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Loss of Insulin in Brain Triggers Alzheimer's, Says
Pioneering Study
Researcher says
insulin question must be addressed to make significant progress in
fighting AD
March 23, 2006 – A loss of insulin in the brain
triggers the onset of Alzheimer's, says the senior author of new
research supported by the National Institutes of Health. She concludes
that by specifically targeting insulin and its actions in the brain new
treatments are possible.
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By depleting insulin and its related proteins in
the brain, researchers at Rhode Island Hospital and Brown Medical School
have replicated the progression of Alzheimer's disease – including
plaque deposits, neurofibrillary tangles, impaired cognitive
functioning, cell loss and overall brain deterioration – in an
experimental animal model.
The study demonstrates that Alzheimer's is a
brain-specific neuroendocrine disorder, distinct from other types of
diabetes.
(Neuroendocrine means relating to or
involving a nerve cell that releases a chemical messenger, especially a
neurohormone - a hormone that acts on nerve cells or the nervous system
- directly into the bloodstream.)
In the study, brain deterioration was not related
to the pancreas, which regulates insulin for the body. When pancreatic
insulin is deficient or the body fails to respond to it, the result is
Type 1 or Type 2 diabetes.
Previous work by the researchers with postmortem
brain tissue of Alzheimer's patients showed a strong link between
insulin depletion in the brain and Alzheimer's disease, raising the
possibility that Alzheimer's is a neuroendocrine disorder, or a Type 3
diabetes.
"We have demonstrated that a loss of insulin in the
brain triggers the onset of Alzheimer's, probably because as the brain
loses insulin, the cells that require insulin to function and survive
also eventually die. The consequences are increased oxidative stress,
brain deterioration, loss of cognitive function, and a buildup of
plaques and tangles in the brain – all hallmarks of Alzheimer's, says
senior author Suzanne M. de la Monte, MD, MPH, a neuropathologist at
Rhode Island Hospital and a professor of pathology and clinical
neuroscience at Brown Medical School in Providence, RI.
"We now know that if you specifically target
insulin and its actions in the brain, you could develop new treatments
for this disease," de la Monte says.
The study is published in the current issue (Volume
9, Issue 1) of the Journal of Alzheimer's Disease (http://www.j-alz.com).
Researchers injected the brains of rats with
Streptozotocin (STZ), a compound that when metabolized, destroys beta
cells in pancreatic islets and produces diabetes. When injected directly
into the brain, the treatment caused neurodegeneration, while the
pancreatic islet cells remained intact. That is because insulin
depletion produced by STZ was confined to the brain, just like what
occurs in most cases of Alzheimer's.
"This study provides definitive evidence that
impairments in insulin/IGF signaling and deficiencies in the
corresponding growth factors can occur in the central nervous system
(CNS) independent of Type 1 or Type 2 diabetes," the authors write.
As a result of the treatment, insulin and its IGF-I
receptors were significantly reduced in the brain, triggering a cascade
of neurodegeneration. Both insulin and IGF-I activate complex signaling
pathways downstream, prompting energy metabolism and growth required for
learning and memory, and inhibition of oxidative stress, which unchecked
could trigger neurodegeneration. As insulin was depleted, neurons died
and the brain dropped to half its size, a result of atrophy which is a
prominent feature of Alzheimer's. At the same time, there was an
increase in astrocytes and microglial cells, which are responsible for
neuroinflammation, another critical and consistent feature of
Alzheimer's and probably related to the increased amyloid deposition in
the brain, the researchers say.
Also, there was increased activation of a kinase
called GSK-3 beta. This kinase is overactive in Alzheimer's and triggers
tau phosphorylation, which is known to be at the core of neurofibrillary
tangles. The researchers had previously shown that tau is regulated by
insulin and insulin-like growth factor (IGF-I). In the current research,
they found that as insulin and IGF-I were depleted in the brain, the
expression of GSK-3 beta increased, leading to oxidative stress and cell
death.
While the link between insulin and tau had been
established, researchers also looked at the connection between insulin
and amyloid precursor protein gene expression, as increased levels could
account for amyloid accumulation, or the buildup of plaques in the
brain. They found that amyloid beta deposits in vessels and plaques did
build up in the brain, and they suggest that these abnormalities
occurred due to increased oxidative stress.
Another feature of Alzheimer's affected by impaired
insulin signaling, acetylcholine deficiency, is linked to dementia and
has long recognized as an early abnormality in Alzheimer's. The enzyme
that makes acetylcholine, choline acetyltransferase (ChAT), was
previously found to be regulated by insulin and IGF-1. In brains with
Alzheimer's, impairment of insulin and IGF-I signaling mechanisms
correlate with deficits in acetylcholine production. In this study, ChAT
was markedly reduced in the experimental Alzheimer's model.
"Our previous work has shown that many of the
important features of Alzheimer's – such as the accumulation of
phosphorylated tau and the death of neurons – were somehow linked to
insulin deficiency in the brain. This study shows that insulin is the
controlling factor in all of these features of Alzheimer's disease," de
la Monte says.
"The evidence suggests that impaired insulin and
IGF signaling must be addressed in order to make significant progress in
the treatment and prevention of Alzheimer's disease," she says.
This study was supported by grants from the
National Institutes of Health.
Founded in 1863, Rhode Island Hospital (www.rhodeislandhospital.org)
is a private, not-for-profit hospital and is the largest teaching
hospital of Brown Medical School. A major trauma center for southeastern
New England, the hospital is dedicated to being on the cutting edge of
medicine and research. Rhode Island Hospital ranks 13th among
independent hospitals who receive funding from the National Institutes
of Health, with research awards of more than $27 million annually. Many
of its physicians are recognized as leaders in their respective fields
of oncology, cardiology, orthopedics and minimally invasive surgery. The
hospital's pediatrics wing, Hasbro Children's Hospital, has pioneered
numerous procedures and is at the forefront of fetal surgery,
orthopedics and pediatric neurosurgery. Rhode Island Hospital is a
founding member of the Lifespan health system.
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