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Alzheimer's, Dementia & Mental Health
Theory That Alzheimer’s Disease is ‘Type 3’ Diabetes
Supported by New Discovery
Toxic protein found Alzheimer’s brains removes
insulin receptors from nerve cells making them insulin resistant.
Sept. 26, 2007 – Is Alzheimer’s Disease actually
“type 3” diabetes? That has been the basis for a growing hypothesis in
recent years as research finds that insulin may be as important for the
mind as it is for the body. Now, scientists at Northwestern University
have discovered why brain insulin signaling - crucial for memory
formation - would stop working in Alzheimer’s disease.
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They have shown that a toxic protein found in the
brains of individuals with Alzheimer’s removes insulin receptors from
nerve cells, rendering those neurons insulin resistant. (The protein,
known to attack memory-forming synapses [point where cells transmit
signals], is called an ADDL for “amyloid ß-derived diffusible ligand.”)
With other research showing that levels of brain
insulin and its related receptors are lower in individuals with
Alzheimer’s disease, the Northwestern study sheds light on the emerging
idea of Alzheimer’s being a “type 3” diabetes.
The new findings, published online by the FASEB
Journal, could help researchers determine which aspects of existing
drugs now used to treat diabetic patients may protect neurons from ADDLs
and improve insulin signaling in individuals with Alzheimer’s. (The
FASEB Journal is a publication of the Federation of American Societies
for Experimental Biology.)
In the brain, insulin and insulin receptors are
vital to learning and memory. When insulin binds to a receptor at a
synapse, it turns on a mechanism necessary for nerve cells to survive
and memories to form. That Alzheimer’s disease may in part be caused by
insulin resistance in the brain has scientists asking how that process
gets initiated.
“We found the binding of ADDLs to synapses somehow
prevents insulin receptors from accumulating at the synapses where they
are needed,” said William L. Klein, professor of neurobiology and
physiology in the Weinberg College of Arts and Sciences, who led the
research team. “Instead, they are piling up where they are made, in the
cell body, near the nucleus. Insulin cannot reach receptors there. This
finding is the first molecular evidence as to why nerve cells should
become insulin resistant in Alzheimer’s disease.”
ADDLS are small, soluble aggregated proteins. The
clinical data strongly support a theory in which ADDLs accumulate at the
beginning of Alzheimer’s disease and block memory function by a process
predicted to be reversible.
In earlier research, Klein and colleagues found
that ADDLs bind very specifically at synapses, initiating deterioration
of synapse function and causing changes in synapse composition and
shape. Now Klein and his team have shown that the molecules that make
memories at synapses -- insulin receptors -- are being removed by ADDLs
from the surface membrane of nerve cells.
“We think this is a major factor in the memory
deficiencies caused by ADDLs in Alzheimer’s brains,” said Klein, a
member of Northwestern’s Cognitive Neurology and Alzheimer's Disease
Center. “We’re dealing with a fundamental new connection between two
fields, diabetes and Alzheimer’s disease, and the implication is for
therapeutics. We want to find ways to make those insulin receptors
themselves resistant to the impact of ADDLs. And that might not be so
difficult.”
Using mature cultures of hippocampal neurons, Klein
and his team studied synapses that have been implicated in learning and
memory mechanisms. The extremely differentiated neurons can be
investigated at the molecular level. The researchers studied the
synapses and their insulin receptors before and after ADDLs were
introduced.
They discovered the toxic protein causes a rapid
and significant loss of insulin receptors from the surface of neurons
specifically on dendrites to which ADDLs are bound. ADDL binding clearly
damages the trafficking of the insulin receptors, preventing them from
getting to the synapses. The researchers measured the neuronal response
to insulin and found that it was greatly inhibited by ADDLs.
“In addition to finding that neurons with ADDL
binding showed a virtual absence of insulin receptors on their
dendrites, we also found that dendrites with an abundance of insulin
receptors showed no ADDL binding,” said co-author Fernanda G. De Felice,
a visiting scientist from Federal University of Rio de Janeiro who is
working in Klein’s lab. “These factors suggest that insulin resistance
in the brains of those with Alzheimer’s is a response to ADDLs.”
“With proper research and development the drug
arsenal for type 2 diabetes, in which individuals become insulin
resistant, may be translated to Alzheimer’s treatment,” said Klein. “I
think such drugs could supercede currently available Alzheimer’s drugs.”
Editor’s Notes:
Klein, Grant A. Krafft, formerly at Northwestern
University’s Feinberg School of Medicine and now chief scientific
officer at Acumen Pharmaceuticals, Inc., and Caleb E. Finch, professor
of biological sciences and gerontology at the University of Southern
California, reported the discovery of ADDLs in 1998. Krafft is a
co-author of the FASEB Journal paper. Northwestern and USC hold joint
patents on the composition and use of ADDLs in neurodisorders.
The patent rights have been licensed to Acumen
Pharmaceuticals, based in South San Francisco, for the development of
drugs that treat Alzheimer’s disease and other memory-related disorders.
In addition to Klein, De Felice and Krafft, other
authors on the paper are Wei-Qin Zhao, a former visiting scientist at
Northwestern, now with Merck & Co., Inc. (lead author); Hui Chen, from
the National Center for Complementary and Alternative Medicine at the
National Institutes of Health; Michael Quo, from Blanchette Rockefeller
Neurosciences Institute; and Sara Fernandez and Mary Lambert, from
Northwestern University.
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