Altering heparan sulfate suppresses cell abnormalities and neuron loss in model of Alzheimer Disease.

We examined the function of heparan-sulfate-modified proteoglycans (HSPGs) in pathways affecting Alzheimer disease (AD)-related cell pathology in human cell lines and mouse astrocytes. Mechanisms of HSPG influences on dependent cell loss were evaluated in using knockdown of the homolog, , together with partial loss-of-function of , a gene specifically affecting HS sulfation HSPG modulation of autophagy, mitochondrial function, and lipid metabolism were shown to be conserved in human cell lines, , and mouse astrocytes. RNA interference (RNAi) of reduced intracellular lipid levels in wild-type mouse astrocytes or those expressing humanized variants of , , and Neuron-directed knockdown of in produced apoptosis and cell loss in the brain, phenotypes suppressed by reductions in expression. Abnormalities in mitochondria, liposomes, and autophagosome-derived structures in animals with knockdown were also rescued by reduction of . These findings support the direct involvement of HSPGs in AD pathogenesis.