Reduction of sortilin-1 in Alzheimer hippocampus and in cytokine-stressed human brain cells

Sortilin 1 (SORL1) is a transmembrane sorting receptor that regulates the intracellular trafficking of β-amyloid precursor protein (βAPP). Interactions between SORL1 and βAPP result in the decreased processing of βAPP into toxic amyloid-β42 (Aβ42) peptides that accumulate in Alzheimer's disease brain. Here, we report selectively decreased levels of SORL1 in limbic and occipital regions of Alzheimer brain that inversely correlate with amyloid plaque and neurofibrillary tangle density. Reduced SORL1, coupled to elevated β-amyloid cleaving enzyme, presenilin-1 and increased Aβ42 peptide secretion, was observed after incubation of cultured human neural cells with the proinflammatory cytokine interleukin-1β. The results suggest that SORL1 deficits may not only promote the pathogenic processing of βAPP but may also contribute to Aβ42-mediated inflammatory signaling in stressed human brain cells.