Age‐Related Enhanced BMP Signaling Elicits APOE‐Isoform Dependent Effects in IPSC Model of Alzheimer’s Disease

Abstract

AbstractBackgroundAging is the strongest risk factor for developing Alzheimer’s Disease (AD), and APOE is the largest genetic risk factor for developing AD. Bone morphogenic protein 4 (BMP4) expression and subsequent signaling increases 10‐fold with age and is increased in AD patients compared to age‐matched controls. Enhanced BMP signaling in aged and AD brains suggest a potential molecular cascade involved in AD pathogenesis. A potential interaction exists between increased BMP signaling across lifespan APOE expression that contribute to risk of AD.MethodAD patient derived iPSC’s (APOE3/E4 genotype) and isogenic controls (APOE3/E3 genotype) were differentiated into astrocytes and neurons. Cells were grown for 35 days before treatment with BMP4 or vehicle for 3 days prior to fixation, protein/media collection, or preparation for single cell RNA sequencing (scRNAseq). For coculture studies, neurons and astrocytes of the same patient background were differentiated separately prior to combined plating and BMP treatment. Cocultures were in matched (APOE3/E4 neurons with APOE3/E4 astrocytes) or mismatched (APOE3/E3 neurons with APOE3/E4 astrocytes) conditions to understand the non‐cell autonomous effects of APOE genotype.ResultUpon BMP treatment, APOE3/E4 compared to APOE3/E3 astrocytes exhibit accumulation of lipid droplets with changes in lipid composition. Increased free cholesterol levels as well as triglyceride accumulation is observed in APOE3/E4 astrocytes and is further exacerbated with BMP treatment. RNA‐sequencing analysis reveals marked decreased expression in genes related to oxidative phosphorylation and increased cholesterol synthesis and metabolism in APOE3/E4 astrocytes that is modulated by BMP treatment. In a non‐cell autonomous fashion, APOE3/E3 neurons, when paired with APOE3/E4 astrocytes, express exacerbated pTau levels and aberrant metabolic processes in a BMP‐dependent manner.ConclusionOur results indicate an interaction between genetic and aging factors in cellular processes relevant to AD. Enhanced BMP signaling confers aberrant lipid composition and metabolic processing in APOE3/E4 astrocytes when compared to APOE3/E3. Subsequent BMP‐dependent non‐cell autonomous effects in APOE3/E3 neurons are observed when cocultured with APOE3/E4 astrocytes. This data suggests age‐associated increase in BMP signaling may modulate APOE isoform‐dependent metabolic processes and increase risk for APOE‐mediated pathological cascades.