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Results for “Protein Aggregation, Pathological”

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PubMedDate not supplied

Molecular pathology of dityrosine cross-links in proteins: structural and functional analysis of four proteins.

The dityrosine bond (DT) is an oxidative covalent cross-link between two tyrosines. DT cross-linking is increasingly identified as a marker of oxidative stress, aging and disease, and has been detected in diverse pathologies. While DT cross- linked proteins have been documented, the consequences of the DT link on the structure and function of the so modified proteins are yet to be understood. With this in view, we have studied the properties of intermolecular DT-dimers of four proteins of diverse functions, namely the enzyme ribonuclease A, the signal protein calmodulin, and the eye lens proteins alpha- and gamma B-crystallins. We find that DT is formed through radical reactions and type I photosensitization (including .OH, O2- and OONO-), but not by 1O2 and NO, (which modify his, trp and met more readily). Tyr residues on the surface of the protein make DT bonds (intra- and intermolecular) most readily and preferentially. The conformation of each of these DT-dimers, monitored by spectroscopy, is seen not to be significantly altered in comparison to that of the parent monomer, but the structural stability of the DT cross-linked molecule is lower than that of the parent native monomer. The DT-dimer is denatured at a lower temperature, and at lower concentrations of urea or guanidinium chloride. The effect of DT-cross-linking on the biological activities of these proteins was next studied. The enzymatic activity of the DT-dimer of ribonuclease A is not lost but lowered. DT-dimerization of lens alpha-crystallin did not significantly affect the chaperone-like ability; it inhibits the self-aggregation and precipitation of target proteins just as well as the parent, unmodified alpha-crystallin does. DT-dimerization of gamma B-crystallin is however seen to lead to more ready aggregation and precipitation, a point of interest in cataract. In the case of calmodulin, we could generate both intermolecular and intramolecular DT cross-linking, and study both the DT-dimer and DT-monomer. The DT-dimer binds smooth muscle light chain kinase and also Ca2+, but less efficiently and over a broad concentration range than the native monomer. The intramolecular DT-monomer is weaker in all these respects, presumably since it is structurally more constrained. These results suggest that DT cross-linking of globular proteins weakens their structural stability and compromises (though does not abolish) their biological activity, both of which are pathologically relevant. The intramolecular DT cross-link would appear to lead to more severe structural and functional consequences.

Animals↗

PubMed1985

The origin of the very variable haemolytic activities of the common human complement component C4 allotypes including C4-A6.

The human complement component C4 occurs in many different forms which show big differences in their haemolytic activities. This phenomenon seems likely to be of considerable importance both physiologically and pathologically. C4 is coded by duplicated genes between HLA-D and HLA-B loci in the major histocompatibility complex in man. Several fold differences in haemolytic activity between products of the two loci C4-A and C4-B have been correlated with changes of six amino acid residues in this large protein of 1722 residues and with differences of several fold in the covalent binding of C4 to antibody-antigen aggregates. Some allotypes of one locus also differ markedly, notably C4-A6 which has 1/10th the haemolytic activity of other C4-A allotypes. A monoclonal antibody affinity column has been prepared which is able to separate C4-A from C4-B proteins and, using serum from an individual expressing only the C4-A6 allele at the C4-A locus, C4-A6 protein has been prepared. Investigation has shown C4-A6 to have the same reactivity as other C4-A allotypes except in the formation of the complex protease, C5 convertase. This protease is formed from C4, C2 and C3 and if C4-A6 is used it has approximately 1/5th the catalytic activity compared with other C4-A allotype. Allelic differences in sequence identified in C4 proteins so far are few and it is probable that the big difference in catalytic activity of C5 convertase is caused by very small changes in structure.

Alleles↗

PubMedDate not supplied

1992 ALZA Distinguished Lecture: bioengineering and vascular biology.

The vascular system is naturally dynamic; fluid mechanics and mass transfer are closely integrated with blood and vascular cell function. We are beginning to understand how local wall shear stress and strain modulate endothelial cell metabolism at the gene level. This knowledge may help explain the focal nature of many vascular pathologies, including atherosclerosis. Understanding mechanical control of gene regulation at the level of specific promoter elements and transcription factors involved will lead to development of novel constructs for localized delivery of specific gene products in regions of high or low shear stress or strain in the vascular system. In addition, recent research has shown how local fluid mechanics can alter receptor specificity in cell-to-cell and cell-to-matrix protein adhesion and aggregation. Knowledge of the specific molecular sequences involved in cell-to-cell recognition will allow development of targeted therapeutics, with applications in thrombosis, inflammation, cancer metastasis, and sickle-cell anemia. Bioengineers are uniquely qualified to be leaders in this field, because advances require a synthesis of cell and molecular biology with systems analysis, transport phenomena, and quantitative modeling. Rapid progress in tissue engineering applications will require this new kind of biomedical engineer, which represents both a challenge and an opportunity for our profession.

