Synergistic interactions between repeats in tau protein and Aβ amyloids may be responsible for accelerated aggregation via polymorphic states

Amyloid plaques and neurofibrillary tangles simultaneously accumulate in Alzheimer's disease (AD). It is known that Aβ and tau exist together in the mitochondria; however, the interactions between Aβ oligomers and tau are controversial. Moreover, it is still unclear which specific domains in the tau protein can interact with Aβ oligomers and what could be the effect of these interactions. Herein, we examine three different Aβ-tau oligomeric complexes. These complexes present interactions of Aβ with three domains in the tau protein; all contain high β-structure propensity in their R2, R3, and R4 repeats. Our results show that, among these, Aβ oligomers are likely to interact with the R2 domain to form a stable complex with better alignment in the turn region and the β-structure domain. We therefore propose that the R2 domain can interact with soluble Aβ oligomers and consequently promote aggregation. EM and AFM images and dimensions revealed highly polymorphic tau aggregates. We suggest that the polymorphic tau and Aβ-tau aggregates may be largely due to repeat sequences which are prone to variable turn locations along the tau repeats.     

Transmission of pathogenic protein aggregates in Alzheimer’s disease

Deposits of amyloid peptide Aβ and intracellular aggregates of hyperphosphorylated tau protein in the brain of patients are major neuropathological features of Alzheimer’s disease (AD). For a long time, the possibility of horizontal transmission of Aβ aggregates from cell to cell and from person to person remained hypothetical, since there was no experimental evidence. However, in 1993, the formation of senile plaques was confirmed in the brains of animals after intracerebral injections of AD patient brain homogenates. or homogenates of the brain of transgenic mice enriched with Aβ aggregates Other experiments indicate that amyloid peptide Aβ and intracellular aggregates of hyperphosphorylated tau protein may be transferred from cell to cell like prions. In 2015 and 2016, it was reported that AD could be transmitted to humans during medical procedures, i.e., that this disease might be iatrogenic. This review discusses the mechanisms by which pathogenic Aβ protein can be transmitted between cells and analyzes the current evidence concerning the possibility of horizontal Aβ transmission from person to person.     

Neuroprotective activity and evaluation of Hsp90 inhibitors in an immortalized neuronal cell line

Alzheimer’s disease (AD) neuropathology is characterized by loss of synapses and neurons, neuritic plaques consisting of β-amyloid (Aβ) peptides, and neurofibrillary tangles consisting of intracellular aggregates of hyperphosphorylated tau protein in susceptible brain regions. Aβ oligomers trigger a cascade of pathogenic events including tau hyperphosphorylation and aggregation, inflammatory reactions, and excitotoxicity that contribute to the progression of AD. The molecular chaperone Hsp90 facilitates the folding of newly synthesized and denatured proteins and is believed to play a role in neurodegenerative disorders in which the defining pathology results in misfolded proteins and the accumulation of protein aggregates. Some agents that inhibit Hsp90 protect neurons against Aβ toxicity and tau aggregation, and assays for rapidly screening potential Hsp90 inhibitors are of interest. We used the release of the soluble cytosolic enzyme lactate dehydrogenase (LDH) as an indicator of the loss of cell membrane integrity and cytotoxicity resulting from exposure to Aβ peptides to evaluate the neuroprotective properties of novel novobiocin analogues and established Hsp90 inhibitors. Compounds were assessed for potency in protecting proliferating and differentiated SH-SY5Y neuronal cells against Aβ-induced cell death; the potential toxicity of each agent alone was also determined. The data indicated that several of the compounds decreased Aβ toxicity even at low nanomolar concentrations and, unexpectedly, were more potent in protecting the undifferentiated cells against Aβ. The novobiocin analogues alone were not toxic even up to 10 μM concentrations whereas GDA and the parent compound, novobiocin, were toxic at 1 and 10 μM, respectively. The results suggest that novobiocin analogues may provide novel leads for the development of neuroprotective drugs.     

