Heparan sulfate modified proteins affect cellular processes central to neurodegeneration and modulatepresenilinfunction

Abstract

SummaryMutations inpresenilin-1 (PSEN1)are the most common cause of familial, early-onset Alzheimer’s disease (AD), typically producing cognitive deficits in the fourth decade. A variant ofAPOE, APOE3 Christchurch (APOE3ch), was found associated with protection from both cognitive decline and Tau accumulation in a 70-year-old bearing the disease-causingPSEN1-E280Amutation. 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. The physiological significance ofApoE3chis supported by studies of a mouse bearing a knock-in of this human variant and its effects on microglia reactivity and Aβ-induced Tau deposition. The studies reported here examine the function of heparan sulfate-modified proteoglycans (HSPGs) in cellular and molecular pathways affecting AD-related cell pathology in human cell lines and mouse astrocytes. The mechanisms of HSPG influences onpresenilin-dependent cell loss and pathology were evaluated inDrosophilausing knockdown of the presenilin homolog,Psn, together with partial loss of function ofsulfateless (sfl), a homolog ofNDST1, a gene specifically affecting HS sulfation. HSPG modulation of autophagy, mitochondrial function, and lipid metabolism were shown to be conserved in cultured human cell lines,Drosophila, and mouse astrocytes. RNAi ofNdst1reduced intracellular lipid levels in wild-type mouse astrocytes or those expressing humanized variants ofAPOE, APOE3, andAPOE4. RNA-sequence analysis of human cells deficient in HS synthesis demonstrated effects on the transcriptome governing lipid metabolism, autophagy, and mitochondrial biogenesis and showed significant enrichment in AD susceptibility genes identified by GWAS. Neuron-directed knockdown ofPsninDrosophilaproduced cell loss in the brain and behavioral phenotypes, both suppressed by simultaneous reductions insflmRNA levels. Abnormalities in mitochondria, liposome morphology, and autophagosome-derived structures in animals withPsnknockdown were also rescued by simultaneous reduction ofsfl. sflknockdown reversedPsn-dependent transcript changes in genes affecting lipid transport, metabolism, and monocarboxylate carriers. These findings support the direct involvement of HSPGs in AD pathogenesis.