Polyunsaturated Fatty Acids Mend Macrophage Transcriptome, Glycome, and Phenotype in the Patients with Neurodegenerative Diseases, Including Alzheimer's Disease.

BACKGROUND: Macrophages of healthy subjects have a pro-resolution phenotype, upload amyloid-ß (Aß) into endosomes, and degrade Aß, whereas macrophages of patients with Alzheimer's disease (AD) generally have a pro-inflammatory phenotype and lack energy for brain clearance of Aß. 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 Aß degradation, MM glycome, and macrophage clearance of Aß. 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 Aß plaques, upload but do not degrade Aß, and release Aß into vessels, which develop cerebrovascular amyloid angiopathy (CAA); PUFA upregulate energy and Aß 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 Aß phagocytosis (p < 0.001). CONCLUSION: Macrophages of SCI, MCI, and AD patients have interrelated defects in the transcriptome, glycome, Aß phagocytosis, and Aß degradation. PUFA mend macrophage transcriptome, enrich glycome, enhance Aß clearance, and benefit the cognition of early-stage AD patients.