Effect of metal chelators on the aggregation of beta-amyloid peptides in the presence of copper and iron

Amyloid β (Aβ) fibrils and amorphous aggregates are found in the brain of patients with Alzheimer’s disease (AD), and are implicated in the etiology of AD. The metal imbalance is also among leading causes of AD, owing to the fact that Aβ aggregation takes place in the synaptic cleft where Aβ, Cu(II) and Fe(III) are found in abnormally high concentrations. Aβ40 and Aβ42 are the main components of plaques found in afflicted brains. Coordination of Cu(II) and Fe(III) ions to Aβ peptides have been linked to Aβ aggregation and production of reactive oxygen species, two key events in the development of AD pathology. Metal chelation was proposed as a therapy for AD on the basis that it might prevent Aβ aggregation. In this work, we first examined the formation of Aβ40 and Aβ42 aggregates in the presence of metal ions, i.e. Fe(III) and Cu(II), which were detected by fluorescence spectroscopy and atomic force microscopy. Second, we studied the ability of the two chelators, ethylenediaminetetraacetic acid and 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol), to investigate their effect on the availability of these metal ions to interact with Aβ and thereby their effect on Aβ accumulation. Our findings show that Fe(III), but not Cu(II), promote aggregation of both Aβ40 and Aβ42. We also found that only clioquinol decreased significantly iron ion-induced aggregation of Aβ42. The presence of ions and/or chelators also affected the morphology of Aβ aggregates.     

The effect of terminal groups and halogenation of KLVFF peptide on its activity as an inhibitor of β‐amyloid aggregation

The aggregation of Aβ peptide into amyloid fibrils in the brain is associated with Alzheimer's disease (AD). Inhibition of Aβ aggregation seemed a potential treatment for AD. It was previously shown that a short fragment of Aβ peptide (KLVFF, 16‐20) bound Aβ inhibited its aggregation. In this work, using KLVFF peptide, we synthesized two peptide families and then evaluated their inhibitory capacities by conventional assays such as thioflavin T (ThT) fluorescence spectroscopy, turbidity measurement, and the 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium (MTS). The effect of peptide terminal groups on its inhibitory activity was first studied. Subsequently, the influence of halogenated amino acids on peptide anti‐aggregation properties was investigated. We found that iodinated peptide with amine in the N and amide in the C termini, respectively, was the best inhibitor of Aβ fibers formation. Halogenated peptides seemed to decrease the number of Aβ fibrils; however, they did not reduce Aβ cytotoxicity. The data obtained in this work seemed promising in developing potential peptide drugs for treatment of AD.     

Isolation of synaptic terminals from Alzheimer's disease cortex

Amyloid beta (Aβ) oligomers and phosphorylated tau (p-tau) aggregates are increasingly identified as potential toxic intermediates in Alzheimer's disease (AD). In cortical AD synapses, p-tau co-localizes with Aβ, but the Aβ and p-tau peptide species responsible for synaptic dysfunction and demise remains unclear. The present experiments were designed to use high-speed cell sorting techniques to purify synaptosome population based on size, and then extend the method to physically isolate Aβ-positive synaptosomes with the goal of understanding the nature of Aβ and tau pathology in AD synapses. To examine the purity of size-gated synaptosomes, samples were first gated on size; particles with sizes between 0.5 and 1.5 microns were collected. Electron microscopy documented a homogenous population of spherical particles with internal vesicles and synaptic densities. Next, size-gated synaptosomes positive for Aβ were collected by fluorescence activated sorting and then analyzed by immunoblotting techniques. Sorted Aβ-positive synaptosomes were enriched for amyloid precursor protein (APP) and for Aβ oligomers and aggregates; immunolabeling for p-tau showed a striking accumulation of p-tau aggregates compared to the original homogenate and purified synaptosomes. These results confirm co-localization of Aβ and p-tau within individual synaptic terminals and provide proof of concept for the utility of flow sorting synaptosomes.     

The Gαq/phospholipase Cβ signaling system represses tau aggregation

Alzheimer's disease is typified by calcium dysfunction and neurofibrillary tangles of tau aggregates along with mitotic proteins. Using PC12 cells as a model system, we determined whether the Gαq/PLCβ/ calcium signaling pathway impacts the manifestation of Alzheimer's disease. Down-regulating PLCβ significantly increases tau protein expression and causes a large increase in tau aggregation. Stimulating Gαq to activate PLCβ results in a modest reduction in tau aggregation while inhibiting PLCβ activity results in a modest enhancement of tau aggregation. These results suggest that PLCβ may effect tau aggregation by an additional mechanism that is independent of its ability to transduce calcium signals. To this end, we found that a cytosolic population of PLCβ binds to a mitotic protein found in neurofibrillary tangles, CDK18, which promotes tau phosphorylation and aggregation. Taken together, our studies show that the loss of PLCβ1 can promote Alzheimer's disease by a combination of its catalytic activity and its interaction with mitotic proteins thus offering an orthogonal method to control tau aggregation.     

