Fas Apoptosis Inhibitory Molecule Blocks and Dissolves Pathological Amyloid-β Species

A number of neurodegenerative diseases are associated with the accumulation of misfolded proteins, including Alzheimer’s disease (AD). In AD, misfolded proteins such as tau and amyloid-β (Aβ) form pathological insoluble deposits. It is hypothesized that molecules capable of dissolving such protein aggregates might reverse disease progression and improve the lives of afflicted AD patients. Here we report new functions of the highly conserved mammalian protein, Fas Apoptosis Inhibitory Molecule (FAIM). We found that FAIM-deficient Neuro 2A cells accumulate Aβ oligomers/fibrils. We further found that recombinant human FAIM prevents the generation of pathologic Aβ oligomers and fibrils in a cell-free system, suggesting that FAIM functions without any additional cellular components. More importantly, recombinant human FAIM disaggregates and solubilizes established Aβ fibrils. Our results identify a previously unknown, completely novel candidate for understanding and treating irremediable, irreversible, and unrelenting neurodegenerative diseases.

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Anti-Parallel β-Hairpin Structure in Soluble Aβ Oligomers of Aβ40-Dutch and Aβ40-Iowa

International Journal of Molecular Sciences ◽

10.3390/ijms22031225 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1225

Author(s):

Ziao Fu ◽

William E. Van Nostrand ◽

Steven O. Smith

Keyword(s):

Amyloid Β ◽

Amyloid Angiopathy ◽

Aβ Oligomers ◽

Dominant Component ◽

Fibril Structure ◽

Predominant Component ◽

Aβ Aggregation ◽

Aβ Fibrils ◽

Soluble Aβ Oligomers ◽

Β Sheet

The amyloid-β (Aβ) peptides are associated with two prominent diseases in the brain, Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Aβ42 is the dominant component of cored parenchymal plaques associated with AD, while Aβ40 is the predominant component of vascular amyloid associated with CAA. There are familial CAA mutations at positions Glu22 and Asp23 that lead to aggressive Aβ aggregation, drive vascular amyloid deposition and result in degradation of vascular membranes. In this study, we compared the transition of the monomeric Aβ40-WT peptide into soluble oligomers and fibrils with the corresponding transitions of the Aβ40-Dutch (E22Q), Aβ40-Iowa (D23N) and Aβ40-Dutch, Iowa (E22Q, D23N) mutants. FTIR measurements show that in a fashion similar to Aβ40-WT, the familial CAA mutants form transient intermediates with anti-parallel β-structure. This structure appears before the formation of cross-β-sheet fibrils as determined by thioflavin T fluorescence and circular dichroism spectroscopy and occurs when AFM images reveal the presence of soluble oligomers and protofibrils. Although the anti-parallel β-hairpin is a common intermediate on the pathway to Aβ fibrils for the four peptides studied, the rate of conversion to cross-β-sheet fibril structure differs for each.

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Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers

Nature Communications ◽

10.1038/s41467-021-23507-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ladan Amin ◽

David A. Harris

Keyword(s):

Amyloid Β ◽

Super Resolution ◽

Structural Motif ◽

Aβ Oligomers ◽

Surface Receptors ◽

Molecular Features ◽

Molecular Determinant ◽

Receptor Interactions ◽

Aβ Fibrils ◽

Super Resolution Microscopy

AbstractSeveral cell-surface receptors for neurotoxic forms of amyloid-β (Aβ) have been described, but their molecular interactions with Aβ assemblies and their relative contributions to mediating Alzheimer’s disease pathology have remained uncertain. Here, we used super-resolution microscopy to directly visualize Aβ-receptor interactions at the nanometer scale. We report that one documented Aβ receptor, PrPC, specifically inhibits the polymerization of Aβ fibrils by binding to the rapidly growing end of each fibril, thereby blocking polarized elongation at that end. PrPC binds neurotoxic oligomers and protofibrils in a similar fashion, suggesting that it may recognize a common, end-specific, structural motif on all of these assemblies. Finally, two other Aβ receptors, FcγRIIb and LilrB2, affect Aβ fibril growth in a manner similar to PrPC. Our results suggest that receptors may trap Aβ oligomers and protofibrils on the neuronal surface by binding to a common molecular determinant on these assemblies, thereby initiating a neurotoxic signal.

