Corporate Banner
Satellite Banner
Technology
Networks
Scientific Communities
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Key Molecular Pathways Leading to Alzheimer’s Identified

Published: Thursday, July 25, 2013
Last Updated: Thursday, July 25, 2013
Bookmark and Share
Research approach highlights potential therapeutic targets.

Key molecular pathways that ultimately lead to late-onset Alzheimer’s disease, the most common form of the disorder, have been identified by researchers at Columbia University Medical Center (CUMC). The study, which used a combination of systems biology and cell biology tools, presents a new approach to Alzheimer’s disease research and highlights several new potential drug targets. The paper was published today in the journal Nature.

Much of what is known about Alzheimer’s comes from laboratory studies of rare, early-onset, familial (inherited) forms of the disease. “Such studies have provided important clues as to the underlying disease process, but it’s unclear how these rare familial forms of Alzheimer’s relate to the common form of the disease,” said study leader Asa Abeliovich, MD, PhD, associate professor of pathology and cell biology and of neurology in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at CUMC. “Most important, dozens of drugs that ‘work’ in mouse models of familial disease have ultimately failed when tested in patients with late-onset Alzheimer’s. This has driven us, and other laboratories, to pursue mechanisms of the common form of the disease.”

Non-familial Alzheimer’s is complex; it is thought to be caused by a combination of genetic and environmental risk factors, each having a modest effect individually. Using so-called genome-wide association studies (GWAS), prior reports have identified a handful of common genetic variants that increase the likelihood of Alzheimer’s. A key goal has been to understand how such common genetic variants function to impact the likelihood of Alzheimer’s.

In the current study, the CUMC researchers identified key molecular pathways that link such genetic risk factors to Alzheimer’s disease. The work combined cell biology studies with systems biology tools, which are based on computational analysis of the complex network of changes in the expression of genes in the at-risk human brain.

More specifically, the researchers first focused on the single most significant genetic factor that puts people at high risk for Alzheimer’s, called APOE4 (found in about a third of all individuals). People with one copy of this genetic variant have a three-fold increased risk of developing late-onset Alzheimer’s, while those with two copies have a ten-fold increased risk. “In this study,” said Dr. Abeliovich, “we initially asked: If we look at autopsy brain tissue from individuals at high risk for Alzheimer’s, is there a consistent pattern?”

Surprisingly, even in the absence of Alzheimer’s disease, brain tissue from individuals at high risk (who carried APOE4 in their genes) harbored certain changes reminiscent of those seen in full-blown Alzheimer’s disease,” said Dr. Abeliovich. “We therefore focused on trying to understand these changes, which seem to put people at risk. The brain changes we considered were based on ‘transcriptomics’—a broad molecular survey of the expression levels of the thousands of genes expressed in brain.”

Using the network analysis tools mentioned above, the researchers then identified a dozen candidate “master regulator” factors that link APOE4 to the cascade of destructive events that culminates in Alzheimer’s dementia. Subsequent cell biology studies revealed that a number of these master regulators are involved in the processing and trafficking of amyloid precursor protein (APP) within brain neurons. APP gives rise to amyloid beta, the protein that accumulates in the brain cells of patients with Alzheimer’s. In sum, the work ultimately connected the dots between a common genetic factor that puts individuals at high risk for Alzheimer’s, APOE4, and the disease pathology.

Among the candidate “master regulators” identified, the team further analyzed two genes, SV2A and RFN219. “We were particularly interested in SV2A, as it is the target of a commonly used anti-epileptic drug, levetiracetam. This suggested a therapeutic strategy. But more research is needed before we can develop clinical trials of levetiracetam for patients with signs of late-onset Alzheimer’s disease.”

The researchers evaluated the role of SV2A, using human-induced neurons that carry the APOE4 genetic variant. (The neurons were generated by directed conversion of skin fibroblasts from individuals at high risk for Alzheimer’s, using a technology developed in the Abeliovich laboratory.) Treating neurons that harbor the APOE4 at-risk genetic variant with levetiracetam (which inhibits SV2A) led to reduced production of amyloid beta. The study also showed that RFN219 appears to play a role in APP-processing in cells with the APOE4 variant.

The paper is titled, “Integrative genomics identifies APOE ɛ4 effectors in Alzheimer’s disease.” The other contributors are all members of CUMC’s Taub Institute for Research on Alzheimer’s Disease and the Aging Brain: Herve Rhinn, Ryousuke Fujita, Liang Qiang, Rong Chen, and Joseph H. Lee. Dr. Lee is also a member of CUMC’s Gertrude H. Sergievsky Center.

