HAPLN2 forms aggregates and promotes microglial inflammation during brain aging in mice

Area of Science:

• Neuroscience
• Aging Research
• Molecular Biology

Background:

• Protein aggregation is a key feature of neurodegenerative diseases and aging.
• The specific protein aggregates driving brain aging are not fully understood.
• Hyaluronan and proteoglycan link protein 2 (HAPLN2) is an extracellular matrix protein found at the nodes of Ranvier.

Purpose of the Study:

• To identify age-dependent protein aggregates in the brain.
• To investigate the role of HAPLN2 in age-related protein aggregation.
• To explore the impact of HAPLN2 aggregation on microglial function and brain inflammation.

Main Methods:

• Analysis of age-dependent protein insolubility in mouse brains.
• Identification and characterization of aggregating proteins.
• In vitro and in vivo studies on HAPLN2 oligomers and microglial responses.
• Examination of HAPLN2 aggregation in human cerebellar tissue.

Main Results:

• HAPLN2 was identified as an age-dependent aggregating protein in mouse brains.
• Elevated hyaluronic acid and impaired microglial clearance contribute to HAPLN2 accumulation.
• HAPLN2 oligomers activate microglial inflammatory responses.
• Age-associated HAPLN2 aggregation is present in the human cerebellum.

Conclusions:

• HAPLN2 aggregation is linked to age-related decline in brain homeostasis.
• Accumulated HAPLN2 exacerbates the brain environment by activating microglia.
• HAPLN2 plays a significant role in age-associated cerebellar changes and brain aging.