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Prions and Neurodegenerative Diseases: A Focus on Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-215171 ◽

2021 ◽

pp. 1-16

Author(s):

Alessio Crestini ◽

Francesca Santilli ◽

Stefano Martellucci ◽

Elena Carbone ◽

Maurizio Sorice ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Protein Misfolding ◽

Amyloid Β ◽

Specific Protein ◽

Cellular Prion Protein ◽

Aβ Oligomers ◽

The Central Nervous System ◽

Induced Signal

Specific protein misfolding and aggregation are mechanisms underlying various neurodegenerative diseases such as prion disease and Alzheimer’s disease (AD). The misfolded proteins are involved in prions, amyloid-β (Aβ), tau, and α-synuclein disorders; they share common structural, biological, and biochemical characteristics, as well as similar mechanisms of aggregation and self-propagation. Pathological features of AD include the appearance of plaques consisting of deposition of protein Aβ and neurofibrillary tangles formed by the hyperphosphorylated tau protein. Although it is not clear how protein aggregation leads to AD, we are learning that the cellular prion protein (PrPC) plays an important role in the pathogenesis of AD. Herein, we first examined the pathogenesis of prion and AD with a focus on the contribution of PrPC to the development of AD. We analyzed the mechanisms that lead to the formation of a high affinity bond between Aβ oligomers (AβOs) and PrPC. Also, we studied the role of PrPC as an AβO receptor that initiates an AβO-induced signal cascade involving mGluR5, Fyn, Pyk2, and eEF2K linking Aβ and tau pathologies, resulting in the death of neurons in the central nervous system. Finally, we have described how the PrPC-AβOs interaction can be used as a new potential therapeutic target for the treatment of PrPC-dependent AD.

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Neuroligin-1 in brain and CSF of neurodegenerative disorders: investigation for synaptic biomarkers

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01119-4 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Elena Camporesi ◽

Tammaryn Lashley ◽

Johan Gobom ◽

Juan Lantero-Rodriguez ◽

Oskar Hansson ◽

...

Keyword(s):

Amyloid Β ◽

Cognitive Disorders ◽

Corticobasal Degeneration ◽

Brain Regions ◽

Synaptic Proteins ◽

Aβ Oligomers ◽

Adhesion Protein ◽

Synaptic Pathology ◽

Brain Extracts ◽

Aβ Fibrils

AbstractSynaptic pathology is a central event in Alzheimer’s disease (AD) and other neurodegenerative conditions, and investigation of synaptic proteins can provide valuable tools to follow synaptic dysfunction and loss in these diseases. Neuroligin-1 (Nlgn1) is a postsynaptic cell adhesion protein, important for synapse stabilization and formation. Nlgn1 has been connected to cognitive disorders, and specifically to AD, as target of the synaptotoxic effect of amyloid-β (Aβ) oligomers and Aβ fibrils. To address changes in Nlgn1 expression in human brain, brain regions in different neurological disorders were examined by Western blot and mass spectrometry. Brain specimens from AD (n = 23), progressive supranuclear palsy (PSP, n = 11), corticobasal degeneration (CBD, n = 10), and Pick’s disease (PiD, n = 9) were included. Additionally, cerebrospinal fluid (CSF) samples of AD patients (n = 43) and non-demented controls (n = 42) were analysed. We found decreased levels of Nlgn1 in temporal and parietal cortex (~ 50–60% reductions) in AD brains compared with controls. In frontal grey matter the reduction was not seen for AD patients; however, in the same region, marked reduction was found for PiD (~ 77%), CBD (~ 66%) and to a lesser extent for PSP (~ 43%), which could clearly separate these tauopathies from controls. The Nlgn1 level was reduced in CSF from AD patients compared to controls, but with considerable overlap. The dramatic reduction of Nlgn1 seen in the brain extracts of tauopathies warrants further investigation regarding the potential use of Nlgn1 as a biomarker for these neurodegenerative diseases.

