Underlying cause of Alzheimer's found and new treatments identified
31 Jan 2011
Alzheimer's disease is a disease of synapses and treatments
that target this can virtually eliminate other characteristics of the
disease, according to a study by the Blanchette Rockefeller
Neurosciences Institute (BRNI) in the US.
The BRNI study, published in the Journal of Neuroscience,
is the first to achieve fundamental molecular understanding of how
synapses are lost in Alzheimer's Disease before the plaques and
tangles develop. At the same time, it is the first study to
demonstrate the comprehensive benefits of synaptogenic compounds in
treating Alzheimer's Disease.
The BRNI study marks an important shift in our understanding of
how Alzheimer's disease is caused and should be treated. Previous
autopsy-based studies have shown the critical role of synaptic loss
in producing dementia (though, not the reason behind the
degeneration), yet for decades scientists and pharmaceutical
companies have focused on ways to target the amyloid plaques and
neurofibrillary tangles thought to play a role in causing
Alzheimer's Disease. By preventing the loss of synapses, BRNI's new
therapeutics prevent the progressive symptoms of Alzheimer's
"Alzheimer's Disease is not primarily a disease of plaques and
tangles as many had previously concluded, it is most importantly a
disease of synapses," said Dr. Daniel Alkon, the scientific director
of BRNI and co-author of the study, "This study found that
treatments that target the loss of synapses in the Alzheimer's
brain, can virtually eliminate all other elements of the disease —
elevation of the toxic protein, A Beta, the loss of neurons, the
appearance of plaques, and loss of cognitive function; the animals'
brains were normalized."
The study utilized mice genetically engineered to express the
symptoms and pathology of human Alzheimer's Disease in two different
strains. BRNI used a difficult training regimen for the mice in
order to reveal that significant cognitive deficits occurred five
months before plaques were detected in their brains, providing
evidence that plaques and tangles are not at the root of the
Treatments of Bryostatin and similar compounds synthesized at
BRNI that target the enzyme PKCepsilon, which controls the creation
of synapses at the molecular level, were administered for twelve
weeks during the study.
While the compounds promoted the growth of new synapses and
preservation of existing synapses, they also stopped the decrease of
PKCepsilon and the increase of soluble beta amyloid, meaning that
the treatments could be used to prevent the familiar hallmarks of
Alzheimer's Disease, the plaques and tangles. BRNI has received
approval to move forward with Phase II clinical testing for
Bryostatin to treat Alzheimer's Disease, which is set to begin
within the next several months.
The synaptogenic BRNI drugs have also shown potential for the
treatment of traumatic brain injury (TBI), as recently reported in
the journal Neurobiology of Disease, and stroke described in the
Proceedings of the National Academy of Science in 2008 and 2009.
The target of the synaptogenic compounds is the same molecule
identified as a biomarker for early diagnosis of Alzheimer's Disease
in clinical trials conducted by BRNI and published in
Neurobiology of Aging in 2010. As a result of that study,
researchers at the Institute are now working to develop a skin test
for identifying Alzheimer's Disease in its early stages before