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Autophagy may be the silver bullet for treating neurodegenerative disease
Serenoa
Posted: Sunday, July 28, 2013 11:24 AM
Joined: 4/24/2012
Posts: 484


Two new drugs currently in clinical trials are both using the activation of autophagy in neurons to treat neurodegeneration.Both of these drugs are currently used for cancer treatment, and thus would be available off label.

 

 

Will Tau Drug Show Its True Colors in Phase 3 Trials?

 

"2 October 2012. Remember Rember®—the blue dye that made headlines in 2008 when Phase 2 clinical trial data suggested it slowed decline in people with Alzheimer’s disease (see ARF related news story)? A revamped version of this compound, which presumably inhibits tau aggregation, is now heading toward Phase 3 testing, though in a different tauopathy. TauRx Therapeutics—a Singapore-based biotech company with research operations in Scotland—announced last month that it received U.S. and European regulatory approval to launch a 12-month, global Phase 3 trial of its experimental drug in behavioral-variant frontotemporal dementia (bvFTD). “The FTD field is excited to finally have an agent worthy of a clinical trial as a potential disease-modifying agent. This is a big deal,” said Bradley Boeve of Mayo Clinic, Rochester, Minnesota."  

 

 

http://www.alzforum.org/new/detail.asp?id=3283

 

 

 

The drug is known as methylthioninium chloride, and here is the journal article describing it's possible benefits.

 

 

Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo.

 

Abstract

"More than 30 neurodegenerative diseases including Alzheimer disease (AD), frontotemporal lobe dementia (FTD), and some forms of Parkinson disease (PD) are characterized by the accumulation of an aggregated form of the microtubule-binding protein tau in neurites and as intracellular lesions called neurofibrillary tangles. Diseases with abnormal tau as part of the pathology are collectively known as the tauopathies. Methylthioninium chloride, also known as methylene blue (MB), has been shown to reduce tau levels in vitro and in vivo and several different mechanisms of action have been proposed. Herein we demonstrate that autophagy is a novel mechanism by which MB can reduce tau levels. Incubation with nanomolar concentrations of MB was sufficient to significantly reduce levels of tau both in organotypic brain slice cultures from a mouse model of FTD, and in cell models. Concomitantly, MB treatment altered the levels of LC3-II, cathepsin D, BECN1, and p62 suggesting that it was a potent inducer of autophagy. Further analysis of the signaling pathways induced by MB suggested a mode of action similar to rapamycin. Results were recapitulated in a transgenic mouse model of tauopathy administered MB orally at three different doses for two weeks. These data support the use of this drug as a therapeutic agent in neurodegenerative diseases."

 

 

http://www.ncbi.nlm.nih.gov/pubmed/22361619
 
 

 

The other drug is Nilotinib. Tests are for Parkinson's, but the similarity is that it is removing a mis-folded, toxic protein from the brain through activation of autophagy.

 

 

 

Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of α-synuclein in Parkinson's disease models

 

 

Abstract

"Parkinson's disease is a movement disorder characterized by death of dopaminergic substantia nigra (SN) neurons and brain accumulation of α-synuclein. The tyrosine kinase Abl is activated in neurodegeneration. Here, we show that lentiviral expression of α-synuclein in the mouse SN leads to Abl activation (phosphorylation) and lentiviral Abl expression increases α-synuclein levels, in agreement with Abl activation in PD brains. Administration of the tyrosine kinase inhibitor nilotinib decreases Abl activity and ameliorates autophagic clearance of α-synuclein in transgenic and lentiviral gene transfer models. Subcellular fractionation shows accumulation of α-synuclein and hyper-phosphorylated Tau (p-Tau) in autophagic vacuoles in α-synuclein expressing brains, but nilotinib enhances protein deposition into the lysosomes. Nilotinib is used for adult leukemia treatment and it enters the brain within US Food and Drug Administration approved doses, leading to autophagic degradation of α-synuclein, protection of SN neurons and amelioration of motor performance. These data suggest that nilotinib may be a therapeutic strategy to degrade α-synuclein in PD and other α-synucleinopathies."

 

 

http://hmg.oxfordjournals.org/content/early/2013/05/09/hmg.ddt192.abstract

 

 

 

 

 

 



Lane Simonian
Posted: Sunday, July 28, 2013 9:21 PM
Joined: 12/12/2011
Posts: 4854


These drugs may reflect a different side of autophagy--not by increasing the body's immune system (although this cannot be ruled out) to remove amyloid plaques, hyperphosphorylated tau proteins, and aggregated alpha synuclein proteins, but by allowing the body to do the job itself.  In all three cases, nitration impedes the clearance or rearrangement of these altered proteins.  And methylene blue (Rember) and Nilotinib reduce nitration so that amyloid plaques can potentially be cleared and hyperphosphorylated tau protein and alpha synuclein aggregates can be reconstituted. 

 

 

Methylene blue inhibits the increase of inducible nitric oxide synthase activity induced by stress and lipopolysaccharide in the medial basal hypothalamus of rats.

http://www.ncbi.nlm.nih.gov/pubmed/11124577 

 

Importantly, nilotinib caused down-regulation of the inflammatory cytokines TNF-α, TGF-β(1) and iNOS levels in the lung.

 

http://www.ncbi.nlm.nih.gov/pubmed/21473879 

 

Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation.

 http://www.ncbi.nlm.nih.gov/pubmed/21903077 

 

 

Further studies demonstrated that the hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis.

 

http://www.ncbi.nlm.nih.gov/pubmed/16816118 

 

In fact, nitration of -synuclein tyrosine residues 39, 125, 

133 or 136, may be an early event in aggregates, 

Lewy bodies, seen in PD. Furthermore, nitrative 

stress leads to the induction of -synuclein 

aggregation at a higher rate than seen in other PD 

mutants. This aggregation may result from a 

stabilization of pre-assembled -synuclein 

filaments, which, upon nitration, may withstand 

denaturing conditions and enhance formation of 

SDS-insoluble, heat-stable high mass aggregates. 

  

http://new.lakeforest.edu/images/userImages/eukaryon/Page_7190/p.%2090-94%20Valtierra%20Review%20PD.pdf  

 

So perhaps if you de-nitrate amyloid plaques, hyperphosphorylated tau proteins, and alpha-synuclein aggregates, the body can clear or reconstitute these proteins.  At the very least, the drugs mentioned here would reduce further nitration.