Ambeka Rajvanshi

Introduction: Alzheimer’s Disease (AD), the most common cause of dementia, affects ~40 million people worldwide.¹ Approximately 90% of AD cases result from mutations in Apolipoprotein (ApoE) E3 and E4, genes associated with proteins involved in lipid transport.^1,2 Increased ApoE4 expression is associated with microglial dysfunction, neurodegeneration, and microglial lipid accumulation.³ Moreover, a deficiency in triggering receptor expressed on myeloid cells 2 (TREM2), an essential ApoE4 regulator, results in microglial lipid metabolism dysfunction.^3,4,5 Mouse model studies have suggested an increase in lipid-droplet-accumulating microglia (LDAM) in aged and neuroinflammatory states such as in AD.⁴ Methods: Hippocampi from young (three-month-old) mice and aged (20-month-old) mice were processed for immunofluorescence studies to visualize the transmembrane protein 119 (TMEM119+), a microglia-specific marker, and boron-dipyrromethene (BODIPY), a marker of lipids.⁴ Lipid-rich and lipid-poor CD11b⁺CD45^lo microglia were also isolated from young and aged hippocampi, and their RNAs were sequenced. Additionally, microglial BV2 cell line and in vivo samples were exposed to lipopolysaccharide (LPS) to induce neuroinflammatory conditions and LDAM formation. CRISPR-Cas9 was then used on BV2 cell lines to determine genes linked to neurodegeneration and lipid droplet formation.⁴ Results: About 52% of microglia in the aged hippocampus were BODIPY⁺TMEM119⁺ compared to 12% of such microglia in the young hippocampus.⁴ RNA sequencing of LD-rich and LD-poor microglia showed 692 differentially expressed genes affecting phagosome maturation and nitric oxide (NO) and reactive oxygen species (ROS) production.^4,6,7 Lysosomal genes such as CD63, ATP6V1A, ATP6V1C1, ATP6V1G1, TUBA1, and CD22 were linked with affected phagosome maturation.^4,8 LPS induced neuroinflammatory conditions resulted in microglia displaying a similar signature as LDAM in aging.^4,6 LDAM generated from the cell line or from in vivo samples showed reduced phagocytosis and released a higher level of multiple proinflammatory cytokines, including the tumor necrosis factor-alpha (TNFα), interleukin-beta (IL-1β), and IL-6.⁴ CRISPR-Cas9 deletions revealed that knocking out genes such as Grn, Slc33a1, and Vps35 resulted in a higher lipid accumulation, but CD22 deletion promoted microglial phagocytosis.^4,8 Furthermore, Grn^-/- mice exhibited frontotemporal dementia-like symptoms with microglia displaying a similar transcriptomic signature as LDAM microglia.⁴ A study in an AD model also suggested that anti-human TREM2 agonistic monoclonal antibody reduced filamentous plaques and microglial inflammatory response.⁹ Conclusion: The studies provide mechanistic insights on potential therapeutic strategies for AD and other neurodegenerative disorders. TREM2, CD22, Grn, and genes associated with NO/ROS production are likely efficacious therapeutic targets.^4,6,7,9 Therefore, a better understanding of LDAM would help in improving the treatment for AD.

1. Scheltens P, Blennow K, Breteler MM, et al. Alzheimer’s disease. The Lancet. 2016;388(10043):505-517. doi:10.1016/s0140-6736(15)01124-1
2. Serrano-Pozo A, Das S, Hyman BT. APOE and Alzheimer’s disease: advances in genetics, pathophysiology, and therapeutic approaches. The Lancet Neurology. 2021;20(1):68-80. doi:10.1016/s1474-4422(20)30412-9
3. Bartels T, De Schepper S, Hong S. Microglia modulate neurodegeneration in Alzheimer’s and Parkinson’s diseases. Science. 2020;370(6512):66-69. doi:10.1126/science.abb8587
4. Marschallinger J, Iram T, Zardeneta M, et al. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nature Neuroscience. 2020;23(2):194-208. doi:10.1038/s41593-019-0566-1
5. Fakhoury M. Microglia and Astrocytes in Alzheimer’s Disease: Implications for Therapy. Current Neuropharmacology. 2018;16(5):508-518. doi:10.2174/1570159×15666170720095240
6. Krasemann S, Madore C, Cialic R, et al. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity. 2017;47(3). doi:10.1016/j.immuni.2017.08.008
7. Brandon C Farmer, Jude Kluemper, Lance A Johnson, et al. Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation. Cells. 2019;8(182). doi:10.3390/cells8020182
8. Pluvinage JV, Haney MS, Smith BA, et al. CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature. 2019;568(7751):187-192. doi:10.1038/s41586-019-1088-4
9. Wang S, Mustafa M, Yuede CM, et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. Journal of Experimental Medicine. 2020;217(9). doi:10.1084/jem.20200785