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Published on: December 26, 2016
Bone Marrow-Derived GCA+ Immune Cells Drive Alzheimer's Disease Progression
Rui Zhou1, Liwen Wang1, Linyun Chen1
1Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, 410008, China.
Insights
Alzheimer's disease patients show elevated grancalcin (GCA) levels. Bone marrow immune cells secreting GCA worsen cognitive decline, but targeting GCA offers a potential therapeutic strategy.
Area of Science:
- Neuroscience
- Immunology
- Gerontology
Background:
- Alzheimer's disease (AD) is a CNS neurodegenerative disorder.
- The role of bone marrow immune cells in AD pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the role of grancalcin (GCA) and GCA-expressing immune cells in Alzheimer's disease.
- To explore GCA as a potential therapeutic target for AD.
Main Methods:
- Measured GCA levels in AD patients and healthy individuals.
- Utilized AD mouse models, including cell transplantation and genetic ablation of GCA.
- Investigated the mechanism of GCA action on microglia and amyloid-beta (Aβ) clearance.
- Administered GCA-neutralizing antibodies in AD mouse models.
Main Results:
- AD patients exhibit higher circulating GCA levels, correlating with cognitive impairment.
- Bone marrow-derived GCA+ immune cells infiltrate the brain (hippocampus, cortex) in an AD mouse model via CCR10.
- GCA exacerbates amyloid plaque load and cognitive deficits; GCA ablation improves function.
- GCA inhibits microglial Aβ clearance by binding to LRP1.
- GCA-neutralizing antibodies improve cognitive function and reduce AD pathology.
Conclusions:
- GCA+ immune cells play a pathological role in AD, driving cognitive and memory decline.
- GCA is a key mediator of neuroinflammation and neurodegeneration in AD.
- Targeting GCA+ immune cells or GCA itself presents a promising therapeutic avenue for Alzheimer's disease.
Abstract:
Alzheimer's disease (AD) is an age-related degenerative disease of the central nervous system (CNS), whereas the role of bone marrow immune cells in the pathogenesis of AD remains unclear. Here, the study reveals that compared to matched healthy individuals, AD patients have higher circulating grancalcin (GCA) levels, which negatively correlate with cognitive function. Bone marrow-derived GCA+ immune cells, which secret abundant GCA and increase during aging, preferentially invaded the hippocampus and cortex of AD mouse model in a C-C Motif Chemokine Receptor 10 (CCR10)-dependent manner. Transplanting GCA+ immune cells or direct stereotaxic injection of recombinant GCA protein intensified amyloid plaque load and aggravated cognitive and memory impairments. In contrast, genetic ablation of GCA in the hematopoietic compartment improves cognitive and memory function. Mechanistically, GCA competitively binds to the low-density lipoprotein receptor-related protein 1 (LRP1) in microglia, thus inhibiting phagocytosis and clearance of Aβ and potentiating neuropathological changes. Importantly, GCA-neutralizing antibody treatment rejuvenated cognitive and memory function and constrained AD progression. Together, the study demonstrates a pathological role of GCA+ immune cells instigating cognitive and memory decline, suggesting that GCA+ immune cells can be a potential target for innovative therapeutic strategies in AD.
