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. In this review we focus on the impact of HSPGs on autophagy, membrane trafficking, mitochondrial quality control and biogenesis, and lipid metabolism. Disruption of these processes are a hallmark of Alzheimer’s disease (AD) and there is evidence that altering heparan sulfate structure and function could counter AD-associated pathological processes. Compromising presenilin function in several systems has provided instructive models for understanding the molecular and cellular underpinnings of AD. Disrupting presenilin function produces a constellation of cellular deficits including accumulation of lipid, disruption of autophagosome to lysosome traffic and reduction in mitochondrial size and number. Inhibition of heparan sulfate biosynthesis has opposing effects on all these cellular phenotypes, increasing mitochondrial size, stimulating autophagy flux to lysosomes, and reducing the level of intracellular lipid. These findings suggest a potential mechanism for countering pathology found in AD and related disorders by altering heparan sulfate structure and influencing cellular processes disrupted broadly in neurodegenerative disease. Vertebrate and invertebrate model systems, where the cellular machinery of autophagy and lipid metabolism are conserved, continue to provide important translational guideposts for designing interventions that address the root cause of neurodegenerative pathology. N-acetyl glucosamine sugars  the pattern of sulfation along one chain is heterogeneous, with alternating patches of highly versus modestly sulfated regions, 4) the heparan sulfate chain is attached to the protein via a tetrasaccharide-linker that is shared with other glycosaminoglycans, such as chondroitin sulfate. It is critical to bear in mind that the pattern of sulfation is critical for function, and disturbances of that pattern have important consequences. In the course of our genetic studies of heparan sulfate biosynthetic enzyme encoding genes in Drosophila it became evident that sulfateless (sfl), the Drosophila homolog of the vertebrate gene encoding N-deacetylase N-sulfotransferase (NDST1), generally has the most dosage sensitive effects (tout velu (ttv), the Drosophila homolog of vertebrate EXT1. This is likely a result of N-sulfation affecting the levels of subsequent O-sulfation at other positions and hence the regional pattern of sulfation along heparan sulfate chains. Reductions in heparan sulfate polymerase function affects chain length, but not sulfation state (Heparan sulfate proteoglycans (HSPGs) are an abundant class of cell surface and extracellular matrix proteins. Two widely expressed members of this protein class include syndecans and glypicans, integral membrane HSPGs represented by 4 syndecan (a transmembrane protein) and 6 glypican (GPI-linked proteins) homologs in vertebrates. Extracellular matrix or basement membrane localized HSPGs include Perlecan, Collagen type XVIII and Agrin. HSPGs typically bear two or three heparan sulfate chains covalently attached to specific serine residues of the protein core. The heparan sulfate modification is a linear polymer of alternating glucuronic acid and e sugars . Glucuroe sugars . The bioe sugars  but the  effects  comparedon state .Drosophila, division abnormally delayed   or Glypic  , for exa  . The lis  . HSPGs a  .via the phosphatidylinositol 3-kinase/Target of Rapamycin (PI3K/TOR) or ERK/MAPK pathways , with disease-associated variants displaying the greatest affinity (ApoE4> ApoE3>ApoE2) . A recenilial AD . NotablyAPOE3-V236E variant has indeed been shown to affect ApoE multimer formation  and APOE ε3 (V236E) . Both vaormation . Furtherormation  and ultiormation  and it iDrosophila. These changes have physiological consequences as animals with reduced sfl/Ndst1 activity for example, show increased resistance to oxidative stress, and an extended lifespan  pathogenesis, a brief review of the history and current understanding of AD pathophysiology is warranted. The modern era of Alzheimer’s Disease (AD) truly began in 1984 with the identification of specific peptides as a principal component of neuritic plaques, an extracellular pathological hallmark of AD also described as amyloid . In 1985onset AD  and estatabolism . These ftabolism . Charactathology . The faiathology . Why theTREM2, SORL1 and ABCA7, genes that are also involved in lipid biology  an integral membrane heparan sulfate modified protein. Another recent large GWAS study using MAGMA gene-set analysis identified 25 gene ontology biological processes enriched in LOAD-associated variants  and whole exome sequencing have identified more than 70 genes that