# Skeletal complications to a TREM2 variant associated with Alzheimer's Disease

> **NIH VA I01** · RLR VA MEDICAL CENTER · 2024 · —

## Abstract

SUMMARY
Alzheimer's disease (AD) is a growing health concern and is the most common type of dementia worldwide.
Veterans who have been prisoners of war have a 50% greater risk to develop dementia later in life, a percentage
that becomes even higher in veterans who develop posttraumatic stress disorder. Evidence indicates that mental
illness and neurological and nervous system disorders can increase the risk of developing osteoporosis leading
to high prevalence of bone fractures. Fractures, in particular of the hip, have been associated with increased
mortality, especially in the elderly. Conversely, osteoporosis is associated with increased risk of dementia diag-
nosis. In spite all this evidence, a direct link between dementia and osteoporosis, frequently occurring with aging,
has never been conclusively demonstrated. Interestingly, some genetic mutations are risk factors for both AD
and osteoporosis. As an example, mutations of the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)
is expressed in microglia in brain and in osteoclasts in bone correlate with AD and dementia, and with bone
fragility. Recent studies led by Dr. Landreth, a Consultant in this application, showed that mice expressing the
R47H TREM2 variant (TREM2R47H/+ mice) exhibit loss of TREM2 function and neuritic dystrophy. However, the
mechanisms responsible for the TREM2 mutation effects on bone mass and strength are completely unclear. In
our preliminary findings, we showed that aged 13-month-old female TREM2R47H/+ mice exhibit a skeletal pheno-
type, with decreased cortical and cancellous bone mass and cortical bone biomechanical properties. In addition,
female, but not male showed reduced bone mineral density accrual between 1 and 12 months of age. Work of
others showed that low bone mass in TREM2-/- mice is ascribed to low osteoclast β-catenin activation, suggesting
defective canonical Wnt signaling in the absence of TREM2 function. Consistent with this possibility, expression
of Wnt target genes cyclin D1 and Cx43 in tibia is lower in TREM2R47H/+ compared to WT mice, whereas cyclin
D1, Lef1 and Axin2 expression is reduced in osteoclastic cells derived from bone marrow cells isolated from
TREM2R47H/+ mice. On the other hand, osteoclastic constitutive β-catenin activation or expression of a high bone
mass (HMB) LRP5 mutant decreased osteoclasts and increased bone mass in mice. Yet, the cellular and mo-
lecular mechanisms for the changes in the bone mass and composition in TREM2R47H/+ mice remain unknown.
Further, the role of low Wnt signaling on the skeletal effect of the TREM2 variant has not been tested. Based on
our preliminary studies and on published evidence we propose that reduced Wnt/β-catenin signaling due to
abnormal TREM2 function leads to increased osteoclastic bone resorption and results in skeletal defi-
ciencies. To test this hypothesis we will 1. Investigate whether abnormal TREM2 function worsens the conse-
quences of sex steroid removal in male and f...

## Key facts

- **NIH application ID:** 10871796
- **Project number:** 5I01BX005154-04
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** Lilian Irene Plotkin
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871796

## Citation

> US National Institutes of Health, RePORTER application 10871796, Skeletal complications to a TREM2 variant associated with Alzheimer's Disease (5I01BX005154-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10871796. Licensed CC0.

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