HIV Tat protein and amyloid-β peptide form multifibrillar structures that cause neurotoxicity

Hategan, Alina; Bianchet, M.A.; Steiner, Joseph P.; Karnaukhova, Elena; Masliah, Eliezer; Fields, Adam C.; Lee, Myoung Hwa; Dickens, Alex M.; Haughey, Norman J.; Dimitriadis, Emilios K.; Nath, Avindra

doi:10.1038/nsmb.3379

Cited by 77 publications

(68 citation statements)

References 73 publications

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“…Likewise, APP transcription was suppressed by Meth sensitization, by Tat expression, as well as by their interaction. Although a decrease in APP is regarded as protective, it could be a factor limiting β-APP supply [106][107][108]. Whether these are replicating human disease and showing signs of accelerated aging in this model, as a consequence of Meth and HIV Tat interaction, needs to be further examined.…”

Section: Discussionmentioning

confidence: 97%

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

Basova

Kesby

Kaul

et al. 2020

Viruses

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Methamphetamine (Meth) abuse is common among humans with immunodeficiency virus (HIV). The HIV-1 regulatory protein, trans-activator of transcription (Tat), has been described to induce changes in brain gene transcription that can result in impaired reward circuitry, as well as in inflammatory processes. In transgenic mice with doxycycline-induced Tat protein expression in the brain, i.e., a mouse model of neuroHIV, we tested global gene expression patterns induced by Meth sensitization. Meth-induced locomotor sensitization included repeated daily Meth or saline injections for seven days and Meth challenge after a seven-day abstinence period. Brain samples were collected 30 min after the Meth challenge. We investigated global gene expression changes in the caudate putamen, an area with relevance in behavior and HIV pathogenesis, and performed pathway and transcriptional factor usage predictions using systems biology strategies. We found that Tat expression alone had a very limited impact in gene transcription after the Meth challenge. In contrast, Meth-induced sensitization in the absence of Tat induced a global suppression of gene transcription. Interestingly, the interaction between Tat and Meth broadly prevented the Meth-induced global transcriptional suppression, by maintaining regulation pathways, and resulting in gene expression profiles that were more similar to the controls. Pathways associated with mitochondrial health, initiation of transcription and translation, as well as with epigenetic control, were heavily affected by Meth, and by its interaction with Tat in anti-directional ways. A series of systems strategies have predicted several components impacted by these interactions, including mitochondrial pathways, mTOR/RICTOR, AP-1 transcription factor, and eukaryotic initiation factors involved in transcription and translation. In spite of the antagonizing effects of Tat, a few genes identified in relevant gene networks remained downregulated, such as sirtuin 1, and the amyloid precursor protein (APP). In conclusion, Tat expression in the brain had a low acute transcriptional impact but strongly interacted with Meth sensitization, to modify effects in the global transcriptome.

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Section: Discussionmentioning

confidence: 97%

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

Basova

Kesby

Kaul

et al. 2020

Viruses

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“…[2,10] Interaction of cell membranes with -sheet nanofibers is a topic research field due to the high potential of peptide-drug amphiphiles for intracell delivery and appearance of these structures in a variety of biological processes such as cell adhesion, signaling and cytotoxicity. [11][12][13][14][15][16][17][18] Newcomb et al [11] investigated cytotoxicity onto surfaces coated with nanofibers obtained from two kinds of surfactant-like peptides; namely, C16H31O-A3G3K3 and C16H31O-V3A3K3 peptide amphiphiles (PAs). These PAs are characterized by cationic head groups (lysines) separated from alkyl tails by amino acid spacers able to drive the formation of -sheet in the resulting nanofibers.…”

Section: Introductionmentioning

confidence: 99%

Sequence length dependence in arginine/phenylalanine oligopeptides: Implications for self-assembly and cytotoxicity

Silva

Listik

Han

et al. 2018

Biophysical Chemistry

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We present a detailed study on the self-assembly and cytotoxicity of arginine-rich fragments with general form [RF] (n=1-5). These highly simplified sequences, containing only two l-amino acids, provide suitable models for exploring both structure and cytotoxicity features of arginine-based oligopeptides. The organization of the sequences is revealed over a range of length scales, from the nanometer range down to the level of molecular packing, and their cytotoxicity toward C6 rat glioma and RAW264.7 macrophage cell lines is investigated. We found that the polymorphism is dependent on peptide length, with a progressive increase in crystalline ordering upon increasing the number of [RF] pairs along the backbone. A dependence on length was also found for other observables, including critical aggregation concentrations, formation of chiral assemblies and half maximum inhibitory concentrations (IC). Whereas shorter peptides self-assemble into fractal-like aggregates, clear fibrillogenic capabilities are identified for longer sequences with octameric and decameric chains exhibiting crystalline phases organized into cross-β structures. Cell viability assays revealed dose-dependent cytotoxicity profiles with very similar behavior for both glioma and macrophage cell lines, which has been interpreted as evidence for a nonspecific mechanism involved in toxicity. We propose that structural organization of [RF] peptides plays a paramount role regarding toxicity due to strong increase of local charge density induced by self-assemblies rich in cationic groups when interacting with cell membranes.

