Indiana University-Purdue University Indianapolis (IUPUI) / Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a receptor expressed
in myeloid cells including microglia in brain and osteoclasts in bone has been proposed as
a link between brain and bone disease. Previous studies identified an AD-associated
mutation (R47H) which is known to confer an increased risk for developing AD. In these
studies, we used a heterozygous model of the TREM2 R47H variant (TREM2R47H/+), which
does not exhibit cognitive defects, as a translational model of genetic risk factors that
contribute to AD, and investigated whether alterations to TREM2 signaling could also
contribute to bone and skeletal muscle loss, independently of central nervous system
defects. Our study found that female TREM2R47H/+ animals experience bone loss in the
femoral mid-diaphysis between 4 and 13 months of age as measured by microCT, which
stalls out by 20 months of age. Female TREM2R47H/+ animals also experience significant
decreases in the mechanical and material properties of the femur measured by three-point
bending at 13 months of age, but not at 4 or 20 months. Interestingly, male TREM2R47H/+
animals do not demonstrate any discernable differences in bone geometry or strength until
20 months of age, where we observed slight changes in the bone volume and material
properties of male TREM2R47H/+ bones. Ex vivo osteoclast differentiation assays
demonstrate that only male TREM2R47H/+ osteoclasts differentiate more after 7 days with
osteoclast differentiation factors compared to WT, but qPCR follow-up showed sexdependent
differences in intracellular signaling. However, bone is not the only
musculoskeletal tissue affected by the TREM2 R47H variant. Skeletal muscle strength measured by both in vivo plantar flexion and ex vivo contractility of the soleus is increased
and body composition is altered in female TREM2R47H/+ mice compared to WT, and this is
not likely due to bone-muscle crosstalk. These studies suggests that TREM2 R47H
expression in the bone and skeletal muscle are likely impacting each tissue independently.
These data demonstrate that AD-associated variants in TREM2 can alter bone and skeletal
muscle strength in a sex-dimorphic manner independent of the presence of central
neuropathology.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/29304 |
| Date | 05 1900 |
| Creators | Essex, Alyson Lola |
| Contributors | Plotkin, Lillian I., Bonetto, Andrea, Allen, Matthew, Landreth, Gary E. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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