scholarly journals Heparan Sulfate Proteoglycans Undergo Differential Expression Alterations in Alzheimer Disease Brains

2020 ◽  
Vol 79 (5) ◽  
pp. 474-483 ◽  
Author(s):  
Laura Lorente-Gea ◽  
Beatriz García ◽  
Carla Martín ◽  
Helena Ordiales ◽  
Olivia García-Suárez ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Heparan Sulfate ◽  
Core Protein ◽  
Amyloid Β ◽  
Heparan Sulfate Proteoglycans ◽  
Amyloid Beta Peptide ◽  
Rt Pcr ◽  
Core Proteins ◽  
Beta Peptide ◽  
The Brain

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.

The role of neuronal versus astrocyte-derived heparan sulfate proteoglycans in brain development and injury

2014 ◽  
Vol 42 (5) ◽  
pp. 1263-1269 ◽  
Author(s):  
Isabella Farhy Tselnicker ◽  
Matthew M. Boisvert ◽  
Nicola J. Allen
Keyword(s):  
Heparan Sulfate ◽  
Synapse Formation ◽  
Heparan Sulfate Proteoglycans ◽  
Synaptic Function ◽  
Current Evidence ◽  
Cell Type ◽  
Injury Response ◽  
Specific Expression ◽  
Core Proteins ◽  
The Brain

Astrocytes modulate many aspects of neuronal function, including synapse formation and the response to injury. Heparan sulfate proteoglycans (HSPGs) mediate some of the effects of astrocytes on synaptic function, and participate in the astrocyte-mediated brain injury response. HSPGs are a highly conserved class of proteoglycans, with variable heparan sulfate (HS) chains that play a major role in determining the function of these proteins, such as binding to growth factors and receptors. Expression of both the core proteins and their HS chains can vary depending on cellular origin, thus the functional impact of HSPGs may be determined by the cell type in which they are expressed. In the brain, HSPGs are expressed by both neurons and astrocytes; however, the specific contribution of neuronal HSPGs compared with astrocyte-derived HSPGs to development and the injury response is largely unknown. The present review examines the current evidence regarding the roles of HSPGs in the brain, describes the cellular origins of HSPGs, and interrogates the roles of HSPGs from astrocytes and neurons in synaptogenesis and injury. The importance of considering cell-type-specific expression of HSPGs when studying brain function is discussed.

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

2021 ◽  
Vol 80 (5) ◽  
pp. 446-456
Author(s):  
Natalia Pérez-López ◽  
Carla Martín ◽  
Beatriz García ◽  
Maria Pilar Solís-Hernández ◽  
David Rodríguez ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Heparan Sulfate ◽  
Structural Complexity ◽  
Brain Regions ◽  
Rt Pcr ◽  
Transcriptional Alterations ◽  
Calcarine Fissure ◽  
Differential Transcription ◽  
Late Stages ◽  
The Brain

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.

G-lymphatic, vascular and immune pathways for Aβ clearance cascade and therapeutic targets for Alzheimer’s disease

2020 ◽  
Vol 23 ◽  
Author(s):  
Saurav Chakraborty ◽  
Jyothsna ThimmaReddygari ◽  
Divakar Selvaraj
Keyword(s):  
Alzheimer Disease ◽  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Complement System ◽  
Therapeutic Targets ◽  
Neuronal Cell ◽  
Precursor Protein ◽  
Amyloid Beta Peptide ◽  
Beta Peptide ◽  
Immune Pathways

The Alzheimer disease is a age related neurodegenerative disease. The factors causing alzheimer disease are numerous. Research on humans and rodent models predicted various causative factors involved in Alzheimer disease progression. Among them, neuroinflammation, oxidative stress and apoptosis play a major role because of accumulation of extracellular amyloid beta peptides. Here, the clearance of amyloid beta peptide plays a major role because of the imbalance in the production and clearance of the amyloid beta peptide. Additionally, neuroinflammation by microglia, astrocytes, cytokines, chemokines and the complement system also have a major role in Alzheimer disease. The physiological clearance pathways involved in amyloid beta peptide are glymphatic, vascular and immune pathways. Amyloid precursor protein, low density lipoprotein receptor-related protein 1, receptor for advanced glycation end product, apolipoprotein E, clusterin, aquaporin 4, auto-antibodies, complement system, cytokines and microglia are involved in amyloid beta peptide clearance pathways across the blood brain barrier. The plaque formation in the brain by alternative splicing of amyloid precursor protein and production of misfolded protein results in amyloid beta agglomeration. This insoluble amyloid beta leads to neurodegenerative cascade and neuronal cell death occurs. Studies had shown disturbed sleep may be a risk factor for dementia and cognitive decline. In this review, the therapeutic targets for alzheimer disease via focussing on pathways for amyloid beta clearance are discussed.

scholarly journals Neuronal spreading and plaque induction of intracellular Aβ and its disruption of Aβ homeostasis

