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.

Heparan sulfate modified proteins affect cellular processes central to neurodegeneration and modulate function.

Mutations in are the most common cause of familial, early-onset Alzheimer's disease (AD), typically producing cognitive deficits in the fourth decade. A variant of , was found associated with protection from both cognitive decline and Tau accumulation in a 70-year-old bearing the disease-causing mutation. The amino acid change in ApoE3ch is within the heparan sulfate (HS) binding domain of APOE, and purified APOEch showed dramatically reduced affinity for heparin, a highly sulfated form of HS.

Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycans.

Heparan sulfate modified proteins or proteoglycans (HSPGs) are an abundant class of cell surface and extracellular matrix molecules. They serve important co-receptor functions in the regulation of signaling as well as membrane trafficking. Many of these activities directly affect processes associated with neurodegeneration including uptake and export of Tau protein, disposition of Amyloid Precursor Protein-derived peptides, and regulation of autophagy.