Biomedical Engineering↗

PubMed2004

Are phospholipid-binding antibodies implicated in the pathogenesis of diabetic microangiopathy?

Diabetic retinopathy (DR) is a major cause of blindness in the working population of the Western world and there is no doubt that its prevalence is strongly related to the duration of diabetes and the glycemic control. However, although intensive diabetes management, with the goal of achieving near-normal glycemia, has been shown to prevent and/or delay the onset of DR, there is now ample of evidence that the development of this microangiopathy is a multifactorial process in which genetic, metabolic, haemostatic and growth factors play an important role. Moreover, given the suggestions that immunological mechanisms might have a role in the pathogenesis of diabetic microangiopathy via immune complex deposition, it has been hypothesized that antiphospholipid antibodies (A-Ab) directed against endothelial antigens could be responsible for initiating vascular injury. In particular, not only A-Ab production was found to be increased in patients with overt nephropathy or macroangiopathy but also Lupus Anticoagulant positivity, representing an intersection point between immune and haemostatic alterations, has been highlighted as a potential and additional risk factor in the pathogenesis of microangiopathy in type 1 diabetics. Moreover, given the high levels of activated protein C, endothelin-1 and thrombo-modulin that have been observed in normo-albuminuric and uncomplicated patients, it has been concluded that the vascular endothelium shifts pathologically from an antithrombotic to a prothrombotic state even in the early phases of the disease. This condition was found to be more pronounced in subjects with anticardiolipin positivity and/or high circulating immune complexes concentrations, since they possess the ability not only to induce platelet activation and aggregation but also to activate the complement system via the classical pathway. Therefore, a potential synergism between generation of autoantibodies, haemostatic alterations and endothelial stress has been suggested, a stimulating hypothesis that needs further studies to be clarified in its complexity.

Antibodies, Antiphospholipid↗

PubMed2004

AATF protects neural cells against oxidative damage induced by amyloid beta-peptide.

Extensive loss of neurons and synapses in vulnerable regions of the brain is one of the most important pathological features of Alzheimer's disease (AD). Increased oxidative stress has been shown to contribute to the neurodegenerative process in AD. Aggregation of amyloid beta-peptide (Abeta) in amyloid plaques is one of the defining features of Alzheimer's disease. Indeed, Abeta has been shown to induce oxidative stress and apoptosis in many in vivo and in vitro models of AD. We now report that AATF (apoptosis-antagonizing transcription factor), a leucine zipper protein initially identified as an interaction partner of DAP like kinase (Dlk, a member of the pro-apoptotic Death-Associated Protein kinase family), is expressed in cortical neurons and in neural PC12 cells. Abeta induces alterations in AATF expression in cortical neurons. Inhibition of AATF induction sensitizes neurons to Abeta toxicity. Overexpression of AATF suppressed superoxide production, inhibited peroxynitrite formation and membrane lipid peroxidation, and protected against Abeta-induced apoptosis in PC12 cells. These results suggest that AATF is a novel neuroprotective factor and it may protect against Abeta-induced apoptosis through its effects on suppressing the production of reactive oxygen species (ROS). AATF may therefore represent a potential candidate for therapeutic intervention of neurodegeneration in both sporadic and familial forms of AD.

Amino Acid Sequence↗

PubMed1996

Can the mechanisms of aluminum neurotoxicity be integrated into a unified scheme?