2021 ◽  
Author(s):  
Tomas T. Roos ◽  
Megg G. Garcia ◽  
Isak Martinsson ◽  
Rana Mabrouk ◽  
Bodil Israelsson ◽  
...  
Keyword(s):  
Brain Homogenate ◽  
Fold Increase ◽  
Amyloid Beta Peptide ◽  
Intracellular Accumulation ◽  
Brain Areas ◽  
Cellular Models ◽  
Beta Peptide ◽  
The Brain

AbstractThe amyloid-beta peptide (Aβ) is thought to have prion-like properties promoting its spread throughout the brain in Alzheimer’s disease (AD). However, the cellular mechanism(s) of this spread remains unclear. Here, we show an important role of intracellular Aβ in its prion-like spread. We demonstrate that an intracellular source of Aβ can induce amyloid plaques in vivo via hippocampal injection. We show that hippocampal injection of mouse AD brain homogenate not only induces plaques, but also damages interneurons and affects intracellular Aβ levels in synaptically connected brain areas, paralleling cellular changes seen in AD. Furthermore, in a primary neuron AD model, exposure of picomolar amounts of brain-derived Aβ leads to an apparent redistribution of Aβ from soma to processes and dystrophic neurites. We also observe that such neuritic dystrophies associate with plaque formation in AD-transgenic mice. Finally, using cellular models, we propose a mechanism for how intracellular accumulation of Aβ disturbs homeostatic control of Aβ levels and can contribute to the up to 10,000-fold increase of Aβ in the AD brain. Our data indicate an essential role for intracellular prion-like Aβ and its synaptic spread in the pathogenesis of AD.

scholarly journals Development and Optimization of a Fluorescent Imaging System to Detect Amyloid-β Proteins: Phantom Study

2018 ◽  
Vol 9 ◽  
pp. 117959721878108 ◽  
Author(s):  
David Tes ◽  
Karl Kratkiewicz ◽  
Ahmed Aber ◽  
Luke Horton ◽  
Mohsin Zafar ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Imaging System ◽  
Ex Vivo ◽  
Amyloid Β ◽  
The United States ◽  
Fluorescent Imaging ◽  
Fluorescent Properties ◽  
In Vivo Experiments ◽  
The Brain

Alzheimer disease is the most common form of dementia, affecting more than 5 million people in the United States. During the progression of Alzheimer disease, a particular protein begins to accumulate in the brain and also in extensions of the brain, ie, the retina. This protein, amyloid-β (Aβ), exhibits fluorescent properties. The purpose of this research article is to explore the implications of designing a fluorescent imaging system able to detect Aβ proteins in the retina. We designed and implemented a fluorescent imaging system with a range of applications that can be reconfigured on a fluorophore to fluorophore basis and tested its feasibility and capabilities using Cy5 and CRANAD-2 imaging probes. The results indicate a promising potential for the imaging system to be used to study the Aβ biomarker. A performance evaluation involving ex vivo and in vivo experiments is planned for future study.

Amyloid beta peptide immunotherapy in Alzheimer disease

2014 ◽  
Vol 170 (12) ◽  
pp. 739-748 ◽  
Author(s):  
J. Delrieu ◽  
P.J. Ousset ◽  
T. Voisin ◽  
B. Vellas
Keyword(s):  
Alzheimer Disease ◽  
Amyloid Beta ◽  
Amyloid Beta Peptide ◽  
Peptide Immunotherapy ◽  
Beta Peptide

scholarly journals Glomerular basement membrane proteoglycans are derived from a large precursor.

1988 ◽  
Vol 106 (3) ◽  
pp. 963-970 ◽  
Author(s):  
D J Klein ◽  
D M Brown ◽  
T R Oegema ◽  
P E Brenchley ◽  
J C Anderson ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Heparan Sulfate ◽  
Glomerular Basement Membrane ◽  
Core Protein ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
Immunological Methods ◽  
Core Proteins ◽  
Single Precursor ◽  
Species Being

The basement membrane heparan sulfate proteoglycan produced by the Englebreth-Holm-Swarm (EHS) tumor and by glomeruli were compared by immunological methods. Antibodies to the EHS proteoglycan immunoprecipitated a single precursor protein (Mr = 400,000) from [35S]methionine-pulsed glomeruli, the same size produced by EHS cells. These antibodies detected both heparan sulfate proteoglycans and glycoproteins in extracts of unlabeled glomeruli and glomerular basement membrane. The proteoglycans contained core proteins of varying size (Mr = 150,000 to 400,000) with a Mr = 250,000 species being predominant. The glycoproteins are fragments of the core protein which lack heparan sulfate side chains. Antibodies to glomerular basement membrane proteoglycan immunoprecipitated the precursor protein (Mr = 400,000) synthesized by EHS cells and also reacted with most of the proteolytic fragments of the EHS proteoglycan. This antibody did not, however, react with the P44 fragment, a peptide situated at one end of the EHS proteoglycan core protein. These data suggest that the glomerular basement membrane proteoglycan is synthesized from a large precursor protein which undergoes specific proteolytic processing.

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