摘要 : Background: Macrophages of healthy subjects have a pro-resolution phenotype, upload amyloid-beta (A beta) into endosomes, and degrade A beta, whereas macrophages of patients with Alzheimer's disease (AD) generally have a pro-infla... 展开 Background: Macrophages of healthy subjects have a pro-resolution phenotype, upload amyloid-beta (A beta) into endosomes, and degrade A beta, whereas macrophages of patients with Alzheimer's disease (AD) generally have a pro-inflammatory phenotype and lack energy for brain clearance of A beta. Objective: To clarify the pathogenesis of sporadic AD and therapeutic effects of polyunsaturated fatty acids (PUFA) with vitamins B and D and antioxidants on monocyte/macrophage (MM) migration in the AD brain, MM transcripts in energy and A beta degradation, MM glycome, and macrophage clearance of A beta. Methods: We followed for 31.3 months (mean) ten PUFA-supplemented neurodegenerative patients: 3 with subjective cognitive impairment (SCI), 2 with mild cognitive impairment (MCI), 3 MCI/vascular cognitive impairment, 2 with dementia with Lewy bodies, and 7 non-supplemented caregivers. We examined: monocyte migration in the brain and a blood-brain barrier model by immunochemistry and electron microscopy; macrophage transcriptome by RNAseq; macrophage glycome by N-glycan profiling and LTQ-Orbitrap mass spectrometry; and macrophage phenotype and phagocytosis by immunofluorescence. Results: MM invade A beta plaques, upload but do not degrade A beta, and release A beta into vessels, which develop cerebrovascular amyloid angiopathy (CAA); PUFA upregulate energy and A beta degradation enzyme transcripts in macrophages; PUFA enhance sialylated N-glycans in macrophages; PUFA reduce oxidative stress and increase pro-resolution MM phenotype, mitochondrial membrane potential, and A beta phagocytosis (p < 0.001). Conclusion: Macrophages of SCI, MCI, and AD patients have interrelated defects in the transcriptome, glycome, A beta phagocytosis, and A beta degradation. PUFA mend macrophage transcriptome, enrich glycome, enhance A beta clearance, and benefit the cognition of early-stage AD patients. 收起