Genetic context controls early microglia-synaptic interactions in mouse models of Alzheimer's disease

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Alzheimer's disease (AD) involves amyloid pathology, microglia activation, and synaptic dysfunction, but causal links are unclear.
• Genetic factors influence AD susceptibility and resilience, yet this is understudied in mouse models.
• Understanding genetic control of AD neuropathology is crucial for developing targeted therapies.

Approach:

• Used viral strategies to label AD-vulnerable neuronal circuits in genetically diverse C57BL/6J (B6) and PWK/PhJ (PWK) APP/PS1 mice.
• Depleted brain microglia using PLX5622 to investigate their role in synaptic changes.
• Examined dendritic spine density and morphology in relation to microglia and genetic background.

Key Points:

• Microglia depletion induced changes in dendritic spine density and morphology in B6 mice (WT and APP/PS1).
• PWK mice exhibited marked stability of dendritic spines across conditions, irrespective of APP/PS1 genotype.
• Synaptic alterations were dependent on direct microglia-dendrite interactions in B6.APP/PS1 mice, but not in PWK.APP/PS1 mice.

Conclusions:

• Microglia-dependent synaptic alterations in AD-vulnerable pathways are differentially regulated by genetic context.
• Genetic background plays a significant role in determining the impact of microglia on synaptic integrity in AD.
• These findings highlight the importance of considering genetic diversity in AD research and therapeutic strategies.