Aβ–ganglioside interactions in the pathogenesis of Alzheimer's disease

Matsuzaki, Katsumi

doi:10.1016/j.bbamem.2020.183233

Cited by 62 publications

(49 citation statements)

References 103 publications

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“…It was proposed that this GM1-bound Aβ might work as a seed for Aβ aggregation ( Yanagisawa et al, 1995 ). A large body of literature showed that GM1 binding to Aβ promotes the amyloidogenic process, a property shared by other gangliosides as well, depending on the specific variants of Aβ used in the experiments ( Matsuzaki, 2020 ). Unilamellar vesicles containing GM1 increase the rate of Aβ fibrillization in vitro ( Choo-Smith et al, 1997 ), by inducing a β-sheet structure in the peptide with a high propensity to aggregate ( Matsuzaki and Horikiri, 1999 ; Kakio et al, 2001 ).…”

Section: Gangliosides In Neurological and Neurodegenerative Conditionmentioning

confidence: 99%

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Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications

et al. 2020

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Gangliosides are glycosphingolipids highly abundant in the nervous system, and carry most of the sialic acid residues in the brain. Gangliosides are enriched in cell membrane microdomains ("lipid rafts") and play important roles in the modulation of membrane proteins and ion channels, in cell signaling and in the communication among cells. The importance of gangliosides in the brain is highlighted by the fact that loss of function mutations in ganglioside biosynthetic enzymes result in severe neurodegenerative disorders, often characterized by very early or childhood onset. In addition, changes in the ganglioside profile (i.e., in the relative abundance of specific gangliosides) were reported in healthy aging and in common neurological conditions, including Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), stroke, multiple sclerosis and epilepsy. At least in HD, PD and in some forms of epilepsy, experimental evidence strongly suggests a potential role of gangliosides in disease pathogenesis and potential treatment. In this review, we will summarize ganglioside functions that are crucial to maintain brain health, we will review changes in ganglioside levels that occur in major neurological conditions and we will discuss their contribution to cellular dysfunctions and disease pathogenesis. Finally, we will review evidence of the beneficial roles exerted by gangliosides, GM1 in particular, in disease models and in clinical trials.

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Section: Gangliosides In Neurological and Neurodegenerative Conditionmentioning

confidence: 99%

“…At more physiological concentrations, GM1 was shown to form microdomains in artificial membranes, and did not induce oligomerization of Aβ ( Amaro et al, 2016 ). Thus, the amyloidogenic properties of GM1 in vitro remain controversial ( Matsuzaki, 2020 ).…”

Section: Gangliosides In Neurological and Neurodegenerative Conditionmentioning

confidence: 99%

Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications

et al. 2020

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“…For GM1 clusters recognition, the His13–Gln15 region is crucial, while binding of Lys18 to sialic acid triggers the helix formation at the C-terminus of Aβ. Other polar and hydrophobic interactions are necessary for finalizing the aggregation process of Aβ on a GM1-containing bilayer [ 148 , 152 , 153 ]. It was shown by Yamamoto et al that aging and apo-E4 expression cooperatively accelerate Aβ aggregation in the brain through the increase and modulation of GM1 distribution in neuronal membranes [ 139 ].…”

Section: Gangliosides and Aβmentioning

confidence: 99%

“…Moreover, the presence of GM1 prevented the oligomerization of Aβ observed in dioleoyl-PC/cholesterol/SM membranes [ 92 ]. As this study was carried out at low ionic strength, electrostatic repulsion between negatively charged Aβ and anionic GM1 inhibiting the Aβ–GM1 interaction was much stronger than that at physiological ionic strength [ 153 ].…”

Section: Gangliosides and Aβmentioning

confidence: 99%

The Role of Lipid Environment in Ganglioside GM1-Induced Amyloid β Aggregation

Rudajev

Novotný

2020

Membranes

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Ganglioside GM1 is the most common brain ganglioside enriched in plasma membrane regions known as lipid rafts or membrane microdomains. GM1 participates in many modulatory and communication functions associated with the development, differentiation, and protection of neuronal tissue. It has, however, been demonstrated that GM1 plays a negative role in the pathophysiology of Alzheimer’s disease (AD). The two features of AD are the formation of intracellular neurofibrillary bodies and the accumulation of extracellular amyloid β (Aβ). Aβ is a peptide characterized by intrinsic conformational flexibility. Depending on its partners, Aβ can adopt different spatial arrangements. GM1 has been shown to induce specific changes in the spatial organization of Aβ, which lead to enhanced peptide accumulation and deleterious effect especially on neuronal membranes containing clusters of this ganglioside. Changes in GM1 levels and distribution during the development of AD may contribute to the aggravation of the disease.

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“…GM1 gangliosides were reported to bind to AβP in AD brains [138]. It was also suggested that GM1-bound AβP behaves as a "seed" for oligomers and enhances AβP oligomerization [139,140]. Our AFM imaging study demonstrated the deposition of AβP(1-40) on ganglioside (GM1)/phospholipid monolayers [15].…”

Section: Channel Formation By Other Amyloidogenic Proteinsmentioning

confidence: 59%

Amyloids: Regulators of Metal Homeostasis in the Synapse

2020

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Conformational changes in amyloidogenic proteins, such as β-amyloid protein, prion proteins, and α-synuclein, play a critical role in the pathogenesis of numerous neurodegenerative diseases, including Alzheimer’s disease, prion disease, and Lewy body disease. The disease-associated proteins possess several common characteristics, including the ability to form amyloid oligomers with β-pleated sheet structure, as well as cytotoxicity, although they differ in amino acid sequence. Interestingly, these amyloidogenic proteins all possess the ability to bind trace metals, can regulate metal homeostasis, and are co-localized at the synapse, where metals are abundantly present. In this review, we discuss the physiological roles of these amyloidogenic proteins in metal homeostasis, and we propose hypothetical models of their pathogenetic role in the neurodegenerative process as the loss of normal metal regulatory functions of amyloidogenic proteins. Notably, these amyloidogenic proteins have the capacity to form Ca2+-permeable pores in membranes, suggestive of a toxic gain of function. Therefore, we focus on their potential role in the disruption of Ca2+ homeostasis in amyloid-associated neurodegenerative diseases.

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Aβ–ganglioside interactions in the pathogenesis of Alzheimer's disease

Cited by 62 publications

References 103 publications

Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications

Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications

The Role of Lipid Environment in Ganglioside GM1-Induced Amyloid β Aggregation

Amyloids: Regulators of Metal Homeostasis in the Synapse

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