Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia

• Published in: Neuron (Cambridge, Mass.) Mass.), 2021-05, Vol.109 (10), p.1657-1674.e7
• Main Authors: Wang, Chao, Xiong, Monica, Gratuze, Maud, Bao, Xin, Shi, Yang, Andhey, Prabhakar Sairam, Manis, Melissa, Schroeder, Caitlin, Yin, Zhuoran, Madore, Charlotte, Butovsky, Oleg, Artyomov, Maxim, Ulrich, Jason D., Holtzman, David M.
• Format: Article
• Language: English
• Subjects: Age; Alzheimer's disease; Animals; APOE; Apolipoprotein E; Apolipoprotein E4; Apolipoprotein E4 - deficiency; Apolipoprotein E4 - genetics; Apolipoprotein E4 - metabolism; Apoptosis; astrocyte; Astrocytes; Astrocytes - metabolism; Atrophy; Gene expression; Humans; Life Sciences; Mice; Mice, Inbred C57BL; Microglia; Microglia - immunology; Neurodegeneration; Neurodegenerative diseases; Oligodendrocytes; Pathology; Phagocytosis; Proteins; Risk factors; Rodents; Sequence analysis; Synapses - metabolism; Synapses - pathology; tau; Tau protein; tau Proteins - metabolism; Tauopathies - metabolism; Tauopathies - pathology; Transcriptome; Transgenic animals; Volumetric analysis
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2021.03.024

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer’s disease and directly influences tauopathy and tau-mediated neurodegeneration. ApoE4 has strong deleterious effects on both parameters. In the brain, apoE is produced and secreted primarily by astrocytes and by activated microglia. The cell-specific role of each form of apoE in the setting of neurodegeneration has not been determined. We generated P301S Tau/Aldh1l1-CreERT2/apoE3flox/flox or Tau/Aldh1l1-CreERT2/apoE4flox/flox mice. At 5.5 months of age, after the onset of tau pathology, we administered tamoxifen or vehicle and compared mice at 9.5 months of age. Removing astrocytic APOE4 markedly reduced tau-mediated neurodegeneration and decreased phosphorylated tau (pTau) pathology. Single-nucleus RNA sequencing analysis revealed striking gene expression changes in all cell types, with astrocytic APOE4 removal decreasing disease-associated gene signatures in neurons, oligodendrocytes, astrocytes, and microglia. Removal of astrocytic APOE4 decreased tau-induced synaptic loss and microglial phagocytosis of synaptic elements, suggesting a key role for astrocytic apoE in synaptic degeneration. •Astrocytic APOE4 depletion reduces tauopathy and tau-mediated neurodegeneration•Removal of astrocytic APOE4 decreases disease-associated gene signatures•Synaptic loss is rescued after astrocytic APOE4 deletion•Lowering astrocytic APOE4 has therapeutic potential for tau-related neurodegeneration Wang et al. demonstrate that removal of astrocytic APOE4 decreases tau-mediated brain atrophy and synaptic loss, as well as ameliorating disease-associated gene signatures in multiple cell types. Removal of astrocytic APOE4 even after the onset of neurodegeneration reduces tauopathy and tau-mediated neurodegeneration.