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FAIM opposes stress-induced loss of viability and blocks the formation of protein aggregates

10.1101/569988 ◽

2019 ◽

Cited By ~ 1

Author(s):

Hiroaki Kaku ◽

Thomas L. Rothstein

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Disease Onset ◽

Protein Aggregates ◽

Ubiquitinated Protein ◽

Free System ◽

Inhibitory Molecule ◽

Fas Apoptosis Inhibitory Molecule ◽

Shock Proteins

AbstractA number of proteinopathies are associated with accumulation of misfolded proteins, which form pathological insoluble deposits. It is hypothesized that molecules capable of blocking formation of such protein aggregates might avert disease onset or delay disease progression. Here we report that Fas Apoptosis Inhibitory Molecule (FAIM) counteracts stress-induced loss of viability. We found that levels of ubiquitinated protein aggregates produced by cellular stress are much greater in FAIM-deficient cells and tissues. Moreover, in an in vitro cell-free system, FAIM specifically and directly prevents pathological protein aggregates without participation by other cellular elements, in particular the proteasomal and autophagic systems. Although this activity is similar to the function of heat shock proteins (HSPs), FAIM, which is highly conserved throughout evolution, bears no homology to any other protein, including HSPs. These results identify a new actor that protects cells against stress-induced loss of viability by preventing protein aggregates.

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Cytotoxic Aβ Protofilaments Are Generated in the Process of Aβ Fibril Disaggregation

International Journal of Molecular Sciences ◽

10.3390/ijms222312780 ◽

2021 ◽

Vol 22 (23) ◽

pp. 12780

Author(s):

Toshisuke Kaku ◽

Kaori Tsukakoshi ◽

Kazunori Ikebukuro

Keyword(s):

Amyloid Fibrils ◽

Epigallocatechin Gallate ◽

Amyloid Β ◽

Neural Cells ◽

Aβ Oligomers ◽

Microscopy Imaging ◽

Force Microscopy ◽

Atomic Force ◽

Significant Research ◽

Aβ Fibrils

Significant research on Alzheimer’s disease (AD) has demonstrated that amyloid β (Aβ) oligomers are toxic molecules against neural cells. Thus, determining the generation mechanism of toxic Aβ oligomers is crucial for understanding AD pathogenesis. Aβ fibrils were reported to be disaggregated by treatment with small compounds, such as epigallocatechin gallate (EGCG) and dopamine (DA), and a loss of fibril shape and decrease in cytotoxicity were observed. However, the characteristics of intermediate products during the fibril disaggregation process are poorly understood. In this study, we found that cytotoxic Aβ aggregates are generated during a moderate disaggregation process of Aβ fibrils. A cytotoxicity assay revealed that Aβ fibrils incubated with a low concentration of EGCG and DA showed higher cytotoxicity than Aβ fibrils alone. Atomic force microscopy imaging and circular dichroism spectrometry showed that short and narrow protofilaments, which were highly stable in the β-sheet structure, were abundant in these moderately disaggregated samples. These results indicate that toxic Aβ protofilaments are generated during disaggregation from amyloid fibrils, suggesting that disaggregation of Aβ fibrils by small compounds may be one of the possible mechanisms for the generation of toxic Aβ aggregates in the brain.

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Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities

Cell Death and Differentiation ◽

10.1038/s41418-020-00706-7 ◽

2021 ◽

Author(s):

Marlene F. Schmidt ◽

Zhong Yan Gan ◽

David Komander ◽

Grant Dewson

Keyword(s):

Neurodegenerative Diseases ◽

Gene Mutations ◽

Protein Aggregates ◽

Ubiquitin Proteasome System ◽

New Drugs ◽

Misfolded Proteins ◽

Neurodegenerative Process ◽

Inflammatory Processes ◽

Ubiquitin Proteasome ◽

A Cell

AbstractNeurodegenerative diseases are characterised by progressive damage to the nervous system including the selective loss of vulnerable populations of neurons leading to motor symptoms and cognitive decline. Despite millions of people being affected worldwide, there are still no drugs that block the neurodegenerative process to stop or slow disease progression. Neuronal death in these diseases is often linked to the misfolded proteins that aggregate within the brain (proteinopathies) as a result of disease-related gene mutations or abnormal protein homoeostasis. There are two major degradation pathways to rid a cell of unwanted or misfolded proteins to prevent their accumulation and to maintain the health of a cell: the ubiquitin–proteasome system and the autophagy–lysosomal pathway. Both of these degradative pathways depend on the modification of targets with ubiquitin. Aging is the primary risk factor of most neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. With aging there is a general reduction in proteasomal degradation and autophagy, and a consequent increase of potentially neurotoxic protein aggregates of β-amyloid, tau, α-synuclein, SOD1 and TDP-43. An often over-looked yet major component of these aggregates is ubiquitin, implicating these protein aggregates as either an adaptive response to toxic misfolded proteins or as evidence of dysregulated ubiquitin-mediated degradation driving toxic aggregation. In addition, non-degradative ubiquitin signalling is critical for homoeostatic mechanisms fundamental for neuronal function and survival, including mitochondrial homoeostasis, receptor trafficking and DNA damage responses, whilst also playing a role in inflammatory processes. This review will discuss the current understanding of the role of ubiquitin-dependent processes in the progressive loss of neurons and the emergence of ubiquitin signalling as a target for the development of much needed new drugs to treat neurodegenerative disease.

