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Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain
Joshua D Crapser1, Elizabeth E Spangenberg1, Rocio A Barahona1
1Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
Background:
Microglia, the brain's principal immune cell, are increasingly implicated in Alzheimer's disease (AD), but the molecular interfaces through which these cells contribute to amyloid beta (Aβ)-related neurodegeneration are unclear. We recently identified microglial contributions to the homeostatic and disease-associated modulation of perineuronal nets (PNNs), extracellular matrix structures that enwrap and stabilize neuronal synapses, but whether PNNs are altered in AD remains controversial.
Methods:
Extensive histological analysis was performed on male and female 5xFAD mice at 4, 8, 12, and 18 months of age to assess plaque burden, microgliosis, and PNNs. Findings were validated in postmortem AD tissue. The role of neuroinflammation in PNN loss was investigated via LPS treatment, and the ability to prevent or rescue disease-related reductions in PNNs was assessed by treating 5xFAD and 3xTg-AD model mice with colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia.
Findings:
Utilizing the 5xFAD mouse model and human cortical tissue, we report that PNNs are extensively lost in AD in proportion to plaque burden. Activated microglia closely associate with and engulf damaged nets in the 5xFAD brain, and inclusions of PNN material are evident in mouse and human microglia, while aggrecan, a critical PNN component, deposits within human dense-core plaques. Disease-associated reductions in parvalbumin (PV)+ interneurons, frequently coated by PNNs, are preceded by PNN coverage and integrity impairments, and similar phenotypes are elicited in wild-type mice following microglial activation with LPS. Chronic pharmacological depletion of microglia prevents 5xFAD PNN loss, with similar results observed following depletion in aged 3xTg-AD mice, and this occurs despite plaque persistence.
Interpretation:
We conclude that phenotypically altered microglia facilitate plaque-dependent PNN loss in the AD brain.
Funding:
The NIH (NIA, NINDS) and the Alzheimer's Association.
Insights
Microglia contribute to Alzheimer's disease (AD) by driving the loss of perineuronal nets (PNNs), crucial neuronal structures. Preventing microglial activation protects PNNs and may offer a therapeutic avenue for AD.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Microglia, the brain's immune cells, are implicated in Alzheimer's disease (AD) pathogenesis.
- The role of microglia in modulating perineuronal nets (PNNs) in AD is unclear.
- PNNs are extracellular matrix structures stabilizing neuronal synapses, and their alteration in AD is debated.
Purpose of the Study:
- To investigate the relationship between microglia, amyloid plaques, and PNNs in Alzheimer's disease.
- To determine if microglia-mediated neuroinflammation contributes to PNN loss in AD.
- To assess the therapeutic potential of targeting microglia to preserve PNNs in AD models.
Main Methods:
- Histological analysis of PNNs, microglia, and amyloid plaques in 5xFAD mice and human AD tissue.
- Investigated neuroinflammation's role using LPS treatment.
- Assessed PNN preservation by depleting microglia with a CSF1R inhibitor (PLX5622) in AD mouse models.
Main Results:
- PNNs are extensively lost in AD brains, correlating with plaque burden.
- Activated microglia engulf PNN material, and aggrecan deposits in human plaques.
- Microglial depletion prevents PNN loss in AD models, despite persistent plaques.
- PNN degradation precedes neuronal loss in parvalbumin interneurons.
Conclusions:
- Phenotypically altered microglia drive plaque-dependent PNN loss in the AD brain.
- Targeting microglia may prevent PNN degradation and mitigate AD-related neurodegeneration.
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