Alterations in the Expression of the Genes Responsible for the Synthesis of Heparan Sulfate in Brains With Alzheimer Disease

Abstract

The saccharide chains of heparan sulfate appear to be involved in several aspects Alzheimer disease (AD) pathogenesis. Their structural complexity is due to the expression of different isoenzymes. We studied the differential transcription of heparan sulfate chain biosynthesis in AD brains, analyzing different brain regions in patients with different extents of AD pathology. The transcriptomic study was performed by RT-PCR using samples of amygdala, anterior hippocampus, posterior hippocampus, claustrum, calcarine fissure, globus pallidus and cerebellum from patients with mild, moderate, or severe AD, as well as healthy individuals. Certain heparan sulfate epitopes were also detected by immunohistochemistry. Several genes, across all stages of heparan sulfate synthesis, showed altered transcription in different brain regions of AD patients. The numbers of alterations were greater in in moderate versus mild AD patients. In severe patients, there were fewer alterations in genes related to early stages of biosynthesis, and overexpression of genes involved in late stages. The alterations correlated with progressive brain atrophy, although alterations were more common in the cerebellum. Detection of some heparan sulfate epitopes by immunohistochemistry was consistent with previous studies. In conclusion, transcriptional alterations in the biosynthetic genes of heparan sulfate depend on the brain region and the degree of AD pathology.

Increased 3- O -sulfated heparan sulfate in Alzheimer’s disease brain is associated with genetic risk gene HS3ST1

“…The reason that we were unable to detect an increase of 3-OST-2– and 3-OST-4–modified products in AD brains could be multifactorial. One possibility is that we analyzed the HS from frontal cortex, not from hippocampus, where 3-OST-2 and/or 3-OST-4 expression are up-regulated ( 31 ). HS3ST1 is reportedly overexpressed in amygdala, claustrum ( 31 ), and cerebellar cortex in patients with AD ( 11 ).…”

“…One possibility is that we analyzed the HS from frontal cortex, not from hippocampus, where 3-OST-2 and/or 3-OST-4 expression are up-regulated ( 31 ). HS3ST1 is reportedly overexpressed in amygdala, claustrum ( 31 ), and cerebellar cortex in patients with AD ( 11 ). Further analysis of the distribution of 3- O -sulfated HS from different areas of AD brains will be of interest and the subject for a subsequent study.…”

Heparan Sulfate Proteoglycans in Tauopathy

“…Consistent with these immunostaining and biochemical analyses, the transcripts of several HS-related genes were up-regulated in the AD brain, including Hs3st2 in Sepulveda-Diaz, J.E. et al study [ 110 ], Ndst2 , Hs3st2 , Hs3st4 and Glce in Huynh et al study, [ 92 ], Hspe and Hspe2 in Garcia et al study [ 140 ], and Extl3 , Hs6st1 , H s3st1 , Hs3st2 , Hs3st3A1 , Hs3stB1 , Hs6st5 and Hs6st6 in severe AD in Pérez-López et al study [ 139 ], and down-regulated, including HS 6- O -endosulfatase-2 (Sulf2) in Roberts et al study [ 138 ] and Sepulveda-Diaz, J.E. et al study [ 110 ].…”

“…et al study [ 110 ]. The Pérez-López et al study has shown, so far, the most comprehensive HS gene expression profile in AD study, analyzing all HS biosynthesis and remodeling/degradation genes expression in different AD stages and different brain regions [ 139 ]. Overall, the results in Pérez-López’s study correlate HS gene expression with AD pathology.…”

“…The most obvious is the upregulation of Extl3 , Hs6st1 , and six of the seven members of the Hs3st family in severe AD. These findings revealed that the aberrant HS gene expression might generate more tau-binding sites to enhance HS-facilitated tau aggregation, thereby exacerbating the tauopathy [ 139 ]. Furthermore, upregulation of HSPE and HSPE2 in AD brains indicates an active role of HS restructuring during disease progression, as the increased expression correlated closely with each concurrent Braak stage of AD [ 141 ].…”