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O2‐11‐04: QUANTIFICATION OF WHITE MATTER CELLULARITY IN PRECLINICAL AND EARLY SYMPTOMATIC ALZHEIMER DISEASE USING NEURO‐IMMNUE IMAGING
Author(s) -
Wang Qing,
Wang Yong,
Shimony Joshua S.,
Liu Jingxia,
Fagan Anne M.,
Cairns Nigel J.,
Ances Beau M.,
Morris John C.,
Benzinger Tammie L.S.
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.2703
Subject(s) - biomarker , neuroinflammation , corpus callosum , white matter , fractional anisotropy , imaging biomarker , medicine , diffusion mri , cerebrospinal fluid , pathology , dementia , inflammation , disease , oncology , magnetic resonance imaging , biology , radiology , biochemistry
Background:Mutations in the progranulin gene (GRN) reduce circulating levels of progranulin (PGRN) and granulins (GRNs) and cause frontotemporal degeneration (FTD). PGRN is neuroprotective and decreases amyloid b (Ab) deposition in APP mice. Strategies to increase PGRN have been proposed to treat PGRN-deficient FTD and Alzheimer’s disease (AD). Although PGRN is expressed in neurons, PGRN is also highly expressed in microglia and other immune cells. Moreover, it is unclear how PGRN loss in immune cells affects neuronal survival. Therefore, we focused on understanding how GRN loss in microglia and all major subsets of peripheral immune cells may promote degeneration. Grn deficiency in mice is associated with marked increases in CD68+ myeloid cells, pro-inflammatory cytokine production, and circuit-specific synaptic pruning via complement activation. Methods: We performed immunohistological, proteomic, and deep-immunophenotyping by flow cytometry on brain, spleen, and peripheral blood of Grn KO and WT mice ages 3-30 months. Results: Aged Grn KO mice microglia make up a smaller fraction of Cd11b+ Ly6Gcells and a large fraction of microglia express higher levels of MHCII and lower levels of CD68 compared to WT mice. Further, the CD45int CD11b hi population in the brain is increased in Grn KO mice relative to that in WT mice and a large fraction of them express MHCII and CD68 relative to WT mice. We also found a generalized increase in cell numbers in the blood with an increased frequency of T cells in Grn KO vs WT mice and decreased frequency of MHCII+ cells within Ly6Clo monocytes (alternative activation) and increased CD68 on Ly6Cmonocytes. In addition, Grn KO mice displayed decreased NK and B cells, and macrophages in the spleen with decreased expression of MHC-II; and non-CD4/CD8 T-cells made up a larger proportion of CD3+ T cells. Proteomics and immunohistology suggest greater peripheral immune cell infiltration in Grn KO versus WT mice. Conclusions: These novel findings suggest that loss of PGRN leads to disruption of innate and adaptive immune responses. Analysis of peripheral immune cells may shed light on the role of PGRN in FTD and AD patients with GRN mutations. Replacement of PGRN/GRNs may be a viable therapeutic strategy.