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“…Moreover, VZV-infection of primary human spinal astrocytes induce an extracellular amyloidogenic environment 57 . Clinical studies reveal a deposition of amyloid-ß plaques in the brains of HIV-infected individuals 58 and infections by HSV cause not only elevated ß-amyloid production but also phosphorylation of Tau 59,60 . Thus, ß-amyloid might correspond to the first antiviral defence strategy in the extracellular matrix targeting the viral particle and lowering its infection potential (Figure 5).…”

Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein causes fusion of promyelocytic leukemia nuclear bodies in human hippocampal areas with high plaque load

Marks

Heinen

Bachmann

et al. 2020

Preprint

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The amyloid precursor protein (APP) is a type I transmembrane protein with unknown physiological function but potential impact in neurodegeneration. The current study demonstrates that APP signals to the nucleus causing the generation of aggregates comprising its adapter protein FE65 and the tumour suppressor proteins p53 and PML. The PML nuclear body generation, known to be of relevance in virus defence and cell division, is induced and fusion occurs over time depending on APP signalling. We further show that the nuclear aggregates of APP C-terminal (APP-CT) fragments together with PML and FE65 are present in the aged human brain but not in cerebral organoids differentiated from iPS cells.Notably, human Alzheimer's disease brains reveal a highly significant loss of these nuclear aggregates in areas with high plaque load compared to plaque-free areas of the same individual. Based on these results we conclude that APP-CT signalling to the nucleus takes DPBS (Gibco) and fixed in 4 % paraformaldehyde in PBS. Cover glasses were mounted with the Shandon™ Immu-Mount™ solution (Thermo Scientific) on glass slides and dried overnight at RT. For immunofluorescence staining, HEK293T cells were seeded in 8-well-µslide-ibi Treat (ibidi ® , Martinsried, Germany) and transfected using calcium phosphate transfection after 24 h. Cells were fixed with Roti ® -Histofix 4 % (4 % phosphate buffered formaldehyde solution; Roth, Karlsruhe, DE) for 20 min at 37 °C, and permeabilized and blocked with 5 % normal goat serum (NGS) in 0.3 % (w/v) Triton X-100/PBS for 30 min at RT. The cells were incubated with primary antibodies diluted in 1 % BSA/0.3 % Triton X-100/DPBS (mouse anti-HA (BioLegend, 901501; 1:1000), mouse anti-myc (NEB/Cell Signaling, 2276; 1:1500) o/n at 4 °C. For the secondary antibody staining and the cell staining, goat-anti-mouse AF568 (Invitrogen, A11004, 1:1000) was used, together with HCS CellMask™ Deep Red Stain (ThermoFisher Scientific, H32721, 1:5000), Hoechst33342 (10 mg/ml in H2O, Applichem, A0741, 1:1000) in DPBS (1 % BSA, 0.3 % Triton) and incubated for 1 h at RT.Immunoprecipitation HEK 293T cells were seeded in 10 cm dishes and co-transfection was performed 24 h after seeding. Whole cell extracts were prepared 24 h after transfection by scraping the cells from the dish with a cell scraper, washing the cell pellet in ice-cold PBS, extracting with 1 ml interaction buffer (50 mM Tris pH 8, 150 mM NaCl, 5 mM EDTA, 0.5% NP40, 1 mM DTT, 1 mM PMSF, 1x complete protease inhibitor cocktail), followed by sonication (15 s at 95 % amplitude) using a Sonopuls mini20 device (Bandelin, Berlin, Germany). The lysates were centrifuged (15,000 g, 15 min, 4 °C) and the supernatant was transferred to a new reaction tube. Input samples of the lysates were stored separately. Immunoprecipitation (IP) was carried out with the µMACS isolation kits for tagged proteins from Miltenyi Biotec (Bergisch-Gladbach, Germany). The eluates, as well as input samples of the lysates were subjected to SDS-PAGE and immunoblotting.

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HIV Tat protein and amyloid-β peptide form multifibrillar structures that cause neurotoxicity

Cited by 77 publications

References 73 publications

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

Sequence length dependence in arginine/phenylalanine oligopeptides: Implications for self-assembly and cytotoxicity

Amyloid precursor protein causes fusion of promyelocytic leukemia nuclear bodies in human hippocampal areas with high plaque load

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