Early accumulation of heparan sulfate in neurons and in the beta-amyloid protein containing lesions of Alzheimer's disease and Down's syndrome

Snow, Alan D.; Mar, Henderson; Nochlin, David; Sekiguchi, Raymond T.; Kimata, Koji; Koike, Y; Wight, Thomas N.

doi:10.1016/0197-4580(90)90765-r

Cited by 71 publications

(1 citation statement)

References 61 publications

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“…Another potential mechanism links the neurological pathology in MPS to Alzheimer's Disease, Huntington's Disease, and Parkinson's Disease [149]. HS associates with tau and alpha-synuclein and can promote their aggregation, cellular uptake, and transcellular propagation of fibrils [150][151][152]. Since sulfation of HS is necessary for tau binding [151], over-sulfated HS in MPS II may promote tau and alpha-synuclein binding, while the presence of non-sulfated HS in MPS I may be protective.…”

Section: Hs In Neurological Manifestationsmentioning

confidence: 99%

Differences in MPS I and MPS II Disease Manifestations

Hampe

Yund

Orchard

et al. 2021

IJMS

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Mucopolysaccharidosis (MPS) type I and II are two closely related lysosomal storage diseases associated with disrupted glycosaminoglycan catabolism. In MPS II, the first step of degradation of heparan sulfate (HS) and dermatan sulfate (DS) is blocked by a deficiency in the lysosomal enzyme iduronate 2-sulfatase (IDS), while, in MPS I, blockage of the second step is caused by a deficiency in iduronidase (IDUA). The subsequent accumulation of HS and DS causes lysosomal hypertrophy and an increase in the number of lysosomes in cells, and impacts cellular functions, like cell adhesion, endocytosis, intracellular trafficking of different molecules, intracellular ionic balance, and inflammation. Characteristic phenotypical manifestations of both MPS I and II include skeletal disease, reflected in short stature, inguinal and umbilical hernias, hydrocephalus, hearing loss, coarse facial features, protruded abdomen with hepatosplenomegaly, and neurological involvement with varying functional concerns. However, a few manifestations are disease-specific, including corneal clouding in MPS I, epidermal manifestations in MPS II, and differences in the severity and nature of behavioral concerns. These phenotypic differences appear to be related to different ratios between DS and HS, and their sulfation levels. MPS I is characterized by higher DS/HS levels and lower sulfation levels, while HS levels dominate over DS levels in MPS II and sulfation levels are higher. The high presence of DS in the cornea and its involvement in the arrangement of collagen fibrils potentially causes corneal clouding to be prevalent in MPS I, but not in MPS II. The differences in neurological involvement may be due to the increased HS levels in MPS II, because of the involvement of HS in neuronal development. Current treatment options for patients with MPS II are often restricted to enzyme replacement therapy (ERT). While ERT has beneficial effects on respiratory and cardiopulmonary function and extends the lifespan of the patients, it does not significantly affect CNS manifestations, probably because the enzyme cannot pass the blood–brain barrier at sufficient levels. Many experimental therapies, therefore, aim at delivery of IDS to the CNS in an attempt to prevent neurocognitive decline in the patients.

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Section: Hs In Neurological Manifestationsmentioning

confidence: 99%

Differences in MPS I and MPS II Disease Manifestations

Hampe

Yund

Orchard

et al. 2021

IJMS

View full text Add to dashboard Cite

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The Impact of the Cellular Environment and Aging on Modeling Alzheimer's Disease in 3D Cell Culture Models

et al. 2023

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Creating a cellular model of Alzheimer's disease (AD) that accurately recapitulates disease pathology has been a longstanding challenge. Recent studies showed that human AD neural cells, integrated into three‐dimensional (3D) hydrogel matrix, display key features of AD neuropathology. Like in the human brain, the extracellular matrix (ECM) plays a critical role in determining the rate of neuropathogenesis in hydrogel‐based 3D cellular models. Aging, the greatest risk factor for AD, significantly alters brain ECM properties. Therefore, it is important to understand how age‐associated changes in ECM affect accumulation of pathogenic molecules, neuroinflammation, and neurodegeneration in AD patients and in vitro models. In this review, mechanistic hypotheses is presented to address the impact of the ECM properties and their changes with aging on AD and AD‐related dementias. Altered ECM characteristics in aged brains, including matrix stiffness, pore size, and composition, will contribute to disease pathogenesis by modulating the accumulation, propagation, and spreading of pathogenic molecules of AD. Emerging hydrogel‐based disease models with differing ECM properties provide an exciting opportunity to study the impact of brain ECM aging on AD pathogenesis, providing novel mechanistic insights. Understanding the role of ECM aging in AD pathogenesis should also improve modeling AD in 3D hydrogel systems.

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Mass spectrometry methods for analysis of extracellular matrix components in neurological diseases

Downs

Zaia

Sethi

2022

Mass Spectrometry Reviews

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The brain extracellular matrix (ECM) is a highly glycosylated environment and plays important roles in many processes including cell communication, growth factor binding, and scaffolding. The formation of structures such as perineuronal nets (PNNs) is critical in neuroprotection and neural plasticity, and the formation of molecular networks is dependent in part on glycans. The ECM is also implicated in the neuropathophysiology of disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and Schizophrenia (SZ). As such, it is of interest to understand both the proteomic and glycomic makeup of healthy and diseased brain ECM. Further, there is a growing need for site‐specific glycoproteomic information. Over the past decade, sample preparation, mass spectrometry, and bioinformatic methods have been developed and refined to provide comprehensive information about the glycoproteome. Core ECM molecules including versican, hyaluronan and proteoglycan link proteins, and tenascin are dysregulated in AD, PD, and SZ. Glycomic changes such as differential sialylation, sulfation, and branching are also associated with neurodegeneration. A more thorough understanding of the ECM and its proteomic, glycomic, and glycoproteomic changes in brain diseases may provide pathways to new therapeutic options.

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Early accumulation of heparan sulfate in neurons and in the beta-amyloid protein containing lesions of Alzheimer's disease and Down's syndrome

Cited by 71 publications

References 61 publications

Differences in MPS I and MPS II Disease Manifestations

Differences in MPS I and MPS II Disease Manifestations

The Impact of the Cellular Environment and Aging on Modeling Alzheimer's Disease in 3D Cell Culture Models

Mass spectrometry methods for analysis of extracellular matrix components in neurological diseases

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