TY - JOUR
T1 - Blood serum from individuals with Alzheimer’s disease alters microglial phagocytosis in vitro
AU - Altendorfer, Barbara
AU - Poupardin , Rodolphe
AU - Lefèvre-Arbogast, Sophie
AU - Manach, Claudine
AU - Low, Dorrain Y.
AU - Urpi-Sarda, Mireia
AU - Andres-Lacueva, Cristina
AU - González-Domínguez, Raúl
AU - Felder , Thomas K
AU - Tevini , Julia
AU - Zattoni , Marco
AU - Koller , Andreas
AU - Reinhold Schmidt , Reinhold
AU - Lucassen, Paul J.
AU - Ruigrok, Silvie R.
AU - De Lucia, Chiara
AU - Du Preez, Andrea
AU - Helmer, Catherine
AU - Neuffer, Jeanne
AU - Proust-Lima, Cécile
AU - Korosi, Aniko
AU - Samieri, Cécilia
AU - Thuret, Sandrine
AU - Aigner, Ludwig
PY - 2025/2/6
Y1 - 2025/2/6
N2 - Microglial phagocytosis is an essential mechanism to maintain functionality of the healthy brain. In age-related neurodegenerative diseases, such as Alzheimer’s disease (AD), microglial phagocytosis is engaged in the pathogenesis as it clears abnormal protein accumulations, debris, and apoptotic cells in the early stages of disease, but fuels neuroinflammation and accelerates disease progression in later stages. In vivo parabiosis experiments have demonstrated that blood-born factors modulate synaptic plasticity, neurogenesis and microglial responses. While the deleterious effects of aged blood on brain cells are intensively studied, less is known about the effects of AD blood per se, and in particular on microglia. Here, we use an immortalized human microglial cell line in an in vitro parabiosis assay to investigate the impact of blood serum from individuals diagnosed with AD (n=30) and age-matched controls (n=30) (PRODEM study) on microglial phagocytosis. Exposure to AD serum increased microglial phagocytic uptake of pH-sensitive fluorescent particles and downregulated expression of the lysosomal master regulator transcription factor EB (TFEB) and of ATPase H+ transporting lysosomal V1 subunit B2 (ATP6V1B2), a component of the vacuolar ATPase. To identify serum components that may relate to changes in phagocytosis, serum samples of the Three-City Study (3C Study) were used. In the 3C Study, blood samples were collected up to 12 years before the onset of cognitive decline or dementia and their serum metabolome is well-defined. Microglia exposed to serum of future AD cases from the 3C Study displayed an increased phagocytic uptake compared to serum of matched controls, depending on the presence of the Apolipoprotein E ε4 allele (ApoE4) in the AD cases. Furthermore, microglial phagocytosis correlated inversely with serum levels of the omega-3 fatty acid eicosapentaenoic acid (EPA). We confirmed this inverse correlation between EPA and phagocytosis in the serum samples of the PRODEM cohort. In addition, in vitro testing of EPA on microglial phagocytosis showed a concentration-dependent decrease in phagocytic uptake. In conclusion, following incubation with AD blood serum, we observed increased microglial phagocytic uptake and the downregulation of TFEB and ATP6V1B2, possibly indicating lysosomal dysfunction. Furthermore, microglial phagocytosis was inversely correlated with serum EPA levels, suggesting an important role for dietary EPA in microglial function.
AB - Microglial phagocytosis is an essential mechanism to maintain functionality of the healthy brain. In age-related neurodegenerative diseases, such as Alzheimer’s disease (AD), microglial phagocytosis is engaged in the pathogenesis as it clears abnormal protein accumulations, debris, and apoptotic cells in the early stages of disease, but fuels neuroinflammation and accelerates disease progression in later stages. In vivo parabiosis experiments have demonstrated that blood-born factors modulate synaptic plasticity, neurogenesis and microglial responses. While the deleterious effects of aged blood on brain cells are intensively studied, less is known about the effects of AD blood per se, and in particular on microglia. Here, we use an immortalized human microglial cell line in an in vitro parabiosis assay to investigate the impact of blood serum from individuals diagnosed with AD (n=30) and age-matched controls (n=30) (PRODEM study) on microglial phagocytosis. Exposure to AD serum increased microglial phagocytic uptake of pH-sensitive fluorescent particles and downregulated expression of the lysosomal master regulator transcription factor EB (TFEB) and of ATPase H+ transporting lysosomal V1 subunit B2 (ATP6V1B2), a component of the vacuolar ATPase. To identify serum components that may relate to changes in phagocytosis, serum samples of the Three-City Study (3C Study) were used. In the 3C Study, blood samples were collected up to 12 years before the onset of cognitive decline or dementia and their serum metabolome is well-defined. Microglia exposed to serum of future AD cases from the 3C Study displayed an increased phagocytic uptake compared to serum of matched controls, depending on the presence of the Apolipoprotein E ε4 allele (ApoE4) in the AD cases. Furthermore, microglial phagocytosis correlated inversely with serum levels of the omega-3 fatty acid eicosapentaenoic acid (EPA). We confirmed this inverse correlation between EPA and phagocytosis in the serum samples of the PRODEM cohort. In addition, in vitro testing of EPA on microglial phagocytosis showed a concentration-dependent decrease in phagocytic uptake. In conclusion, following incubation with AD blood serum, we observed increased microglial phagocytic uptake and the downregulation of TFEB and ATP6V1B2, possibly indicating lysosomal dysfunction. Furthermore, microglial phagocytosis was inversely correlated with serum EPA levels, suggesting an important role for dietary EPA in microglial function.
M3 - Article
SN - 1673-5374
JO - Neural regeneration research
JF - Neural regeneration research
ER -