamic calculations to model Aβ aggregate association with cortical capillaries.

Main Results:

• Large Aβ aggregates were identified in the plasma of MCI patients (n=38).
• Plasma Aβ aggregates correlated with early AD-like brain pathology and reduced levels of CD18-rich monocytes.
• Complement receptor 4 was confirmed as a high-affinity binder of amyloids, mediating Aβ aggregate phagocytosis and lysosomal stimulation in microglia.
• Monocyte integrin activation (KIM127) promoted size-selective phagocytosis of Aβ.
• Aβ aggregates may adhere to cortical capillary walls, potentially recruiting monocytes to the brain cortex.

Conclusions:

• Plasma Aβ aggregates are present in MCI and are linked to early AD brain pathology.
• Complement receptor 4 plays a crucial role in microglial phagocytosis of Aβ aggregates and amyloid homeostasis.
• Monocyte recruitment to the brain may be influenced by Aβ aggregates adhering to cerebral vasculature.