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Basic Science and Pathogenesis.

Bruce T Lamb1,2, Claudia Rangel-Barajas2, Ravi S Pandey3

  • 1Indiana University School of Medicine, Indianapolis, IN, USA.

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|December 24, 2025
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Summary
This summary is machine-generated.

The LOAD2.Plcg2M28L mouse model reveals how a genetic variant and high-fat diet impact Alzheimer's disease. Diet worsens neuroinflammation and neuron loss, but the variant offers some protection.

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Area of Science:

  • Neuroscience
  • Genetics
  • Pathology

Background:

  • The LOAD2.Plcg2M28L mouse model incorporates the PLCG2-M28L variant, a known genetic risk factor for late-onset Alzheimer's disease (LOAD).
  • Comprehensive phenotyping, including transcriptomic, proteomic, and cellular analyses, was performed to elucidate disease mechanisms in this model.

Purpose of the Study:

  • To investigate the interplay of genetic predisposition (PLCG2-M28L variant) and environmental factors (high-fat diet) in LOAD pathogenesis.
  • To characterize age- and diet-dependent molecular and cellular changes in the LOAD2.Plcg2M28L mouse model.

Main Methods:

  • Mice aged to 4, 12, and 18 months were fed standard chow or a high-fat diet (HFD).
  • Transcriptomic and proteomic profiling, alongside quantitative assessments of microglia, astrocytes, and neurons, were conducted.
  • Analyses focused on neuroinflammation, lipid metabolism, immune response, synaptic function, and neuronal loss.

Main Results:

  • HFD exacerbated neuroinflammation and microglial/astrocytic activation at 12 and 18 months, with the PLCG2-M28L variant modulating these effects.
  • Transcriptomic and proteomic data revealed significant alterations in lipid metabolism, immune response, and synaptic function pathways.
  • Progressive neuronal loss was observed, particularly with HFD, though PLCG2-M28L carriers showed some resilience.

Conclusions:

  • The PLCG2-M28L variant plays a role in modulating LOAD pathology, interacting with environmental factors like diet.
  • Diet significantly influences disease progression, highlighting the importance of lifestyle in Alzheimer's.
  • The LOAD2.Plcg2M28L model is a valuable platform for studying therapeutic strategies targeting genetic and environmental interactions in LOAD.