Major Alzheimer's Risk Gene Opens New Pathway to Prevention

MORGANTOWN, W.Va., May 13, 2015 /PRNewswire/ -- In a groundbreaking new study, researchers from the Blanchette Rockefeller Neurosciences Institute (BRNI) have discovered that the Apolipoprotein E4 (ApoE4) gene, the major genetic risk factor for the vast majority of late, age-dependent Alzheimer's patients, can reduce the number of mature, functional synapses in the brain by interfering with the DNA responsible for synapse formation and maintenance. Synaptic loss, a key element of Alzheimer's disease, often occurs before the onset of amyloid plaques or tangles in Alzheimer's patients. This new finding could potentially shift current thinking around Alzheimer's disease—from treatment of the disease to prevention.

In the study published May 13 in the Journal of Neuroscience, scientists found that the ApoE4 gene increases nuclear translocation and activity of histone deacetylases (HDACs) in human neurons. (HDACs are enzymes that act like on/off buttons for genes.) This activity reduces levels of DNA-programmed brain-derived neurotrophic factor (BDNF), which is a critical component in the formation, repair and plasticity of synapses between brain cells. The loss of mature, functional synapses is a key element of early Alzheimer's disease and its associated cognitive deficits.

"We know that people with the complete ApoE4 genes are 10 times more likely to suffer from the most common form of late, age-dependent Alzheimer's disease. We also know from previous autopsy studies that Alzheimer's patients have deficits of BDNF, Protein Kinase C (PKC) epsilon and synapses," said Dr. Daniel Alkon, Scientific Director of BRNI. "Now, in the present study, the brains of Alzheimer's patients were found to have increased levels of HDACs. These findings, taken together, suggest that substituting the abnormal ApoE4 gene for the ApoE3 gene is one of the earliest causes of synaptic loss in Alzheimer's disease."

A Shift in Thinking around Alzheimer's

To date, every single late-phase clinical trial for Alzheimer's drugs—even those that held promise in preclinical studies—has failed. The majority of these studies has focused on the pathologic hallmarks of brains of Alzheimer's sufferers, particularly on sticky extracellular clumps of proteins and cellular debris known as "amyloid plaques," and twisted intracellular tau fibers, often referred to as "tangles."

"Our study provides evidence for a major shift in current thinking around Alzheimer's disease and research," said Dr. Alkon. "Synaptic loss often occurs before the onset of amyloid plaques or tangles in Alzheimer's patients, so our latest findings suggest that many of today's trials that only focus on plaques and tangles aren't targeting a critical pathway responsible for early synaptic loss and, therefore, Alzheimer's disease." 

A Pathway to Prevention

But there may be hope for prevention. BRNI has shown in pre-clinical studies that activating PKC with potent activators such as Bryostatin can prevent ApoE4 from inhibiting BDNF production. Bryostatin, by increasing PKC epsilon, has also been shown in previous pre-clinical studies to lower soluble A Beta oligomers that lead to plaque formation. Since A Beta oligomers also function like ApoE4 to interfere with DNA-controlled BDNF production through HDACs, Bryostatin could potentially block this A Beta oligomer effect as well. This would offer further Alzheimer's disease prevention potential. Elevated HDACs, lower PKC epsilon, reduced BDNF and increased A Beta oligomers, working together, compromise synaptic function, growth and maintenance in the absence of amyloid plaques and tangles.

Discoveries from the present study suggest that these same PKC activators in trials to treat Alzheimer's disease patients could potentially be given to healthy individuals who have the ApoE4 genes – even before Alzheimer's disease begins – thereby preventing the onset of debilitating dementia and brain degeneration.

"We are excited and encouraged by these results," said Alkon. "In essence, our findings suggest that Bryostatin could be used in some patients to prevent Alzheimer's disease before it ever begins."

To read BRNI's full study, visit http://www.jneurosci.org/content/35/19/7538.abstract

About the Blanchette Rockefeller Neurosciences Institute

The Blanchette Rockefeller Neurosciences Institute (www.brni.org) is a unique, independent, non-profit institute dedicated to the study of memory and finding solutions to memory disorders. BRNI was founded in 1999 in memory of Blanchette Ferry Hooker Rockefeller, an Alzheimer patient and mother of U.S. Senator John D. Rockefeller IV. BRNI is operated in alliance with West Virginia University as well as in collaboration with other academic institutions.

About Bryostatin

Bryostatin, originally identified by Dr. George Pettit of the University of Arizona, is a natural product produced by a marine invertebrate organism called Bugula neritina and is isolated from organic matter harvested from the ocean. Several variations of this complex product have been achieved in recent years in various academic chemistry laboratories. Drug equivalents of Bryostatin, but with different chemical structures have been developed at BRNI.

For additional information, please contact:

Alissa Momberg Lawver
727-688-3398
[email protected]

SOURCE Blanchette Rockefeller Neurosciences Institute

Related Links

http://www.brni.org