Regardless of the host, the route of administration, or the speciation, aluminum is a potent neurotoxicant. In the young adult or developmentally mature host, the neuronal response to Al exposure can be dichotomized on morphological grounds. In one, intraneuronal neurofilamentous aggregates are formed, whereas in the other, significant neurochemical and neurophysiological perturbations are induced without neurofilamentous aggregate formation. Evidence is presented that the induction of neurofilamentous aggregates is a consequence of alterations in the posttranslational processing of neurofilament (NF), particularly with regard to phosphorylation state. Although Al has been reported to impact on gene expression, this does not appear to be critical to the induction of cytoskeletal pathology. In hosts responding to Al exposure without the induction of cytoskeletal pathology, impairments in glucose utilization, agonist-stimulated inositol phosphate accumulation, free radical-mediated cytotoxicity, lipid peroxidation, reduced cholinergic function, and altered protein phosphorylation have been described. The extent to which these neurochemical modifications correlate with the induction of a characteristic neurobehavioral state is unknown. In addition to these paradigms, Al is toxic in the immediate postnatal interval. Whether unique mechanisms of toxicity are involved during development remains to be determined. In this article, the mechanisms of Al neurotoxicity are reviewed and recommendations are put forth with regard to future research. Primary among these is the determination of the molecular site of Al toxicity, and whether this is based on Al substitution for divalent metals in a number of biological processes. Encompassed within this is the need to further understand the genesis of host- and developmental-specific responses.

Adult↗

PubMed2006

Treatment and prevention of the amyloidoses: can the lessons learned be applied to sporadic inclusion-body myositis?

The amyloid fibril represents a final common pathologic pathway for a variety of human proteins, all of which have a propensity to misfold. Each seems to require a predisposing event to realize its fibrillogenic potential. It may be mutation, inappropriate or incomplete cleavage, overproduction, or the availability of a template for misfolding. Therapies have been based on decreasing the stimulus (inflammation in the case of AA) reducing the number of producing cells (AL) and a variety of approaches to removing the extracellular aggregates. Sporadic inclusion-body myositis (sIBM), while physically resembling the extracellular amyloidoses, is an intracellular disease, hence imposes the additional requirement of developing a therapy that can access and function inside the affected or potentially affected, cell. Current approaches to the treatment of other forms of amyloidosis are discussed in the context of their applicability, or lack thereof, to sIBM.

Amyloid↗

PubMedDate not supplied

Peptide-based approaches to treat asthma, arthritis, other autoimmune diseases and pathologies of the central nervous system.

In this review we focus on peptide- and peptidomimetic-based approaches that target autoimmune diseases and some pathologies of the central nervous system. Special attention is given to asthma, allergic rhinitis, osteoarthritis, and Alzheimer's disease, but other related pathologies are also reviewed, although to a lesser degree. Among others, drugs like Diacerhein and its active form Rhein, Pralnacasan, Anakinra (Kineret), Omalizumab, an antibody "BION-1", directed against the common beta-chain of cytokine receptors, are described below as well as attempts to target beta-amyloid peptide aggregation. Parts of the review are also dedicated to targeting of pathologic conditions in the brain and in other tissues with peptides as well as methods to deliver larger molecules through the "blood--brain barrier" by exploring receptor-mediated transport, or elsewhere in the body by using peptides as carriers through cellular membranes. In addition to highlighting current developments in the field, we also propose, for future drug targets, the components of the inflammasome protein complex, which is believed to initiate the activation of caspase- 1 dependent signaling events, as well as other pathways that signal inflammation. Thus we discuss the possibility of targeting inflammasome components for negative or positive modulation of an inflammatory response.

Amyloid beta-Peptides↗

PubMed1997

Specific modulation of the fusogenic properties of the Alzheimer beta-amyloid peptide by apolipoprotein E isoforms.

C-terminal fragments of the Alzheimer amyloid peptide (amino acids 29-40 and 29-42) have physico-chemical properties related to those of the fusion peptides of viral proteins and they are able to induce the fusion of liposomes in vitro. We proposed that these properties could mediate a direct interaction of the amyloid peptide with cell membranes and account for part of the cytotoxicity of the amyloid peptide. In view of the epidemiologic and biochemical linkages between the pathology of Alzheimer's disease and apolipoprotein E (apoE) polymorphism, we examined the potential interaction between the three common apoE isoforms and the C-terminal fragments of the amyloid peptide. We show that, at low concentration, only apoE2 and apoE3 are potent inhibitors of the amyloid peptide fusogenic and aggregational properties, whereas the apoE4 isoform has no effect. We further show that the protective effect of apoE is mediated by the formation of stable apoE/amyloid peptide complexes, as determined by tryptophan emission fluorescence measurements and by gel electrophoresis. The interaction specificity between apoE2 and apoE3 and the amyloid fragments is demonstrated here, since other apolipoproteins (e.g. apolipoprotein A-I and A-II), with similar amphipathic structures, do not interact with the amyloid C-terminal fragments. Finally, we show that, reciprocally, the amyloid peptide can interact directly with the apoE2 and apoE3 isoforms to decrease or perturb their normal association with lipids. These data suggest that the 29-40 and 29-42 domains of the amyloid peptide could be critical for the amyloid-apoE interaction, and that apoE2 and apoE3 isoforms, but not apoE4, could play a protective role against the formation of amyloid aggregates and/or against their interaction with cellular membranes.

