Tau Clearance Mechanisms and Their Possible Role in the Pathogenesis of Alzheimer Disease

Chesser, Adrianne S.; Pritchard, Susanne M.; Johnson, Gail V.W.

doi:10.3389/fneur.2013.00122

Cited by 191 publications

(171 citation statements)

References 109 publications

(196 reference statements)

Supporting

Mentioning

162

Contrasting

Unclassified

Order By: Relevance

“…In addition, there are other pathological brain proteins such as α-synuclein and tau protein which are also cleared by a number of enzymes and the processes are not efficient enough during old age. Thus the accumulation of the mentioned proteins is known to be the main causes of a number of chronic brain diseases [135].…”

Section: On Drainage During Sleepmentioning

confidence: 99%

The Integrative Five-Fluid Circulation System in the Human Body

Fung¹,

Kong²

2016

OJMIP

View full text Add to dashboard Cite

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.

show abstract

Section: On Drainage During Sleepmentioning

confidence: 99%

The Integrative Five-Fluid Circulation System in the Human Body

Fung¹,

Kong²

2016

OJMIP

View full text Add to dashboard Cite

show abstract

“…T h e m e c h a n i s m l e a d i n g n o r m a l t a u t o b e c o m e hyperphosphorylated remains unknown and posttranslational modifications besides phosphorylation could regulate tau function and aggregation [58] , such as ubiquitination [59] , glycation [60] , glycosylation [61] , nitration [62] , polyamination [63] , proteolysis [64] , acetylation [58] , and methylation [65] .…”

Section: Other Post-translational Modifi Cationsmentioning

confidence: 99%

Tau-induced neurodegeneration: mechanisms and targets

Beharry

Cohen

et al. 2014

Neurosci. Bull.

View full text Add to dashboard Cite

The accumulation of hyperphosphorylated tau is a common feature of several dementias. Tau is one of the brain microtubule-associated proteins. Here we discuss tau's functions in microtubule assembly and stabilization and with regard to its interactions with other proteins. We describe and analyze important post-translational modifications: hyperphosphorylation, ubiquitination, glycation, glycosylation, nitration, polyamination, proteolysis, acetylation, and methylation. We discuss how these post-translational modifi cations can alter tau's biological function. We analyze the role of mitochondrial health in neurodegeneration. We propose that microtubules could be a therapeutic target and review different approaches. Finally, we consider whether tau accumulation or its conformational change is related to tau-induced neurodegeneration, and propose a mechanism of neurodegeneration.Keywords: tau; phosphorylation; neurodegeneration; tauopathies; mitochondria; microtubules; tubulin; kinases; phosphatases; Alzheimer's disease ·Review· IntroductionAlzheimer 's disease (AD), first described by Alois Alzheimer more than 100 years ago [1] , is a progressive neurodegenerative disorder, characterized by an insidious onset with irreversible cognitive declines that lead to profound mental deterioration causing dementia [2] . Two major forms of lesion characterize AD: amyloid as diffuse neurotic plaques primarily composed of the Aβ peptide [3] , which are mainly insoluble deposits of protein and cellular material, and neurofibrillary tangles composed of fi lamentous hyperphosphorylated tau protein that builds up inside the neuron [4,5] .Amyloid precursor protein (APP) is a highly conserved transmembrane protein [6] believed to play a role in synapse formation, synaptic plasticity, and neuronal survival [7][8][9] .In AD, APP is cleaved by β-and γ-secretases leading to the overproduction of an abnormal proteolytic byproduct called amyloid beta (Aβ) [10] . Upon cleavage fragments of Aβ of various sizes are released from the membrane and aggregate in the brain to form the characteristic plaques seen in AD. Plaques are composed primarily of the 40 and 42 amino-acid peptide fragments Aβ40 and Aβ42, the latter being the predominant species. In addition, Aβ42 is more prone to aggregation and deposition and therefore the cause of neurotoxicity, as well as synaptic loss [11] .The second lesion in AD is formed by aggregates of the microtubule-associated protein tau, which forms intracytoplasmic neuronal inclusions or neurofibrillary tangles when hyperphosphorylated [12] . Tau is associated with neurons of the central nervous system [13] and its main biological function is promoting the in vitro assembly and stabilization of microtubules in the cytoskeleton [14,15] . Tau is a phosphoprotein that is encoded by a single gene, MAPT, located on chromosome 17q21 [16] ; alternative splicing of the gene produces six major isoforms expressed in the adult human brain [17] . Isoforms derive their names from the number of microtubule-binding repeat s...

show abstract

“…1). Mechanisms of clearance include proteolysis, autophagy, and proteasomal degradation [37,38]. In this context, it has been suggested that Aβ, tau, and α-syn toxic aggregates might be major therapeutic targets for these neurodegenerative disorders (Fig.…”

Section: Introductionmentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

View full text Add to dashboard Cite

Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer's disease, α-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia.

show abstract

Tau Clearance Mechanisms and Their Possible Role in the Pathogenesis of Alzheimer Disease

Cited by 191 publications

References 109 publications

The Integrative Five-Fluid Circulation System in the Human Body

The Integrative Five-Fluid Circulation System in the Human Body

Tau-induced neurodegeneration: mechanisms and targets

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Contact Info

Product

Resources

About