confer susceptibility to AD  Figures, 3. The  biology . Pathway biology . These f biology . A largevariants , includiTREM2 for example is primarily placed in the immunoregulatory group yet it has lipid ligands, namely APOE, and it mediates myelin phagocytosis, a membrane trafficking function. APP, the gene encoding the transmembrane protein clearly implicated in AD, and the source of amyloid accumulation, also affects lipid metabolism. Recent work shows that a 99 amino acid APP-derived peptide that serves as a substrate of γ-secretase in the ER influences de novo cholesterol synthesis and uptake into the plasma membrane , the catalytic unit, as well as Nicastrin (Nct), an important regulatory component that influences substrate selection , as well as the complex machinery required to synthesize and modify heparan sulfate chains . We have used r4Gal4>UAS-shPsnRNAi or r4Gal4>UAS-shNctRNAi to achieve knockdown of Presenilin or Nicastrin in fat body cells and evaluate the effects on mitochondrial number and morphology, autophagosomes, lysosomes, and liposomes, using both fluorescent markers for these compartments as well as transmission electron microscopy. Our preliminary findings indicate that compromising presenilin function in Drosophila has profound effects on mitochondria, autophagosome to lysosome traffic and lipid metabolism (data not shown), as has been documented for vertebrate systems. Drosophila therefore provides a powerful model to examine how presenilin and nicastrin deficits can lead to conserved cell pathology and what pathways can counter these deficits.Given the effects of presenilin mutations in vertebrate systems on mitochondrial function and lipid metabolism we have chosen to examine these processes in the principal metabolic regulatory organ of insects, the fat body. Fat body cells store both triglycerides and glycogen, releasing those energy reserves under conditions of high demand, such as the transition from larvae to the adult body plan that occurs during metamorphosis. Fat body cells provide functions served by both hepatocytes and adipocytes in vertebrate physiology. Experimentally they offer some definite advantages, namely their large size (60 μ) and ready access for confocal microscopy in both larvae and adult animals. It is also readily possible to knockdown genes selectively in fat body cells, using Gal4 bearing P-elements that express GAL4 in fat body, together with C. elegans  mutants have greatly informed our understanding of how a heparan sulfate modified protein regulates these processes. First, loss of perlecan in muscle can activate autophagy. Evidence suggests that this regulation of autophagy occurs  pathway . These ftabolism . White aparkin that produce degeneration of flight muscle cells (Earlier work has shown that reducing the function of key heparan sulfate biosynthetic enzyme encoding genes increases autophagy flux, with elevation of both autophagosome and lysosome markers in both muscle and fat body. This change in autophagy has the capacity to rescue cell death in two contexts, dysfunction of presenilin expressed in the retina, and mutations in le cells . Given tDrosophila. The capacity of these simpler organisms to reveal the biology in an intact animal provides a powerful tool to invigorate our fundamental understanding of a set of disorders that currently remain out of reach of any effective treatment. There is good evidence to suggest that targeting of heparan sulfate biosynthesis could counter several cellular pathological processes common to neurodegenerative disease.HSPGs play important roles in several processes involved in neurodegenerative pathology, including growth factor signaling, endocytosis, interaction with ApoE, propagation of misfolded Tau, and disposition of APP-derived peptides. In addition, their newfound roles in autophagy, mitochondrial function and lipid catabolism indicates that suppressing HSPG function could provide multiple ways of ameliorating cellular pathology found in neurodegenerative disease. While the direct role of amyloid deposition, or soluble APP-derived fragments in disease is open to question, the importance of APP and presenilin remains well supported by an abundance of genetic data. Both GWAS findings of late onset disease, and cellular biology of cells with characterized mutations in APP or presenilin point to dysfunction of lipid metabolism, mitochondria, and autophagy as common elements of neurodegeneration. Immune regulation in microglia, and the interaction of neurons with both microglia and astrocytes are also important determinants in AD outcomes. These cellular and genetic processes are conserved in model organisms, including