Amyloid beta-Peptides↗

PubMed2004

Disease progression despite early loss of polyglutamine protein expression in SCA7 mouse model.

Nine neurodegenerative diseases including Huntington's disease (HD) and spinocerebellar ataxia type 7 (SCA7) are caused by an expansion of a polyglutamine (polyQ) stretch in the respective proteins. Aggregation of expanded polyQ-containing proteins into the nucleus is a hallmark of these diseases. Recent evidence indicates that transcriptional dysregulation may contribute to the molecular pathogenesis of these diseases. Using SCA7 and HD mouse models in which we recently described a retinal phenotype, we investigated whether altered gene expression underlies photoreceptor dysfunction. In both models, rhodopsin promoter activity was early and dramatically repressed, suggesting that downregulation of photoreceptor-specific genes plays a major role in polyQ-induced retinal dysfunction. Because the rhodopsin promoter drives mutant ataxin-7 expression in our SCA7 mice, we also assessed whether downregulation of mutant SCA7 transgene would reverse retinopathy progression and aggregate formation. Although residual expression of mutant ataxin-7 was found negligible from 9 weeks of age, SCA7 transgenic mice showed a progressive decline of photoreceptor activity leading to a complete loss of electroretinographic responses from 1 year of age. At this age, aggregates were cleared in only half of the photoreceptors, indicating that their formation is not fully reversible in this model. We demonstrate here that abolishing full-length mutant ataxin-7 expression did not reverse retinopathy progression in SCA7 mice, raising the possibility that some polyQ-induced pathological events might be irreversible.

Age Factors↗

PubMed1993

Transglutaminase catalyzes the formation of sodium dodecyl sulfate-insoluble, Alz-50-reactive polymers of tau.

Paired helical filaments, a constituent of neurofibrillary tangles in Alzheimer's disease, consist primarily of the microtubule-associated protein tau. However, the process by which the detergent-insoluble filaments of the neurofibrillary tangles are formed from soluble tau remains unknown. Here, we present a potential mechanism for the abnormal aggregation of tau in Alzheimer's disease: the covalent cross-linking of tau by the enzyme transglutaminase. Macromolecular complexes of tau, formed in the presence of transglutaminase, were found to be insoluble in ionic detergent, beta-mercaptoethanol, guanidine-HCl, and urea and, furthermore, demonstrated an increased immunoreactivity with the monoclonal antibody Alz-50. Electron microscopic studies revealed that tau cross-linked by transglutaminase has a defined filamentous structure. These results indicate that transglutaminase, the activity of which has been shown to increase during programmed cell death, may play a role in the formation of pathology associated with Alzheimer's disease.

Animals↗

PubMed1996

Alterations in neural intermediate filament organization: functional implications and the induction of pathological changes related to motor neuron disease.

The properties regulating the supramolecular organization of neural intermediate filament (NIF) networks have been investigated in cultured dorsal root ganglion (DRG) neurons. The studies described take advantage of the ability of endogenous NIF to incorporate purified biotinylated neurofilament triplet (NFT) proteins, NF-L, NF-M and NF-H. When injected at concentrations of 0.8-1.0 mg/ml injection buffer, each of these proteins is incorporated without perturbing the endogenous NIF network. However, at progressively higher concentrations, NF-H induces the aggregation and accumulation of NIF in the cell body. Subsequent to the induction of these aggregates, numerous alterations in the cytoarchitecture of neurons can be detected. The latter occur in a temporal sequence which appears to begin with the fragmentation of the Golgi complex. At later times, accumulation of mitochondria within the proximal region of neurites, peripheralization of the nucleus, and a significant decrease in neurite caliber become obvious. After longer time periods, the NIF aggregates are seen to react with an antibody which reveals abnormally phosphorylated NF-H. These observations demonstrate that an imbalance in the normal stoichiometric relationships among the NFT proteins rapidly alters the supramolecular organization of the NIF network. These changes most likely reflect the normal functions of neurofilaments in cell shape and the organization and cytoplasmic distribution of membranous organelles. Interestingly, virtually all of these changes closely resemble those which have been reported in motor neuron diseases such as amyotrophic lateral sclerosis (ALS). These findings suggest that cultured neurons can be used as models for more precisely defining the relationships between the formation of NIF aggregates and the sequence of cytopathological events which typify neurodegenerative diseases.

