Heparan Sulfate Proteoglycans Undergo Differential Expression Alterations in Alzheimer Disease Brains

Abstract

Previous studies have reported that heparan sulfate proteoglycans (HSPGs) promote amyloid-beta peptide and tau fibrillization in Alzheimer disease (AD) and provide resistance against proteolytic breakdown. We compared the expression levels of 17 HSPG core proteins in 18 AD cases and 6 controls. RT-PCR was used to analyze transcription levels. Immunohistochemistry was performed to localize HSPGs in the brain tissue. We detected expression of all HSPG genes investigated. SDC1, GPC3, and CD44v3 showed the lowest levels of expression, while SDC3 and GPC1 showed the highest. Remarkably, SDC4 and SRGN were overexpressed in most of the areas analyzed. Immunohistochemistry revealed the presence of both SDC4 and SRGN mostly associated with tau and amyloid-β pathology throughout the AD brains. In conclusion, in view of the involvement of HSPGs in AD pathology, especially SDC4 and SRGN, there would seem to be a relationship between the regulation of core protein expression and the pathological features suggesting HSPGs are potential inducers of the disease.

Knockin’ on heaven’s door: Molecular mechanisms of neuronal tau uptake

“…Syndecans belong to one of three subtypes of HSPGs and consist of four members (syndecan 1–4) (Condomitti & de Wit, 2018). A significant elevation of the level of all syndecans except syndecan‐1 was detected in post‐mortem AD brains compared to controls (Liu et al., 2016; Lorente‐Gea et al., 2020), suggesting their involvement in AD. Indeed, increased expression of syndecans 2–4 has been associated with neurodegeneration vulnerability in AD (Grothe et al., 2018).…”

Exposure of Mesenchymal Stem Cells to an Alzheimer’s Disease Environment Enhances Therapeutic Effects

“…Heparin sulfate proteoglycan, which contains SRGN, was responsible for promoting the brillization of Aβ and tau proteins [60]. Interestingly, it was also reported that SRGN gene expression and protein expression were signi cantly increased in AD patients compared to normal controls [61]. Thus, SRGN may be thought of as a possible biomarker for AD, suggesting that the pre-conditioning of SRGN in MSCs may be a possible to generate enhance MSC for AD treatment.…”

The Sulfation Code of Tauopathies: Heparan Sulfate Proteoglycans in the Prion Like Spread of Tau Pathology

“…The group also reported that AD derived HS exhibited a higher binding capacity for tau protein compared to HS derived from healthy brains, indicating AD associated changes in HS enhance the strength of its interactions with tau protein. Lorente-Gea et al (2020) conducted a systematic analysis of major HSPG core protein expression across the regions of the brains of patients with AD. While changes in the expression of extracellular HSPG core proteins were limited in AD brains, the study revealed upregulation of cell surface syndecan and intracellular serglycin.…”

“…While changes in the expression of extracellular HSPG core proteins were limited in AD brains, the study revealed upregulation of cell surface syndecan and intracellular serglycin. In particular, there is extensive overexpression of syndecan 4 and serglycin, which are associated with both amyloid and tau pathology in most AD brain samples ( Lorente-Gea et al, 2020 ), indicating a potentially undiscovered role for intracellular HSPGs in tauopathies. Some strides have been taken in recent years toward clinical translation of this line of research into potential drugs for AD and related dementias.…”