Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies

Šimić, Goran; Leko, Mirjana Babić; Wray, Selina; Harrington, Charles R.; Delalle, Ivana; Jovanov-Milošević, Nataša; Bažadona, Danira; Buée, Luc; Silva, Rohan de; Giovanni, Giuseppe Di; Wischik, Claude M.; Hof, Patrick R.

doi:10.3390/biom6010006

Cited by 518 publications

(330 citation statements)

References 184 publications

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“…This process is considered a normal physiological function of tau phosphorylation that is necessary to regulate MT stability. However, hyperphosphorylation of tau often coexists with tau aggregation in the diseased brain (Augustinack et al , 2002; Iqbal et al , 2005), but the data for a causal relationship of tau aggregation to tau phosphorylation are conflicting (Kumar et al , 2014; Tepper et al , 2014; Šimić et al , 2016). It has been reported though that tau phosphorylation, for example, by GsK3β at multiple sites, may precede the aggregation of tau in AD (Iqbal et al , 2005; Stoothoff & Johnson, 2005; Mondragón‐Rodríguez et al , 2008).…”

Section: Discussionmentioning

confidence: 99%

Tau protein liquid–liquid phase separation can initiate tau aggregation

et al. 2018

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The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid–liquid phase separation (LLPS) under cellular conditions and that phase‐separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho‐tau isolated from human Alzheimer brain. Droplet‐like tau can also be observed in neurons and other cells. We found that tau droplets become gel‐like in minutes, and over days start to spontaneously form thioflavin‐S‐positive tau aggregates that are competent of seeding cellular tau aggregation. Since analogous LLPS observations have been made for FUS, hnRNPA1, and TDP43, which aggregate in the context of amyotrophic lateral sclerosis, we suggest that LLPS represents a biophysical process with a role in multiple different neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Tau protein liquid–liquid phase separation can initiate tau aggregation

et al. 2018

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“…The longest brain isoform of tau, tau 1–441 , has about 80 Ser/Thr and 5 Tyr residues that can be phosphorylated by various protein kinases encoded by 518 protein kinase genes in the human genome (Buée et al, 2000; Manning et al, 2002; Šimić et al, 2016). Immunolabeling with phopho-dependent antibodies raised against various tau phosphorylation sites, as well as spectrometric analysis, revealed that over 40 Ser/Thr and 2 Tyr residues are phosphorylated in PHF (Buée et al, 2000; Iqbal et al, 2016; Šimić et al, 2016). In AD, Ser/Thr residues followed by Pro are the most frequently phosphorylated sites, accounting for about half of phosphorylated residues.…”

Section: Clinical and Neuropathological Criteria For Ad Diagnosismentioning

confidence: 99%

“…According to Luna-Muñoz and collaborators, at least five different events take place in the “pre-tangle” stage: 1) C-terminal truncation of tau species (Glu-391); 2) a cascade of specific phosphorylations of tau protein in the N-terminus; 3) C-terminal truncation by the action of caspase-3; 4) oligomerization and aggregation of tau; and 5) assembly of tau into PHF (Luna-Muñoz et al, 2013; reviewed in Šimić et al, 2016). However, which form of tau is the most toxic (aggregated misfolded/fibrillar, soluble hyperphosphorylated/mislocalized, or both) and whether that toxicity represents a gain or loss of function continues to be debated.…”

Section: Clinical and Neuropathological Criteria For Ad Diagnosismentioning

confidence: 99%

“…What is much better known is that microtubule-binding repeat region R3, which is common to all six tau isoforms, and R2, which is an extra repeat in 4R tau, contain the two hydrophobic hexapeptide motifs with β-sheet structure (VQIINK and VQIVYK, respectively, see Fig. 2 in Šimić et al, 2016), which are responsible for downstream tau aggregation by a nucleation-elongation mechanism (von Bergen et al, 2000) and PHF formation (for review, see Šimić et al, 2016). It is believed that generation of tau transgenic mouse strains with ‘pro-aggregant’ (e.g.…”

Section: Clinical and Neuropathological Criteria For Ad Diagnosismentioning

confidence: 99%

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Monoaminergic neuropathology in Alzheimer’s disease

