Progressive accumulation of amyloid-β peptide (Aβ) in the brain is implicated as 
the central event in the development of Alzheimer's disease (AD). It is thought 
that extracellular Aβ triggers toxic signals leading to neurodegeneration. The 
events downstream of Aβ however are not entirely clear. Clusterin (Apo J) is one 
of the major risk factors for sporadic form of AD. Clusterin binds to Aβ and 
prevents Aβ aggregation. In addition, clusterin promotes Aβ degradation and 
accelerates Aβ clearance from the brain. Clusterin thus protects neurons from Aβ 
and loss of clusterin level in the brain is implicated as promoting AD 
pathology. In this study, we found that the level of clusterin protein but not 
mRNA is reduced in the brains of 3xTg-AD mice. When rat hippocampal primary 
neurons were treated with Aβ1-42, level of clusterin protein but not mRNA was 
downregulated. Aβ1-42-induced downregulation of clusterin was blocked by 
lysosome inhibitors bafilomycin A1 and ammonium chloride. In neurons, Aβ1-42 
induced expression of sortilin, a lysosomal sorting protein that targets 
proteins to lysosome for degradation. In BE(2) M17 human neuroblastoma cells, 
clusterin bound to sortilin and when sortilin expression was silenced, 
Aβ1-42-induced clusterin downregulation was almost completely blocked. Our data 
demonstrate that in neurons, Aβ1-42 promotes lysosomal degradation of clusterin 
by inducing expression of sortilin and provide a novel mechanism by which Aβ 
promotes AD pathogenesis.