Progress and Developments in Tau Aggregation Inhibitors for Alzheimer Disease

Bulic, Bruno; Pickhardt, Marcus; Mandelkow, Eckhard

doi:10.1021/jm3017317

Cited by 103 publications

(83 citation statements)

References 212 publications

(434 reference statements)

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“…4B) and the outcome of the miniscreen, we attempted to counterbalance the observed phenotype by using the adenosine A 1 receptor antagonist rolofylline. An adenosine A 2A receptor antagonist (ZM-241385), an adenosine A 1 receptor agonist (N 6 -cyclopentyladenosine), and a Tau aggregation inhibitor (BSc3094) were used as controls (Table S4) (22)(23)(24). Rolofylline increases neuronal activity (Fos mRNA) both in proaggregant Tau transgenic slices and controls, although in case of the proaggregant slices neuronal activity is almost doubled, yielding levels similar to those of treated littermate control slices (Fig.…”

Section: High Aggregation Propensity Is Not Necessary For Tau Missortmentioning

confidence: 99%

Adenosine A ₁ receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

Dennissen

Anglada-Huguet

Sydow

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Accumulation of Tau is a characteristic hallmark of several neurodegenerative diseases but the mode of toxic action of Tau is poorly understood. Here, we show that the Tau protein is toxic due to its aggregation propensity, whereas phosphorylation and/or missorting is not sufficient to cause neuronal dysfunction. Aggregate-prone Tau accumulates, when expressed in vitro at near-endogenous levels, in axons as spindle-shaped grains. These axonal grains contain Tau that is folded in a pathological (MC-1) conformation. Proaggregant Tau induces a reduction of neuronal ATP, concomitant with loss of dendritic spines. Counterintuitively, axonal grains of Tau are not targeted for degradation and do not induce a molecular stress response. Proaggregant Tau causes neuronal and astrocytic hypoactivity and presynaptic dysfunction instead. Here, we show that the adenosine A 1 receptor antagonist rolofylline (KW-3902) is alleviating the presynaptic dysfunction and restores neuronal activity as well as dendritic spine levels in vitro. Oral administration of rolofylline for 2-wk to 14-mo-old proaggregant Tau transgenic mice restores the spatial memory deficits and normalizes the basic synaptic transmission. These findings make rolofylline an interesting candidate to combat the hypometabolism and neuronal dysfunction associated with Tau-induced neurodegenerative diseases.tauopathies | rolofylline | hypoactivity | axons | treatment

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Section: High Aggregation Propensity Is Not Necessary For Tau Missortmentioning

confidence: 99%

Adenosine A ₁ receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

Dennissen

Anglada-Huguet

Sydow

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The analysis of Aβ and tau protein from the patients of AD helps to sought out the model and formation of toxic Aβ protein and p-tau [42] .…”

Section: Proteomics Of Aβ and Tau Proteinmentioning

confidence: 99%

Pathogenesis of Alzheimer's Disease: Role of Amyloid-beta and Hyperphosphorylated Tau Protein

Sajjad¹,

Arif²,

Shah³

et al. 2018

pharmaceutical-sciences

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Sajjad, et al.: Pathogenesis of Alzheimer's DiseaseThe pathological emblems of Alzheimer's disease are the accumulation of amyloid-β plaques and neurofibrillary tangles. The alluvium of toxic amyloid-β-protein in the form of aggregates is central to the pathogenesis of Alzheimer's disease. The aggregate formation is due to the structural refitting of α-helical sheet of normal, soluble amyloid-β-protein to the β-sheets, which lead to oligomeric, fibrillar, insoluble and disease causing amyloid-β 42. Mounting data suggests that another factor, the tau protein ripens into highly phosphorylated form by several kinases after Aβ-stimulation leads to tangle formation resulting in neuronal bereavement in hippocampus and entorhinal regions as the disease progresses further. An overview has been presented in this review of the role of tau as an important partner of amyloid-β in the pathogenesis of Alzheimer's disease, both of which could be used as biomarkers for diagnosis and risk assessment with other molecular chaperones, which are associated with Alzheimer's disease. As a part of common pathophysiological mechanism the understanding of amyloid-β and tau toxicities might be helpful for finding molecular targets for the prevention or even cure of Alzheimer's disease.

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“…In vitro tau and p-tau aggregation (amyloidogenesis) assays will help shed light on the pathway and pathological roles of tau fibrillization, and they will provide a platform for high-throughput screening for tau aggregation modulators and potential AD therapeutics (21). To date, all tau-aggregation-based drug screens use unmodified tau (22,23), despite the fact that the pathological tau species are hyperphosphorylated. We posited that PIMAX-Cat would be a viable choice for the production of p-tau more suitable for tau fibrillization studies and AD drug discovery.…”

Section: Design Of Pimax and Its Applications-mentioning

confidence: 99%

Protein Interaction Module–assisted Function X (PIMAX) Approach to Producing Challenging Proteins Including Hyperphosphorylated Tau and Active CDK5/p25 Kinase Complex

Sui

et al. 2015

Molecular & Cellular Proteomics

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Many biomedically critical proteins are underrepresented in proteomics and biochemical studies because of the difficulty of their production in Escherichia coli. These proteins might possess posttranslational modifications vital to their functions, tend to misfold and be partitioned into bacterial inclusion bodies, or act only in a stoichiometric dimeric complex. Successful production of these proteins requires efficient interaction between these proteins and a specific "facilitator," such as a protein-modifying enzyme, a molecular chaperone, or a natural physical partner within the dimeric complex. Here we report the design and application of a protein interaction moduleassisted function X (PIMAX) system that effectively overcomes these hurdles. By fusing two proteins of interest to a pair of well-studied protein-protein interaction modules, we were able to potentiate the association of these two proteins, resulting in successful production of an enzymatically active cyclin-dependent kinase complex and hyperphosphorylated tau protein, which is intimately linked to Alzheimer disease. Furthermore, using tau isoforms quantitatively phosphorylated by GSK-3␤ and CDK5 kinases via PIMAX, we demonstrated the hyperphosphorylation-stimulated tau oligomerization in vitro, paving the way for new Alzheimer disease drug discoveries. Vectors for PIMAX can be easily modified to meet the needs of different applications. This approach thus provides a convenient and modular suite with broad implications for proteomics and biomedical research. Molecular & Cellular Proteomics

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Progress and Developments in Tau Aggregation Inhibitors for Alzheimer Disease

Cited by 103 publications

References 212 publications

Adenosine A ₁ receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

Adenosine A ₁ receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

Pathogenesis of Alzheimer's Disease: Role of Amyloid-beta and Hyperphosphorylated Tau Protein

Protein Interaction Module–assisted Function X (PIMAX) Approach to Producing Challenging Proteins Including Hyperphosphorylated Tau and Active CDK5/p25 Kinase Complex

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Progress and Developments in Tau Aggregation Inhibitors for Alzheimer Disease

Cited by 103 publications

References 212 publications

Adenosine A 1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

Adenosine A 1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

Pathogenesis of Alzheimer's Disease: Role of Amyloid-beta and Hyperphosphorylated Tau Protein

Protein Interaction Module–assisted Function X (PIMAX) Approach to Producing Challenging Proteins Including Hyperphosphorylated Tau and Active CDK5/p25 Kinase Complex

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Adenosine A ₁ receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

Adenosine A ₁ receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280