Šimić

Leko

Wray³

et al. 2017

Progress in Neurobiology

Self Cite

223

142

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None of the proposed mechanisms of Alzheimer’s disease (AD) fully explains the distribution patterns of the neuropathological changes at the cellular and regional levels, and their clinical correlates. One aspect of this problem lies in the complex genetic, epigenetic, and environmental landscape of AD: early-onset AD is often familial with autosomal dominant inheritance, while the vast majority of AD cases are late-onset, with the ε4 variant of the gene encoding apolipoprotein E (APOE) known to confer a 5–20 fold increased risk with partial penetrance. Mechanisms by which genetic variants and environmental factors influence the development of AD pathological changes, especially neurofibrillary degeneration, are not yet known. Here we review current knowledge of the involvement of the monoaminergic systems in AD. The changes in the serotonergic, noradrenergic, dopaminergic, histaminergic, and melatonergic systems in AD are briefly described. We also summarize the possibilities for monoamine-based treatment in AD. Besides neuropathologic AD criteria that include the noradrenergic locus coeruleus (LC), special emphasis is given to the serotonergic dorsal raphe nucleus (DRN). Both of these brainstem nuclei are among the first to be affected by tau protein abnormalities in the course of sporadic AD, causing behavioral and cognitive symptoms of variable severity. The possibility that most of the tangle-bearing neurons of the LC and DRN may release amyloid β as well as soluble monomeric or oligomeric tau protein trans-synaptically by their diffuse projections to the cerebral cortex emphasizes their selective vulnerability and warrants further investigations of the monoaminergic systems in AD.

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“…As the brain is a heavy-duty organ, a lot of wastes, both soluble and in soluble exist in the mixture CSF-BISF, which is the Fourth Fluid of our model. In particular, there is ample evidence that β-Amyloid and τ-protein have been found to be deposited inside the brains of patients suffering from Alzheimer, Parkinson and other neurodegenerative diseases [93]. For many decades, whereas the Figure 4.…”

Section: Csf Follows Special Pathways To MIX With Bisf In the Brain Pmentioning

confidence: 99%

The Integrative Five-Fluid Circulation System in the Human Body

Fung¹,

Kong²

2016

OJMIP

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Water is the key medium to transport numerous constituents and to provide a platform for physiological processes to take place in the living organisms in general; it also participates actively in many of these processes. In humans, there are different vehicles to contain water and its constituents. Our objective is to find out whether there is an overall water-base circulation system in the human body by analyzing the updated findings of different research groups on the physiological functions of various seemingly isolated fluid systems. By 1963, there were five separate fluid systems discovered in mammalians: (i) The Primo Vasculature Fluid (PVF) with protein precursors and micro cells held in the Primo Vasculature System (PVS). (ii) Blood with its constituents held in the cardio vasculature. (iii) Extracranial interstitial fluid (ISF) whose vehicle had a very irregular structure-the interstitium all over the body. (iv) The cerebrospinal fluid had been considered to be within the brain ventricles and spinal canal. (v) The extra-cranial lymphatic system which drained ISF, and had been known to join the subclavian vein. Fluid (i) was first reported in 1963 and fluids (ii) to (v) have been known for many decades, but the failure to detect a lymphatic system inside the skull has also been a mystery for many decades. The intra-cranial ISF (which we name as BISF) has drawn little attention, apart from discussing the mechanism of the blood-brain-barrier. During the past decade, there has been direct evidence indicating that CSF and BISF are actually mixed. After that, the intracranial lymphatic system was discovered and confirmed in animal models only slightly over one year back, and we called such fluid as glymphatic-fluid. After reviewing the stated "classical" five fluid systems together with the new findings in Sections 2 -7, we propose, for the first time, that the PVF, the blood, ISF, a mixture of CSF-BISF, and a mixture of glymphatic-fluid and lymph form an integrative circulation system in water base in the human and other mammalian bodies, as schematically represented in the last section. In this paper, we point out the positive correlation of chronic neuro degenerative diseases such as Alzheimer's disease, Parkinson's diseases and the insufficient brain wastes clearance by the glymphatic system. We also discuss the role played by the venous vessels as part of such clearance in upright posture. Moreover, simple non-invasive maneuver techniques are introduced here, as one example of enhancement of glymphatic fluid flow out of the skull to join the lymphatic system. A series of questions are raised in Section 8, the answers to which would help us to understand the transition from physio-to pathological states in the development of many diseases. Detailed analysis of this paper leads us to consider that research in understanding this integrative circulation system is only at the infancy stage, and fluid dynamics investigation seems to be the plausible modality of approach in the near future.

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Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies

Cited by 518 publications

References 184 publications

Tau protein liquid–liquid phase separation can initiate tau aggregation

Tau protein liquid–liquid phase separation can initiate tau aggregation

Monoaminergic neuropathology in Alzheimer’s disease

The Integrative Five-Fluid Circulation System in the Human Body

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