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Functional alterations of myeloid cells during the course of Alzheimer's disease
Aaron D Thome1, Alireza Faridar1, David R Beers1
1Department of Neurology, Houston Methodist Neurological Institute, 6560 Fannin St. Suite 802, Houston, TX, 77030, USA.
Background:
Neuroinflammation is a hallmark of neurodegenerative disease and a significant component of the pathology of Alzheimer's disease (AD). Patients present with extensive microgliosis along with elevated pro-inflammatory signaling in the central nervous system and periphery. However, the role of peripheral myeloid cells in mediating and influencing AD pathogenesis remains unresolved.
Methods:
Peripheral myeloid cells were isolated from peripheral blood of patients with prodromal AD (n = 44), mild AD dementia (n = 25), moderate/severe AD dementia (n = 28), and age-matched controls (n = 54). Patients were evaluated in the clinic for AD severity and categorized using Clinical Dementia Rating (CDR) scale resulting in separation of patients into prodromal AD (CDR0.5) and advancing forms of AD dementia (mild-CDR1 and moderate/severe-CDR2/3). Separation of peripheral myeloid cells into mature monocytes or immature MDSCs permitted the delineation of population changes from flow cytometric analysis, RNA phenotype analysis, and functional studies using T cell suppression assays and monocyte suppression assays.
Results:
During stages of AD dementia (CDR1 and 2/3) peripheral myeloid cells increase their pro-inflammatory gene expression while at early stages of disease (prodromal AD-CDR0.5) pro-inflammatory gene expression is decreased. MDSCs are increased in prodromal AD compared with controls (16.81% vs 9.53%) and have markedly increased suppressive functions: 42.4% suppression of activated monocyte-produced IL-6 and 78.16% suppression of T cell proliferation. In AD dementia, MDSC populations are reduced with decreased suppression of monocyte IL-6 (5.22%) and T cell proliferation (37.61%); the reduced suppression coincides with increased pro-inflammatory signaling in AD dementia monocytes.
Conclusions:
Peripheral monocyte gene expression is pro-inflammatory throughout the course of AD, except at the earliest, prodromal stages when pro-inflammatory gene expression is suppressed. This monocyte biphasic response is associated with increased numbers and suppressive functions of MDSCs during the early stages and decreased numbers and suppressive functions in later stages of disease. Prolonging the early protective suppression and reversing the later loss of suppressive activity may offer a novel therapeutic strategy.
Insights
Peripheral myeloid cells show a biphasic response in Alzheimer's disease (AD). Early stages involve increased suppressive myeloid-derived suppressor cells (MDSCs), while later stages show reduced suppression and increased inflammation, suggesting new therapeutic targets.
Area of Science:
- Neuroimmunology
- Neurodegenerative Diseases
- Cellular Immunology
Background:
- Neuroinflammation is central to Alzheimer's disease (AD) pathology, characterized by microgliosis and elevated pro-inflammatory signaling.
- The precise role of peripheral myeloid cells in AD pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the dynamic changes in peripheral myeloid cells, including monocytes and myeloid-derived suppressor cells (MDSCs), throughout the progression of Alzheimer's disease.
- To analyze the functional capacity of these cells in modulating immune responses during different AD stages.
Main Methods:
- Peripheral blood myeloid cells were isolated from individuals with prodromal AD, mild AD dementia, moderate/severe AD dementia, and age-matched controls.
- Flow cytometry, RNA phenotype analysis, and functional assays (T cell and monocyte suppression) were employed to assess cell populations and their immune-modulating functions.
Main Results:
- Peripheral myeloid cells exhibit a biphasic inflammatory response: suppressed pro-inflammatory gene expression in early (prodromal) AD, and increased expression in later dementia stages.
- Myeloid-derived suppressor cells (MDSCs) are increased and exhibit enhanced suppressive function in prodromal AD, reducing IL-6 and T cell proliferation.
- In AD dementia, MDSC populations decrease, leading to reduced suppressive capacity and coinciding with heightened pro-inflammatory monocyte signaling.
Conclusions:
- Peripheral monocyte response in AD is biphasic, with early suppression mediated by increased, highly functional MDSCs, and later pro-inflammatory activity due to reduced MDSC function.
- Therapeutic strategies targeting the modulation of MDSC numbers and suppressive activity could offer novel treatment avenues for Alzheimer's disease.