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 beta-amyloid precursor protein (betaAPP). Interactions between SORL1 and betaAPP result in the decreased processing of betaAPP into toxic amyloid-beta42 (Abeta42) 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 beta-amyloid cleaving enzyme, presenilin-1 and increased Abeta42 peptide secretion, was observed after incubation of cultured human neural cells with the proinflammatory cytokine interleukin-1beta. The results suggest that SORL1 deficits may not only promote the pathogenic processing of betaAPP but may also contribute to Abeta42-mediated inflammatory signaling in stressed human brain cells.