Dityrosine Cross-links are Present in Alzheimer’s Disease-derived Tau Oligomers and Paired Helical Filaments (PHF) which Promotes the Stability of the PHF-core Tau (297–391) In Vitro

A characteristic hallmark of Alzheimer’s Disease (AD) is the pathological aggregation and deposition of tau into paired helical filaments (PHF) in neurofibrillary tangles (NFTs). Oxidative stress is an early event during AD pathogenesis and is associated with tau-mediated AD pathology. Oxidative environments can result in the formation of covalent dityrosine crosslinks that can increase protein stability and insolubility. Dityrosine cross-linking has been shown in Aβ plaques in AD and α-synuclein aggregates in Lewy bodies in ex vivo tissue sections, and this modification may increase the insolubility of these aggregates and their resistance to degradation. Using the PHF-core tau fragment (residues 297 – 391) as a model, we have previously demonstrated that dityrosine formation traps tau assemblies to reduce further elongation. However, it is unknown whether dityrosine crosslinks are found in tau deposits in vivo in AD and its relevance to disease mechanism is unclear. Here, using transmission electron microscope (TEM) double immunogold-labelling, we reveal that neurofibrillary NFTs in AD are heavily decorated with dityrosine crosslinks alongside tau. Single immunogold-labelling TEM and fluorescence spectroscopy revealed the presence of dityrosine on AD brain-derived tau oligomers and fibrils. Using the tau (297–391) PHF-core fragment as a model, we further showed that prefibrillar tau species are more amenable to dityrosine crosslinking than tau fibrils. Dityrosine formation results in heat and SDS stability of oxidised prefibrillar and fibrillar tau assemblies. This finding has implications for understanding the mechanism governing the insolubility and toxicity of tau assemblies in vivo.     

Tissue Transglutaminase and Its Product Isopeptide Are Increased in Alzheimer’s Disease and APPswe/PS1dE9 Double Transgenic Mice Brains

Alzheimer’s disease (AD) is characterized by intracellular and extracellular protein aggregates, including microtubule-associated protein tau and cleavage product of amyloid precursor protein, β-amyloid (Aβ). Tissue transglutaminase (tTG) is a calcium-dependent enzyme that cross-links proteins forming a γ-glutamyl-ε-lysine isopeptide bond. Highly resistant to proteolysis, this bond can induce protein aggregation and deposition. We set out to determine if tTG may play a role in pathogenesis of AD. Previous studies have shown that tTG and isopeptide are increased in advanced AD, but they have not addressed if this is an early or late feature of AD. In the present study, we measured tTG expression levels and enzyme activity in the brains of individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD, as well as a transgenic mouse model of AD. We found that both enzyme expression and activity were increased in MCI as well as AD compared to NCI. In the transgenic model of AD, tTG expression and enzyme activity increased sharply with age and were relatively specific for the hippocampus. We also assessed overlap of isopeptide immunoreactivity with neurodegeneration-related proteins with Western blots and found neurofilament, tau, and Aβ showed co-localization with isopeptide in both AD and transgenic mice. These results suggest that tTG might be a key factor in pathogenesis of abnormal protein aggregation in AD.     

Retracted: S14G‐humanin inhibits Aβ1–42 fibril formation,disaggregates preformed fibrils,and protects against Aβ‐induced cytotoxicity in vitro

The aggregation of soluble amyloid‐beta (Aβ) peptide into oligomers/fibrils is one of the key pathological features in Alzheimer's disease (AD). The Aβ aggregates are considered to play a pivotal role in the pathogenesis of AD. Therefore, inhibiting Aβ aggregation and destabilizing preformed Aβ fibrils would be an attractive therapeutic target for prevention and treatment of AD. S14G‐humanin (HNG), a synthetic derivative of Humanin (HN), has been shown to be a strong neuroprotective agent against various AD‐related insults. Recent studies have shown that HNG can significantly improve cognitive deficits and reduce insoluble Aβ levels as well as amyloid plaque burden without affecting amyloid precursor protein processing and Aβ production in transgenic AD models. However, the potential mechanisms by which HNG reduces Aβ‐related pathology in vivo remain obscure. In the present study, we found that HNG could significantly inhibit monomeric Aβ1–42 aggregation into fibrils and destabilize preformed Aβ1–42 fibrils in a concentration‐dependent manner by Thioflavin T fluorescence assay. In transmission electron microscope study, we observed that HNG was effective in inhibiting Aβ1–42 fibril formation and disrupting preformed Aβ1–42 fibrils, exhibiting various types of amorphous aggregates without identifiable Aβ fibrils. Furthermore, HNG‐treated monomeric or fibrillar Aβ1–42 was found to significantly reduce Aβ1–42‐mediated cytotoxic effects on PC12 cells in a dose‐dependent manner by MTT assay. Collectively, our results demonstrate for the first time that HNG not only inhibits Aβ1–42 fibril formation but also disaggregates preformed Aβ1–42 fibrils, which provides the novel evidence that HNG may have anti‐Aβ aggregation and fibrillogenesis, and fibril‐destabilizing properties. Together with previous studies, we concluded that HNG may have promising therapeutic potential as a multitarget agent for the prevention and/or treatment of AD. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.     

