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

Sortilin I (SORLI) is a transmembrane sorting receptor that regulates the intracellular trafficking of beta-amyloid precursor protein (beta APP). Interactions between SORLI and PAPP result in the decreased processing of PAPP into toxic amyloid-beta 42 (A beta 42) peptides that accumulate in Alzheimer's disease brain. Here, we report selectively decreased levels of SORLI in limbic and occipital regions of Alzheimer brain that inversely correlate with amyloid plaque and neurofibrillary tangle density. Reduced SORLI, coupled to elevated beta-amyloid cleaving enzyme, presenilin-I and increased A beta 42 peptide secretion, was observed after incubation of cultured human neural cells with the proinflammatory cytokine interleukin-I beta The results suggest that SORLI deficits may not only promote the pathogenic processing of beta APP but may also contribute to A beta 42-mediated inflammatory signaling in stressed human brain cells.