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Sialylated glycosylphosphatidylinositols suppress the production of toxic amyloid-β oligomers

Biochemical Journal ◽

10.1042/bcj20170239 ◽

2017 ◽

Vol 474 (17) ◽

pp. 3045-3058 ◽

Cited By ~ 2

Author(s):

William Nolan ◽

Harriet McHale-Owen ◽

Clive Bate

Keyword(s):

Cell Model ◽

Amyloid Β ◽

Critical Factor ◽

Cellular Prion Protein ◽

Progressive Dementia ◽

Aβ Oligomers ◽

Key Factor ◽

A Cell ◽

Synapse Degeneration ◽

Soluble Aβ Oligomers

The production of amyloid-β (Aβ) is a key factor driving pathogenesis in Alzheimer's disease (AD). Increasing concentrations of soluble Aβ oligomers within the brain lead to synapse degeneration and the progressive dementia characteristic of AD. Since Aβ exists in both disease-relevant (toxic) and non-toxic forms, the factors that affected the release of toxic Aβ were studied in a cell model. 7PA2 cells expressing the human amyloid precursor protein released Aβ oligomers that caused synapse damage when incubated with cultured neurones. These Aβ oligomers had similar potency to soluble Aβ oligomers derived from the brains of Alzheimer's patients. Although the conditioned media from 7PA2 cells treated with the cellular prion protein (PrPC) contained Aβ, it did not cause synapse damage. The loss of toxicity was associated with a reduction in Aβ oligomers and an increase in Aβ monomers. The suppression of toxic Aβ release was dependent on the glycosylphosphatidylinositol (GPI) anchor attached to PrPC, and treatment of cells with specific GPIs alone reduced the production of toxic Aβ. The efficacy of GPIs was structure-dependent and the presence of sialic acid was critical. The conditioned medium from GPI-treated cells protected neurones against Aβ oligomer-induced synapse damage; neuroprotection was mediated by Aβ monomers. These studies support the hypothesis that the ratio of Aβ monomers to Aβ oligomers is a critical factor that regulates synapse damage.

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Mitochondrial ubiquitin ligase alleviates Alzheimer’s disease pathology via blocking the toxic amyloid-β oligomer generation

Communications Biology ◽

10.1038/s42003-021-01720-2 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Keisuke Takeda ◽

Aoi Uda ◽

Mikihiro Mitsubori ◽

Shun Nagashima ◽

Hiroko Iwasaki ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Ubiquitin Ligase ◽

Mitochondrial Dynamics ◽

Amyloid Β ◽

Mitochondrial Morphology ◽

Aβ Oligomers ◽

Key Factor ◽

Aβ Fibrils

AbstractMitochondrial pathophysiology is implicated in the development of Alzheimer’s disease (AD). An integrative database of gene dysregulation suggests that the mitochondrial ubiquitin ligase MITOL/MARCH5, a fine-tuner of mitochondrial dynamics and functions, is downregulated in patients with AD. Here, we report that the perturbation of mitochondrial dynamics by MITOL deletion triggers mitochondrial impairments and exacerbates cognitive decline in a mouse model with AD-related Aβ pathology. Notably, MITOL deletion in the brain enhanced the seeding effect of Aβ fibrils, but not the spontaneous formation of Aβ fibrils and plaques, leading to excessive secondary generation of toxic and dispersible Aβ oligomers. Consistent with this, MITOL-deficient mice with Aβ etiology exhibited worsening cognitive decline depending on Aβ oligomers rather than Aβ plaques themselves. Our findings suggest that alteration in mitochondrial morphology might be a key factor in AD due to directing the production of Aβ form, oligomers or plaques, responsible for disease development.

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