Different tau epitopes define Abeta42-mediated tau insolubility

Alzheimer's disease (AD) is characterized by extracellular beta-amyloid (Abeta(42))-containing plaques and intracellular neurofibrillary tangles. The latter are composed of hyperphosphorylated filamentous aggregates of the microtubule-associated protein tau. Previously we demonstrated pathological interactions between these two histopathological hallmarks using human SH-SY5Y neuroblastoma cells overexpressing wild-type and mutant forms of human tau. Exposure to pre-aggregated forms of Abeta(42) caused both the formation of AD-like tau-containing filaments and a decreased solubility of tau, both of which were prevented by mutating the S422 phospho-epitope of tau. Here, we expressed additional tau mutants in SH-SY5Y cells to assess the role of phosphorylation and cleavage sites of tau in tau aggregation. We found that the Abeta(42)-mediated decrease in tau solubility depends on the interplay of distinct phospho-epitopes of tau and not only on phosphorylation of the S422 epitope.     

Characterization of Aβ aggregation mechanism probed by congo red

β-Amyloid peptide (1) (Aβ) aggregates are toxic to neuron and the main cause of Alzheimer's disease (AD). The role of congo red (CR) on Aβ aggregation is controversial in aqueous solution. Both prevention and promotion of Aβ aggregation have been proposed, suggesting that CR may interact with Aβ of different structural conformations resulting in different effects on Aβ aggregation behavior. CR with these characteristics can be applied to probe the molecular mechanism of Aβ aggregation. Therefore, in the present study, we used CR as a probe to study the Aβ aggregation behavior in sodium dodecyl sulfate (SDS) condition. Our results show that Aβ(40) adopts two short helices at Q15-S26 and K28-L34 in the SDS environment. CR can interact with the helical form of Aβ(40), and the main interaction site is located at the first helical and hydrophobic core region, residues 17-25, which is assigned as a discordant helix region. Furthermore, CR may prevent Aβ(40) undergoing α-helix to β-strand conversion, and therefore aggregation through stabilizing the helical conformation of discordant helix in SDS environment, suggesting that the discordant helix plays a key role on the conformational stabilization of Aβ. Our present study implies that any factors or molecules that can stabilize the discordant helical conformation may also prevent the Aβ aggregation in membrane associated state. This leads to a new therapeutic strategy for the development of lead compounds to AD.     

Modulating amyloid-β aggregation: The effects of peptoid side chain placement and chirality

Alzheimer’s disease (AD) is characterized by the buildup of insoluble aggregated amyloid-β protein (Aβ) into plaques that accumulate between the neural cells in the brain. AD is the sixth leading cause of death in the United States and is the only cause of death among the top ten that cannot currently be treated or cured (Alzheimer’s Association, 2011; Selkoe, 1996). Researchers have focused on developing small molecules and peptides to prevent Aβ aggregation; however, while some compounds appear promising in vitro, the research has not resulted in a viable therapeutic treatment. We previously reported a peptoid-based mimic (JPT1) of the peptide KLVFF (residues 16–20 of Aβ) that modulates Aβ40 aggregation, specifically reducing the total number of fibrillar, β-sheet structured aggregates formed. In this study, we investigate two new variants of JPT1 that probe the importance of aromatic side chain placement (JPT1s) and side chain chirality (JPT1a). Both JPT1s and JPT1a modulate Aβ40 aggregation by reducing total β-sheet aggregates. However, JPT1a also has a pronounced effect on the morphology of fibrillar Aβ40 aggregates. These results suggest that Aβ40 aggregation may follow a different pathway in the presence of peptoids with different secondary structures. A better understanding of the interactions between peptoids and Aβ will allow for improved design of AD treatments.     