Amyotrophic Lateral Sclerosis↗

PubMedDate not supplied

Towards Alzheimer's beta-amyloid vaccination.

Beta-amyloid pathology, the main hallmark of Alzheimer's disease (AD), has been linked to its conformational status and aggregation. We recently showed that site-directed monoclonal antibodies (mAbs) towards the N-terminal region of the human beta-amyloid peptide bind to preformed beta-amyloid fibrils (Abeta), leading to disaggregation and inhibition of their neurotoxic effect. Here we report the development of a novel immunization procedure to raise effective anti-aggregating amyloid beta-protein (AbetaP) antibodies, using as antigen filamentous phages displaying the only EFRH peptide found to be the epitope of these antibodies. Due to the high antigenicity of the phage no adjuvant is required to obtain high affinity anti-aggregating IgG antibodies in animals model, that exhibit identity to human AbetaP. Such antibodies are able to sequester peripheral AbetaP, thus avoiding passage through the blood brain barrier (BBB) and, as recently shown in a transgenic mouse model, to cross the BBB and dissolve already formed beta-amyloid plaques. To our knowledge, this is the first attempt to use as a vaccine a self-anti-aggregating epitope displayed on a phage, and this may pave the way to treat abnormal accumulation-peptide diseases, such as Alzheimer's disease or other amyloidogenic diseases.

Alzheimer Disease↗

PubMedDate not supplied

Endoplasmic reticulum: a primary target in various acute disorders and degenerative diseases of the brain.

Changes in neuronal calcium activity in the various subcellular compartments have divergent effects on affected cells. In the cytoplasm and mitochondria, where calcium activity is normally low, a prolonged excessive rise in free calcium levels is believed to be toxic, in the endoplasmic reticulum (ER), in contrast, calcium activity is relatively high and severe stress is caused by a depletion of ER calcium stores. Besides its role in cellular calcium signaling, the ER is the site where membrane and secretory proteins are folded and processed. These calcium-dependent processes are fundamental to normal cell functioning. Under conditions of ER dysfunction unfolded proteins accumulate in the ER lumen, a signal responsible for activation of the unfolded protein response (UPR) and the ER-associated degradation (ERAD). UPR is characterized by activation of two ER-resident kinases, PKR-like ER kinase (PERK) and IRE1. PERK induces phosphorylation of the eukaryotic initiation factor (eIF2alpha), resulting in a shut-down of translation at the initiation step. This stress response is needed to block new synthesis of proteins that cannot be correctly folded, and thus to protect cells from the effect of unfolded proteins which tend to form toxic aggregates. IRE1, on the other hand, is turned after activation into an endonuclease that cuts out a sequence of 26 bases from the coding region of xbp1 mRNA. Processed xbp1 mRNA is translated into the respective protein, an active transcription factor specific for ER stress genes such as grp78. In acute disorders and degenerative diseases, the ER calcium pool is a primary target of toxic metabolites or intermediates, such as oxygen free radicals, produced during the pathological process. Affected neurons need to activate the entire UPR to cope with the severe form of stress induced by ER dysfunction. This stress response is however hindered under conditions where protein synthesis is suppressed to such an extent that processed xbp1 mRNA is not translated into the processed XBP1 protein (XBP1(proc)). Furthermore, activation of ERAD is important for the degradation of unfolded proteins through the ubiquitin/proteasomal pathway, which is impaired in acute disorders and degenerative diseases, resulting in further ER stress. ER functioning is thus impaired in two different ways: first by the direct action of toxic intermediates, produced in the course of the pathological process, hindering vital ER reactions, and second by the inability of cells to fully activate UPR and ERAD, leaving them unable to withstand the severe form of stress induced by ER dysfunction.

