Browsing by Author "Cheng-Hathaway, Paul J."

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    Active PSF shaping and adaptive optics enable volumetric localization microscopy through brain sections
    (Springer Nature, 2018-08) Mlodzianoski, Michael J.; Cheng-Hathaway, Paul J.; Bemiller, Shane M.; McCray, Tyler J.; Liu, Sheng; Miller, David A.; Lamb, Bruce T.; Landreth, Gary E.; Huang, Fang; Anatomy and Cell Biology, IU School of Medicine
    Application of single-molecule switching nanoscopy (SMSN) beyond the coverslip surface poses substantial challenges due to sample-induced aberrations that distort and blur single-molecule emission patterns. We combined active shaping of point spread functions and efficient adaptive optics to enable robust 3D-SMSN imaging within tissues. This development allowed us to image through 30-μm-thick brain sections to visualize and reconstruct the morphology and the nanoscale details of amyloid-β filaments in a mouse model of Alzheimer's disease.
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    The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease
    (BMC, 2018-06-01) Cheng-Hathaway, Paul J.; Reed-Geaghan, Erin G.; Jay, Taylor R.; Casali, Brad T.; Bemiller, Shane M.; Puntambekar, Shweta S.; von Saucken, Victoria E.; Williams, Roxanne Y.; Karlo, J. Colleen; Moutinho, Miguel; Xu, Guixiang; Ransohoff, Richard M.; Lamb, Bruce T.; Landreth, Gary E.; Anatomy and Cell Biology, School of Medicine
    BACKGROUND: The R47H variant of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) confers greatly increased risk for Alzheimer's disease (AD), reflective of a central role for myeloid cells in neurodegeneration. Understanding how this variant confers AD risk promises to provide important insights into how myeloid cells contribute to AD pathogenesis and progression. METHODS: In order to investigate this mechanism, CRISPR/Cas9 was used to generate a mouse model of AD harboring one copy of the single nucleotide polymorphism (SNP) encoding the R47H variant in murine Trem2. TREM2 expression, myeloid cell responses to amyloid deposition, plaque burden, and neuritic dystrophy were assessed at 4 months of age. RESULTS: AD mice heterozygous for the Trem2 R47H allele exhibited reduced total Trem2 mRNA expression, reduced TREM2 expression around plaques, and reduced association of myeloid cells with plaques. These results were comparable to AD mice lacking one copy of Trem2. AD mice heterozygous for the Trem2 R47H allele also showed reduced myeloid cell responses to amyloid deposition, including a reduction in proliferation and a reduction in CD45 expression around plaques. Expression of the Trem2 R47H variant also reduced dense core plaque number but increased plaque-associated neuritic dystrophy. CONCLUSIONS: These data suggest that the AD-associated TREM2 R47H variant increases risk for AD by conferring a loss of TREM2 function and enhancing neuritic dystrophy around plaques.