Comprehensive analysis of the molecular docking of small molecule inhibitors to the Aβ1–40 peptide and its Osaka-mutant: insights into the molecular mechanisms of Aβ-peptide inhibition

Abstract

Alzheimer’s disease (AD) is the most common form of age-related neurodegeneration occurs because of deposition of proteins in the form of extracellular plaques containing aggregated amyloid beta (Aβ) peptide and intracellular neurofibrillary tangles composed of aggregated microtubule-binding protein tau. Amyloid aggregation process can be enhanced by several familial AD-associated mutations in Aβ peptide. In this study, we have unravelled the interactions of 40 small molecule inhibitors with the Osaka-mutant of Aβ_1–40 peptide at atomic level and characterized modes of their binding to mutant Aβ by docking approaches. We have also compared docking energies of these inhibitors with Osaka-mutant with those previously determined for the wild-type and Iowa-mutant peptides and discussed in light of the peptide conformations and non-covalent interactions. We have also discussed inhibition mechanisms of these three peptides. Our analyses revealed that these small molecules can efficiently inhibit Osaka-mutant. The binding modes of drugs with these three peptides are markedly different and so are the mechanisms of inhibition of these three peptides. Overall analysis of the data reveals that binding energy of Iowa-mutant drug complex is lowest and most stable which is followed wild-type peptide-drug complex followed by Osaka-mutant drug complex.

Communicated by Ramaswamy H. Sarma     

Impact of phospholipid bilayer saturation on amyloid-β protein aggregation intermediate growth: A quartz crystal microbalance analysis

Evidence that membrane-associated amyloid aggregate growth can impart membrane damage represents one possible mechanism for the neurodegeneration associated with deposited amyloid-β protein (Aβ) aggregates in the brains of Alzheimer’s disease (AD) patients. This potential pathogenic event necessitates an understanding of the impact that cellular membrane composition may have on Aβ aggregate growth. In the current study, a quartz crystal microbalance (QCM) was employed to examine the growth of Aβ_1-40 aggregation intermediates on supported phospholipid bilayers (SPBs) assembled at the crystal surface. These surface-specific measurements illustrate that zwitterionic SPBs selectively bind aggregated but not monomeric protein, and these bound aggregates are capable of supporting nonsaturable reversible growth via monomer addition. Growth-capable Aβ_1-40 aggregation intermediates more readily bind SPBs composed of phospholipids with a greater degree of carbon saturation. Furthermore, kinetic analysis afforded by the quantitative real-time QCM measurements reveals that SPBs with greater saturation also better support the growth of bound Aβ_1-40 aggregation intermediates as a result of the slower dissociation of bound monomer rather than more efficient recognition between aggregate and monomeric protein. These findings correlate with epidemiological and experimental evidence that links increased dietary intake of polyunsaturated fatty acids to a reduced risk of AD.     

Granular tau oligomers as intermediates of tau filaments

Neurofibrillary tangles (NFTs) are pathological hallmarks of several neurodegenerative disorders, including Alzheimer's disease (AD). NFTs are composed of microtubule-binding protein tau, which assembles to form paired helical filaments (PHFs) and straight filaments. Here we show by atomic force microscopy that AD brain tissue and in vitro tau form granular and fibrillar tau aggregates. CD spectral analysis and immunostaining with conformation-dependent antibodies indicated that tau may undergo conformational changes during fibril formation. Enriched granules generated filaments, suggesting that granular tau aggregates may be an intermediate form of tau fibrils. The amount of granular tau aggregates was elevated in prefrontal cortex of Braak stage I cases compared to that of Braak stage 0 cases, suggesting that granular tau aggregation precedes PHF formation. Thus, granular tau aggregates may be a relevant marker for the early diagnosis of tauopathy. Reducing the level of these aggregates may be a promising therapy for tauopathies and for promoting healthy brain aging.     

Aluminum, copper, iron and zinc differentially alter amyloid-Aβ(1-42) aggregation and toxicity

