APR 05, 2016 6:35 PM PDT

A Novel Pathway to Enhance Clearance of Amyloid-β From the Brain

WRITTEN BY: Cassidy Reich
Alzheimer’s Disease (AD) is the most common form of dementia, currently affecting 5.5 million people in the U.S. There are currently no means of preventing or significantly slowing down disease progression, and unless there are some major advancements in the next few years, the number of people with AD in the U.S. will grow to 13.8 million by 2050.
 

Amyloid-β accumulation is the main pathological feature of AD and so most of the therapeutics designed and tested have been focused on the production or clearance of amyloid-β. Drugs that have been tested to reduce the production of amyloid-β include ?-secretase inhibitors and BACE1 inhibitors. BACE1 and ?-secretase are two of the enzymes that cleave the amyloid precursor protein into amyloid-β. Thus far, this strategy of targeting amyloid-β by targeting the proteases that create it has not been successful. With that said, most major pharmaceutical companies have a new generation type of BACE1 inhibitor somewhere in the pipeline, so there could be some exciting developments on the horizon. Anti-amyloid antibodies have been developed to enhance the clearance of amyloid-β from the brain. Again, there has been limited success with this strategy, but one antibody in particular, aducanumab, has had some success in the very early, prodromal stages of AD. Because there has been such limited success thus far, we are in need of novel therapeutic targets for the prevention of AD.

A recent paper published in Science Translational Medicine describes a potential new method to enhance clearance of amyloid-β from the brain that could be targeted for AD therapeutics.
Heparan sulfate proteoglycans (HSPGs) are a type of very abundant cell membrane and extracellular space molecule that consist of a protein core covalently bonded to multiple heparan sulfate (HS) chains. HSPGs have been shown to bind to amyloid-β and accelerate its aggregation while HS alone has been implicated in cellular uptake of amyloid-β and in the mediation of amyloid-β neurotoxicity and inflammatory response. Because of these observations, Guojun Bu from the Mayo Clinic Department of Neuroscience led his team to investigate the interaction between HSPGs and amyloid-β metabolism.

Long story short, they discovered in vivo evidence that neuronal HS exacerbates amyloid plaque deposition and inhibits clearance of amyloid-β from the brain. To study the effects of HS, they created a conditional knockout mouse model using the APP/PS1 mouse model of AD. To get rid of HS and HSPG expression, the researchers knocked out the Ext1 gene in adult forebrain neurons. Ext1 encodes an enzyme that is required for the formation of HS, so without it, there are no HSPGs or HS chains. Using microdialysis to capture the real-time kinetics of amyloid-β in vivo, they saw that the mice lacking HS were able to clear amyloid-β from the brain faster than the APP/PS1 mice fully expressing HS. In addition, the conditional knockout APP/PS1 mice had significantly less amyloid deposition and neuroinflammation, as measured by activated microglia.
 
Quantification of Thioflavin-S stained amyloid plaques.

To confirm that these findings in mice is translatable to human AD pathology, the researchers also evaluated postmortem brain tissue from AD patients. They found that several HSPG species were upregulated compared to non-demented age-matched controls.

Amyloid pathology in AD is ultimately the result of an imbalance in amyloid-β processing and metabolism. The research presented here offers a new pathway to target for the treatment of AD. Inhibiting Ext1 could be a good target, or inhibiting the interaction between HS, HSPGs, and amyloid-β could also be exploited for drug development.
About the Author
  • Cassidy is a curious person, and her curiosity has led her to pursue a PhD in Pharmacology at the New York University Sackler Institute of Biomedical Sciences. She likes to talk about science way too much, so now she's going to try writing about it.
You May Also Like
NOV 19, 2019
Drug Discovery & Development
NOV 19, 2019
Psychedelic DMT Creates Vivid Waking Dream State in Brain
In a new study, scientists at Imperial College London investigated how powerful psychedelic dimethyltryptamine (DMT) alters the brain’s electrical ac...
DEC 06, 2019
Neuroscience
DEC 06, 2019
Gut Bacteria Influences Response to Fear
The last decade has seen an increasing amount of interest on how our gut bacteria, or microbiome, influences our health. Now, from a new study looking at m...
DEC 21, 2019
Drug Discovery & Development
DEC 21, 2019
Magic Mushrooms Pass First Clinical Trial Against Depression
With the efficacy of selective serotonin reuptake inhibitors such as Prozac increasingly coming under question, the search for new pharmaceutical treatment...
DEC 20, 2019
Neuroscience
DEC 20, 2019
Hand-Motion Center of the Brain Involved in Speech
During a long-term study focused on improving computer-assistant interfaces for quadriplegia patients, researchers at Stanford University were able to use...
JAN 16, 2020
Drug Discovery & Development
JAN 16, 2020
Fatty Acid Supplement Repairs Brain After Stroke in Mice
Researchers have found that supplements containing short chain fatty acids (SCFAs) may be able to help the brain recover from having a stroke. This comes a...
JAN 19, 2020
Cell & Molecular Biology
JAN 19, 2020
Scientists Create Neuromuscular Organoids That Contract
This work is a breakthrough for the study of neuromuscular diseases including ALS, muscular dystrophy and multiple sclerosis....
Loading Comments...