Researchers at Rhode Island Hospital and Brown Medical School have
discovered that insulin and its receptors drop significantly in the
brain during the early stages of Alzheimer's disease, and that levels
decline progressively as the disease becomes more severe, leading to
further evidence that Alzheimer's is a new type of diabetes. They also
found that acetylcholine deficiency, a hallmark of the disease, is
linked directly to the loss of insulin and insulin-like growth factor
function in the brain.
The study, published in the November issue of the Journal of
Alzheimer's Disease (http://www.j-alz.com), is the first to look at
insulin levels early in the course of the disease. The authors'
previous work published earlier this year primarily focused on the
late stages of Alzheimer's.
"Insulin disappears early and dramatically in Alzheimer's disease. And
many of the unexplained features of Alzheimer's, such as cell death
and tangles in the brain, appear to be linked to abnormalities in
insulin signaling. This demonstrates that the disease is most likely a
neuroendocrine disorder, or another type of diabetes," says senior
author Suzanne M. de la Monte, a neuropathologist at Rhode Island
Hospital and a professor of pathology at Brown Medical School in
Providence, RI.
The study analyzed postmortem brain tissue of 45 patients with a
diagnosis of either normal aging or different degrees of Alzheimer's
neurodegeneration, termed "Braak Stages."
Researchers analyzed insulin and insulin receptor function in the
frontal cortex, a major area affected by Alzheimer's. They found that
with increasing severity of the disease, levels of insulin receptors
and the brain's ability to respond to insulin decreased markedly.
"In the most advanced stage of Alzheimer's, insulin receptors were
nearly 80 percent lower than in a normal brain," de la Monte says.
Researchers found two parallel abnormalities related to insulin in
Alzheimer's. First, insulin levels decline as the disease progresses.
Second, insulin and its related protein IGF-I lose their ability to
bind to corresponding cell receptors, creating a resistance to the
growth factors and thus causing cells to malfunction and eventually
die.
"This has important implications for treatment," de la Monte says. "If
you could target the disease early, you could prevent the further loss
of neurons. But you would have to target not just the loss of insulin
but the resistance of its receptors in the brain."
Researchers also offer an explanation for the acetylcholine deficiency
that is linked to dementia and has long been recognized as an early
abnormality in Alzheimer's. They found that insulin and IGF-I
stimulate the expression of choline acetyltransferase (ChAT), the
enzyme responsible for making acetylcholine. This discovery shows a
direct link between insulin and IGF-I deficiency and dementia.
"We're able to show that insulin impairment happens early in the
disease. We're able to show it's linked to major neurotransmitters
responsible for cognition. We're able to show it's linked to poor
energy metabolism, and it's linked to abnormalities that contribute to
the tangles characteristic of advanced Alzheimer's disease. This work
ties several concepts together, and demonstrates that Alzheimer's
disease is quite possibly a Type 3 diabetes," de la Monte says.
Earlier this year, de la Monte and co-authors provided the first
evidence that insulin and its related proteins are produced in the
brain and that reduced levels of both are linked to the late stages of
Alzheimer's.
They surmised that Alzheimer's is a complex neuroendocrine disease
that originates in the central nervous system, raising the possibility
of a new type of diabetes.
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