Biology subjects

Bekris, L. M.

Publications and source records attributed to Bekris, L. M..

3 recordsLinked to original sources

bioRxiv2021

Peripheral sTREM2-related inflammatory activity alterations in early stage Alzheimer's disease

Alzheimers disease (AD) has been linked to multiple immune system genetic variants, implicating potential broad alterations in inflammatory profiles in the disease. Triggering receptor expressed on myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. A soluble TREM2 isoform (sTREM2) is elevated in cerebrospinal fluid in the early stages of AD suggesting it may be a biomarker of progressive alterations in immune response to AD-related pathology. Multiple studies have reported an altered peripheral immune response in AD. However, less is known about the relationship between plasma sTREM2 and the altered peripheral immune response in AD. The objective of this exploratory study was to examine the relationship between sTREM2 and inflammatory activity in human participants defined by clinically characterized cognitive symptoms and groups defined by the cerebrospinal fluid biomarkers amyloid beta, phosphorylated tau, and neurodegeneration (NIA-AA Research Framework: "ATN continuum".) The hypothesis of this exploratory study was that sTREM2 related inflammatory activity differs by AD stage. We observed different patterns of inflammatory activity across disease groups and ATN categories that implicates peripheral sTREM2 related inflammatory activity as altered in the early stages of AD. Notably, fractalkine showed a significant relationship with sTREM2 across different analyses in the control groups that was lost as disease progressed, and fractalkine, IL-5 and IL-17A were decreased in AD. These preliminary data provide important support to the hypothesis that sTREM2-related inflammatory activity is a stage-specific biomarker of AD progression, providing the groundwork for future studies and therapeutic strategies.

neuroscience↗

bioRxiv2020

TREM2 alters the phagocytic, apoptotic and inflammatory response to Aβ42 in HMC3 cells

Alzheimers disease (AD) is characterized by the accumulation in the brain of extracellular amyloid {beta} (A{beta}) plaques as well as intraneuronal inclusions (neurofibrillary tangles) consisting of total tau and phosphorylated tau. Also present are dystrophic neurites, loss of synapses, neuronal death, and gliosis. AD genetic studies have highlighted the importance of inflammation in this disease by identifying several risk associated immune response genes, including TREM2. TREM2 has been strongly implicated in basic microglia function including, phagocytosis, apoptosis, and the inflammatory response to A{beta} in mouse brain and primary cells. These studies show that microglia are key players in the response to A{beta} and in the accumulation of AD pathology. However, details are still missing about which apoptotic or inflammatory factors rely on TREM2 in their response to A{beta}, especially in human cell lines. Given these previous findings our hypothesis is that TREM2 influences the response to A{beta} toxicity by enhancing phagocytosis and inhibiting both the BCL-2 family of apoptotic proteins and pro-inflammatory cytokines. A{beta}42 treatment of the human microglial cell line, HMC3 cells, was performed and TREM2 was overexpressed or silenced and the phagocytosis, apoptosis and inflammatory response were evaluated. Results indicate that a robust phagocytic response to A{beta} after 24 hours requires TREM2 in HMC3 cells. Also, TREM2 inhibits A{beta} induced apoptosis by activating the Mcl-1/Bim complex. TREM2 is involved in activation of IP-10, MIP-1a, and IL-8, while it inhibits FGF-2, VEGF and GRO. Taken together, TREM2 plays a role in enhancing the microglial functional response to A{beta} toxicity in HMC3 cells. This novel information suggests that therapeutic strategies that seek to activate TREM2 may not only enhance phagocytosis, but it may also inhibit beneficial inflammatory factors, emphasizing the need to define TREM2-related inflammatory activity in not only mouse models of AD, but also in human AD.

molecular biology↗

bioRxiv2019

Altered Relationship between Soluble TREM2 and Inflammatory Markers in Young Adults with Down Syndrome

Individuals with Down syndrome (DS) develop Alzheimers disease (AD) - related neuropathology, characterized by amyloid plaques with amyloid {beta} (A{beta}) and neurofibrillary tangles with tau accumulation more frequently and at an earlier age than their neurotypical counterparts. Peripheral inflammation and the innate immune response are elevated in DS. Triggering receptor expressed in myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. A soluble cleavage product of TREM2 (sTREM2) has been described as elevated in AD cerebrospinal fluid and positively correlates with A{beta} and cognitive decline. There is relatively little information about TREM2 in DS. The objective of this study was to examine the relationship between sTREM2 and inflammatory markers in DS, prior to the development of dementia symptoms. Since TREM2 plays a role in the innate immune response and has been associated with dementia, the hypothesis of this exploratory study was that young adults with DS pre-dementia (n=15, mean age 29.5 years) would exhibit a different relationship between sTREM2 and inflammatory markers in plasma, compared to neurotypical, age-matched controls (n=16, mean age 29.6 years). Indeed, young adults with DS had significantly elevated plasma sTREM2 and inflammatory markers. In addition, in young adults with DS, sTREM2 correlated positively with 24 of the measured cytokines, while there were no significant correlations in the control group. Hierarchical clustering of sTREM2 and cytokine concentrations also differed between the group with DS and controls, supporting the hypothesis that its function is altered in people with DS pre-dementia. This exploratory study provides a basis for future studies investigating the relationship between TREM2 and the broader immune response pre-dementia.

neuroscience↗