The authors declare no financial or other conflicts of interest. Subsequent to the acceptance of this paper, Dr. Abeliovich received a grant from UCB, Inc. for an unrelated study.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,500+ scientific posters on ePosters
  • More Than 5,000+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Detecting Alzheimer's with a Smell Test
Odour identification test may offer low-cost alternative for predicting cognitive decline and detecting early-stage Alzheimer’s disease.
Thursday, July 28, 2016
Contagious Cancers Are Spreading in Shellfish
Direct transmission of cancer among some marine animals may be more common than once thought, suggests a new study published in Nature by researchers at Columbia University Medical Center (CUMC).
Tuesday, June 28, 2016
Contagious Cancers Are Spreading in Shellfish
Direct transmission of cancer among some marine animals may be more common than once thought, suggests a new study published in Nature by researchers at Columbia University Medical Center (CUMC).
Tuesday, June 28, 2016
New Neurodevelopmental Syndrome Identified
Study pinpoints underlying genetic mutations, raising hopes for targeted therapies.
Friday, April 22, 2016
Major Complication of Parkinson’s Therapy Explained
Researchers have discovered why long-term use of ¬¬¬L-DOPA (levodopa), the most effective treatment for Parkinson’s disease, commonly leads to a movement problem called dyskinesia, a side effect that can be as debilitating as Parkinson’s disease itself.
Monday, September 14, 2015
An Innovative Algorithm to Decipher How Drugs Work Inside the Body
Researchers at Columbia University Medical Center (CUMC) have developed a computer algorithm that is helping scientists see how drugs produce pharmacological effects inside the body.
Friday, July 24, 2015
Neurons Controlling Appetite Made from Skin Cells
Cells provide individualized model for studying obesity and testing treatments.
Monday, March 02, 2015
Bone Stem Cells Shown To Regenerate Bone And Cartilage In Adult Mice
Cells could be exploited to treat osteoarthritis and osteoporosis.
Monday, January 19, 2015
Non-Gluten Proteins as Targets of Immune Response to Wheat in Celiac Disease
The results were reported online in the Journal of Proteome Research.
Thursday, December 18, 2014
Human Stem Cells Converted to Functional Lung Cells
Possibility of generating lung tissue for transplant using a patient’s own cells.
Thursday, December 05, 2013
New Link Between Obesity and Diabetes Found
Targeting a single enzyme that raises both sugar and insulin levels in the obese could prevent and treat diabetes.
Monday, November 25, 2013
Human Stem Cells Elucidate Mechanisms of Beta-Cell Failure in Diabetes
Mechanisms that impair insulin production in diabetes identified using a human stem cell model of Wolfram syndrome, a rare form of diabetes.
Thursday, November 14, 2013
Researchers Discover Cells that Restore Bladder’s Unique Lining
Finding that could lead to new ways to treat chronic bladder pain or to produce new tissue for patients with damaged bladders.
Tuesday, September 24, 2013
Trial Aims to Advance Prenatal Diagnosis of Genetic Defects
High-risk pregnant women being recruited for research on chromosomal abnormalities and incidence of birth defects, developmental delays.
Thursday, August 22, 2013
Is There a Role for Vitamins in Cancer Prevention?
According to recent national surveys, approximately 40 percent of U.S. adults take multivitamins/multiminerals.
Monday, August 12, 2013
Scientific News
Point of Care Diagnostics - A Cautious Revolution
Advances in molecular biology, coupled with the miniaturization and improved sensitivity of assays and devices in general, have enabled a new wave of point-of-care (POC) or “bedside” diagnostics.
Mass Spec Technology Drives Innovation Across the Biopharma Workflow
With greater resolving power, analytical speed, and accuracy, new mass spectrometry technology and techniques are infiltrating the biopharmaceuticals workflow.
One Step Closer to Precision Medicine for Chronic Lung Disease Sufferers
A study led by University of North Carolina at Chapel Hill, and National Jewish Health, has provided evidence of links between SNPs and known COPD blood protein biomarkers.
ReadCoor Launched to Commercialize 3D Sequencing Tech
ReadCoor will leverage the Wyss Institute’s method for simultaneously sequencing and mapping RNAs within cells and tissues to advance development of diagnostics.
Ancient Eggshell Protein Breaks Through DNA Time Barrier
Fossil proteins from a 3.8million year-old eggshell have been identifed, suggests proteins could give insight into evolutionary tree.
Monkeys Protected by Zika DNA Vaccine
Experimental Zika virus DNA vaccines successfully protected monkeys against Zika infection.
NCI Collaborates with Multiple Myeloma Research Foundation
NCI collaborates with MMRF to incorporate genomic and clinical data into NCI Genomic Data Commons database.
New Imaging Technique in Alzheimer’s Disease
Study confirms new imaging technique corresponds a higher degree of actual brain changes.
Anti-Inflammatory Drugs Could Strengthen Airway Immunity
Mold toxins can weaken the airways' clearing mechanisms and immunity, but PKC inhibitors showed promise as a treatment.
Regulatory RNA Essential to DNA Damage Response
Researchers discover a tumour suppressor is stabilized by an RNA molecule, which helps cells respond to DNA damage.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
5,000+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!