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Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Alzheimer's disease associated isoforms of human CD33 distinctively modulate microglial cell responses in 5XFAD mice
Ghazaleh Eskandari-Sedighi1, Madeline Crichton1, Sameera Zia2
1Department of Chemistry, University of Alberta, Edmonton, Canada.
Abstract:
Microglia play diverse pathophysiological roles in Alzheimer's disease (AD), with genetic susceptibility factors skewing microglial cell function to influence AD risk. CD33 is an immunomodulatory receptor associated with AD susceptibility through a single nucleotide polymorphism that modulates mRNA splicing, skewing protein expression from a long protein isoform (CD33M) to a short isoform (CD33m). Understanding how human CD33 isoforms differentially impact microglial cell function in vivo has been challenging due to functional divergence of CD33 between mice and humans. We address this challenge by studying transgenic mice expressing either of the human CD33 isoforms crossed with the 5XFAD mouse model of amyloidosis and find that human CD33 isoforms have opposing effects on the response of microglia to amyloid-β (Aβ) deposition. Mice expressing CD33M have increased Aβ levels, more diffuse plaques, fewer disease-associated microglia, and more dystrophic neurites compared to 5XFAD control mice. Conversely, CD33m promotes plaque compaction and microglia-plaque contacts, and minimizes neuritic plaque pathology, highlighting an AD protective role for this isoform. Protective phenotypes driven by CD33m are detected at an earlier timepoint compared to the more aggressive pathology in CD33M mice that appears at a later timepoint, suggesting that CD33m has a more prominent impact on microglia cell function at earlier stages of disease progression. In addition to divergent roles in modulating phagocytosis, scRNAseq and proteomics analyses demonstrate that CD33m+ microglia upregulate nestin, an intermediate filament involved in cell migration, at plaque contact sites. Overall, our work provides new functional insights into how CD33, as a top genetic susceptibility factor for AD, modulates microglial cell function.
Insights
Genetic variations in CD33 influence Alzheimer's disease (AD) risk by altering microglial function. The short CD33m isoform shows protective effects against AD pathology, while the long CD33M isoform exacerbates it.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia are key players in Alzheimer's disease (AD) pathogenesis, with genetic factors influencing their role.
- CD33 is an AD susceptibility gene; a common polymorphism affects its mRNA splicing, leading to two protein isoforms: CD33M (long) and CD33m (short).
- Investigating the distinct in vivo functions of human CD33 isoforms in microglia is crucial but challenging due to species-specific differences.
Purpose of the Study:
- To elucidate the differential effects of human CD33 long (CD33M) and short (CD33m) isoforms on microglial function and Alzheimer's disease pathology.
- To understand how these isoforms impact the brain's response to amyloid-beta (Aβ) deposition in vivo.
Main Methods:
- Generation of transgenic mice expressing human CD33M or CD33m isoforms.
- Crossbreeding these mice with the 5XFAD mouse model of amyloidosis.
- Analysis of amyloid plaque load, microglial activation, neuritic pathology, and gene/protein expression using techniques like scRNAseq and proteomics.
Main Results:
- Human CD33 isoforms exhibit opposing effects on AD pathology in 5XFAD mice.
- CD33M expression is associated with increased Aβ levels, diffuse plaques, fewer disease-associated microglia, and more dystrophic neurites.
- CD33m expression promotes plaque compaction, enhances microglia-plaque interactions, reduces neuritic plaque pathology, and is linked to upregulated nestin in microglia, suggesting a protective role, particularly in earlier disease stages.
Conclusions:
- Human CD33 isoforms differentially modulate microglial responses to amyloid pathology in Alzheimer's disease.
- The CD33m isoform demonstrates a protective role by mitigating AD pathology, while CD33M exacerbates it.
- These findings provide critical insights into CD33's function as an AD genetic risk factor and its impact on microglial cell biology.