Acute Disease↗

PubMed2003

Alzheimer's disease: the pharmacological pathway.

The current pharmacological treatment of Alzheimer's disease (AD) comes down to four marketed drugs (tacrine, donepezil, rivastigmine and galantamine) all of which are cholinesterase inhibitors, conforming to the cholinergic hypothesis. The future is clearly directed at new biological targets closely linked to the pathophysiology of the disease and more precisely, the pathological hallmark of AD which includes widespread neuronal degeneration, neuritic plaques containing beta-amyloid and tau-rich neurofibrillary tangles. For clinicians, this means that new curative drugs will have to be prescribed early in the course of the disease. This review describes the main entry pathways for drug discovery in AD: (1) supplementation therapy, (2) anti-apoptotic compounds, (3) substances with a mitochondrial impact, (4) anti-amyloid substances, (5) anti-protein aggregation and (6) lipid-lowering drugs. The rapidity at which these compounds will be at our disposal is highly dependent on the policy of the pharmaceutical companies.

Alzheimer Disease↗

PubMed1999

Biological activity and pathological implications of misfolded proteins.

The physiological metabolism of proteins guarantees that different cellular compartments contain the appropriate concentration of proteins to perform their biological functions and, after a variable period of wear and tear, mediates their natural catabolism. The equilibrium between protein synthesis and catabolism ensures an effective turnover, but hereditary or acquired abnormalities of protein structure can provoke a premature loss of biological function, an accelerated catabolism and diseases caused by the loss of an irreplaceable function. In certain proteins, abnormal structure and metabolism are associated with a strong tendency to self-aggregation into a polymeric fibrillar structure, and in these cases the disease is not principally caused by the loss of an irreplaceable function but by the action of this new biological entity. Amyloid fibrils are an apparently inert, insoluble, mainly extracellular protein polymer that kills the cell without tissue necrosis but by activation of the apoptotic mechanism. We analyzed the data reported so far on the structural and functional properties of four prototypic proteins with well-known biological functions (lysozyme, transthyretin, beta 2-microglobulin and apolipoprotein AI) that are able to create amyloid fibrils under certain conditions, with the perspective of evaluating whether the achievement of biological function favors or inhibits the process of fibril formation. Furthermore, studying the biological functions carried out by amyloid fibrils reveals new types of protein-protein interactions in the transmission of messages to cells and may provide new ideas for effective therapeutic strategies.

Alzheimer Disease↗

PubMed1989

Molecular pathology of the amyloid A4 precursor of Alzheimer's disease.

The precursor of the Alzheimer's disease-specific amyloid A4 protein is an integral, glycosylated membrane protein which spans the bilayer once. The carboxy-terminal domain of 47 residues was located at the cytoplasmic site of the membrane. The three domains following the transient signal sequence of 17 residues face the opposite side of the membrane. The C-terminal 100 residues of the precursor comprising the amyloid A4 part and the cytoplasmic domain have a high tendency to aggregate. This finding suggests that there is a precursor-product relationship between precursor and amyloid A4. We suggest that besides proteolytic cleavage, other events, such as membrane damage are primary events that precede the release of the small, aggregating amyloid A4 subunit.

Alzheimer Disease↗

PubMed2006

The regulation of tau phosphorylation by PCTAIRE 3: implications for the pathogenesis of Alzheimer's disease.

In the course of Alzheimer's disease, phosphorylated tau aggregates to form paired helical filaments, highly ordered filamentous structures that accumulate within neurons and contribute to the formation of neurofibrillary tangles. This study examines the role of PCTAIRE 3, a cdc2 family protein kinase, within this disease process. We report an elevation in the protein levels of PCTAIRE 3 in the temporal cortex of AD relative to control brains. Analysis of paired helical filaments prepared from AD brain tissue indicates that PCTAIRE 3 is concentrated within this pathological material. Overexpression of PCTAIRE 3 in cell culture suggests that the protein acts indirectly to stimulate phosphorylation at the pT231 and pS235 sites on tau, residues that are modified early in the process of AD pathogenesis. The resurgence of cell cycle proteins is an important mechanism in Alzheimer's disease (AD), and we propose that PCTAIRE 3 is a PHF-associated kinase that modulates tau phosphorylation.

Actins↗