Is speeding up the key to slowing down Parkinson’s?

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A recent study found that rats treated with the antidepressant nortriptyline had reduced abnormal levels of alpha-synuclein, a protein critical to the development of Parkinson’s disease.  Alpha-synuclein is normally found throughout nerve cells, but in Parkinson’s, this protein abnormally clumps together and forms Lewy bodies.  These Lewy bodies surround and destroy nerve cells, which are responsible for coordinating movements.  As these nerve cells die, patients exhibit hand tremors, limb stiffness and coordination problems.  So what triggers alpha-synuclein to clump together and eventually form Lewy bodies?

Researchers at Michigan State University suggest that speed may be the key.  In healthy brains, alpha-nuclein naturally reconfigures and folds into clusters at a specific speed.  This process is hypothesized to be slower in Parkinson’s, resulting in a toxic buildup of alpha-nuclein.  When the antidepressant nortriptyline was given to a rat model of Parkinson’s, they observed a faster rate of alpha-nuclein reconfiguration, resulting in less abnormal levels of alpha-nuclein in the brain.

While the choice of an antidepressant to treat Parkinson’s may seem unusual, this was, in fact, intentional. The authors previously examined newly-diagnosed Parkinson’s disease patients, and studied how well they fared in clinical trials.  Surprisingly, patients taking antidepressants were less likely to need additional drug therapy.  This suggested that antidepressants could help slow the progression of Parkinson’s.   Based on their recent study in rats, antidepressants appear to slow the development of Parkinson’s by speeding up the reconfiguration of alpha-nuclein.

While the current study didn’t test motor coordination in the rats treated with nortriptyline, it will be important for future studies to examine.  In addition, nortriptyline did not affect rats with existing abnormal levels of alpha-nuclein.  This suggests that nortriptyline may be most effective when administered during the early development of the disease.  Still, nortriptyline has a long history of safety and efficacy, which makes it a promising therapeutic to test in a clinical setting.

Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form

https://www.ncbi.nlm.nih.gov/pubmed/?term=collier+2017+neurobiology+of+disease

How null green tea results and a gap in protein expression is exciting news for Down syndrome researchers

Identifying when and where a specific protein is elevated may be the key to improving the deficits observed in Down syndrome (DS), according to a review published in Molecular Genetics & Genomic Medicine.  Dual-specificity tyrosine-phosphorylated regulated kinase 1A (DYRK1A) is a gene that is triplicated in DS, and has recently been touted as a target for drug development in DS.  DYRK1A plays a critical role in the development of the central nervous system, and when its expression level is normalized, behavioral deficits are improved.  So, why haven’t researchers administered a DYRK1A inhibitor to fix the deficits in DS?  Well, that’s where things get tricky.

First, there are only a few DYRK1A inhibitors that are safe to use, and you may have already consumed one without knowing it.  Epigallocatechin-3-gallate (EGCG) is the main polyphenol found in green tea, and inhibits DYRK1A in cells.  However, studies that administer EGCG have yielded contrasting results, largely due to factors like the dose and timing of EGCG treatments.  In addition, EGCG has been shown to inhibit numerous targets besides DYRK1A , thus, more specific inhibitors need to be developed.

Second, the “When” and “Where” of DYRK1A elevation during early life development is a mystery.  The levels of DYRK1A are largely unknown between embryonic day 11.5 and 45 days of age in DS mouse models.  This large age gap represents a crucial period of early brain development, and the authors hypothesize that the elevation of DYRK1A during this age range could be causing the abnormal phenotypes observed in DS.  Understanding at what age, and in what brain regions DYRK1A is elevated will be essential for scientists to better administer DYRK1A inhibitors.  

In summary, researchers are left with green tea that may (or may not) work, and a large gap in understanding when DYRK1A is elevated.  While these findings may look dismal at first glance, scientists are currently testing improved DYRK1A inhibitors, and examining levels of DYRK1A during early development.  If future studies can combine these two avenues of research, then DYRK1A inhibition may provide a means to improve the lives of individuals with DS.

Article: Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits

Published in Molecular Genetics & Genomic Medicine on September 20th, 2017

http://onlinelibrary.wiley.com/doi/10.1002/mgg3.334/full

 

Image credit: https://pixabay.com/en/brain-biology-abstract-cerebrum-951874/

Put down the bread and pick up the…bacon?