Amyloid-β(1-42) (Aβ) is believed to play a crucial role in the ethiopathogenesis of Alzheimer's Disease (AD). In particular, its interactions with biologically relevant metal ions may lead to the formation of highly neurotoxic complexes. Here we describe the species that are formed upon reacting Aβ with several biometals, namely copper, zinc, iron, and with non-physiological aluminum to assess whether different metal ions are able to differently drive Aβ aggregation. The nature of the resulting Aβ-metal complexes and of the respective aggregates was ascertained through a number of biophysical techniques, including electrospray ionization mass spectrometry, dynamic light scattering, fluorescence, transmission electron microscopy and by the use of conformation-sensitive antibodies (OC, αAPF). Metal binding to Aβ is shown to confer highly different chemical properties to the resulting complexes; accordingly, their overall aggregation behaviour was deeply modified. Both aluminum(III) and iron(III) ions were found to induce peculiar aggregation properties, ultimately leading to the formation of annular protofibrils and of fibrillar oligomers. Notably, only Aβ-aluminum was characterized by the presence of a relevant percentage of aggregates with a mean radius slightly smaller than 30 nm. In contrast, both zinc(II) and copper(II) ions completely prevented the formation of soluble fibrillary aggregates. The biological effects of the various Aβ-metal complexes were studied in neuroblastoma cell cultures: Aβ-aluminum turned out to be the only species capable of triggering amyloid precursor and tau181 protein overproduction. Our results point out that Al can effectively interact with Aβ, forming "structured" aggregates with peculiar biophysical properties which are associated with a high neurotoxicity.     

A novel peptide derived from vascular endothelial growth factor prevents amyloid beta aggregation and toxicity

Amyloid-β oligomers (Aβo) are the most pathologically relevant Aβ species in Alzheimer's disease (AD), because they induce early synaptic dysfunction that leads to learning and memory impairments. In contrast, increasing VEGF (Vascular Endothelial Growth Factor) brain levels have been shown to improve learning and memory processes, and to alleviate Aβ-mediated synapse dysfunction. Here, we designed a new peptide, the blocking peptide (BP), which is derived from an Aβo-targeted domain of the VEGF protein, and investigated its effect on Aβ-associated toxicity. Using a combination of biochemical, 3D and ultrastructural imaging, and electrophysiological approaches, we demonstrated that BP strongly interacts with Aβo and blocks Aβ fibrillar aggregation process, leading to the formation of Aβ amorphous aggregates. BP further impedes the formation of structured Aβo and prevents their pathogenic binding to synapses. Importantly, acute BP treatment successfully rescues long-term potentiation (LTP) in the APP/PS1 mouse model of AD, at an age when LTP is highly impaired in hippocampal slices. Moreover, BP is also able to block the interaction between Aβo and VEGF, which suggests a dual mechanism aimed at both trapping Aβo and releasing VEGF to alleviate Aβo-induced synaptic damage. Our findings provide evidence for a neutralizing effect of the BP on Aβ aggregation process and pathogenic action, highlighting a potential new therapeutic strategy.     

Tau oligomers mediate aggregation of RNA‐binding proteins Musashi1 and Musashi2 inducing Lamin alteration

The exact mechanisms leading to neurodegeneration in Alzheimer's disease (AD) and other tauopathies are not yet entirely understood. However, it is known that several RNA‐binding proteins (RBPs) form toxic aggregates and also interact with tau in such granules in tauopathies, including AD. The Musashi (MSI) family of RBPs, consisting of two homologues: Musashi1 and Musashi2, have not been extensively investigated in neurodegenerative diseases. Here, using a tau inducible HEK (iHEK) model we investigate whether MSI proteins contribute to the aggregation of toxic tau oligomers (TauO). Wild‐type and mutant P301L tau iHEK cells are used to study the effect of different tau variants on the cellular localization of MSI proteins. Interestingly, we observe that tau co‐localizes with MSI in the cytoplasm and nuclei, altering the nuclear transport of MSI. Furthermore, incremental changes in the size and density of nuclear MSI/tau foci are observed. We also report here that TauO interact with MSI to cause the formation of distinct nuclear aggregates. Moreover, tau/MSI aggregates induce structural changes to LaminB1, leading to nuclear instability. These results illustrate a possible mechanism of neurodegeneration mediated by the aggregation of MSI proteins and TauO, suggesting that MSI plays a critical role in cellular dysfunction.     

Practical assay and molecular mechanism of aggregation inhibitors of beta-amyloid.

Beta-Amyloid peptide (Abeta) is the main protein component of neuritic plaques in the brain of patients of Alzheimer's disease (AD), and its neurotoxicity would be exposed by the formation of aggregates. The aggregation inhibitors composed of an Abeta recognition element (KLVFF) and a hydrophilic moiety are evaluated by a novel fluorescence assay. These compounds inhibit growth of the model aggregates on the KLVFF immobilized surface. In addition, some compounds also possess disrupting activities of preformed aggregates. These compounds could be a key candidate for therapeutic drugs for AD by their novel molecular mechanisms.