      Two independent studies published in Cell Metabolism found that a ketogenic diet- high fat, low protein and extremely low carbohydrates- significantly improved memory performance and reduced early mortality in aging mice.  These studies are one of the first to examine long term effects of ketogenic diets on the longevity and health span of normal mice.  The goal of ketogenic diets is to force the body to burn fats, rather than carbohydrates.  Typically, our bodies convert carbohydrates into glucose, which is then used for energy.  However, if very few carbohydrates are consumed, the body will be in a state of ketosis, and the liver will convert fat into ketone bodies.  These ketone bodies replace glucose as the body’s energy source.

      The UC Davis study found that aged mice fed a ketogenic diet had a 13% increase in median lifespan versus mice fed the control diet.  In addition, mice receiving the ketogenic diet displayed improved memory, motor function, and muscle mass.  The Buck Institute study found that aged mice given a ketogenic diet, alternated with a control, non-ketogenic diet, also had reduced early mortality, and improvements in memory tasks.  Interestingly, the improvements in memory where observed when the aging mice were on the control diet, suggesting that a cyclic ketogenic diet may have long lasting effects.  While the exact mechanism of how a ketogenic diet improves memory and health in aged mice is unknown, the authors hypothesize that the elevation of the ketone beta-hydroxybutryrate (BHB) may alter the expression of genes involved in aging and insulin regulation.

      But don’t abandon your plate of spaghetti just yet.  Most health professionals caution against individuals starting a ketogenic diet without consulting a doctor, and research has even found that a continuous ketogenic diet leads to obesity. Future studies need to examine these ketogenic diets in different strains of mice, as well as determine if the timing of the diets produces similar effects.  However, these findings get researchers one step closer to better understanding dietary interventions that impact aging.  So while there’s no need to avoid spaghetti, maybe spoon an extra helping of meatballs on top.

A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice http://www.cell.com/cell-metabolism/abstract/S1550-4131(17)30490-4

Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice http://www.cell.com/cell-metabolism/fulltext/S1550-4131(17)30489-8

Both articles published September 5, 2017 in Cell Metabolism

Could our eyes be the window to detecting Alzheimer’s?

We use our eyes to scan the menu and watch our favorite show, but could they also help doctors determine if we are at risk for developing Alzheimer’s?  We may be one step closer to this reality, thanks to researchers at Cedars-Sinai Medical Center.  They showed that non-invasive retinal imaging could detect and quantify beta-amyloid deposits in the eyes of patients with Alzheimer’s disease.

Looking at the eyes for Alzheimer biomarkers is somewhat novel, as researchers have largely focused on the role of beta-amyloid deposits in the brain.  Beta-amyloid deposits are formed by fragments of the amyloid precursor protein, which is found in the tissue surrounding brain cells.  In Alzheimer’s, these fragments will aggregate together, and form plaques that surround healthy brain cells.  These plaques can disrupt cell communication and can trigger inflammatory processes.  The accumulation of these plaques can occur years before a clinical diagnosis of dementia (often referred to as prodromal Alzheimer’s disease) can be given.

In order to image the retina, subjects were orally administered curcumin, a component of the spice turmeric.  Curcumin labels amyloid plaques, and emits a fluorescence signal, which allows researchers to identify and quantify amyloid-beta plaques using their imaging software.  After scanning the eyes of 10 Alzheimer’s disease (AD) patients, and 10 healthy controls, they found that those with AD had a 4.7 fold increase in the number of retinal amyloid-plaques.  Researchers also found similar results when analyzing the retinas of 23 deceased AD patients and 14 controls, reporting an increase in amyloid-plaques in AD patients.

Importantly, a strong correlation was observed between the number of retinal and brain plaques in patients with AD.  Future studies will look to determine when the accumulation of retinal plaques begin, as well as testing the imaging on a larger sample size.  Taken together, these findings provide a promising non-invasive, cost-effective, diagnostic for a disease that will cost the nation $259 billion dollars in 2017.

https://insight.jci.org/articles/view/93621

Published August 17, 2017 in JCI Insight

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