Novel way to stimulate immune system reduces amyloid deposits in
mice with Alzheimer’s
22 February 2009
A novel way to stimulate the immune system of mice with Alzheimer's
disease (AD) led to reduced amyloid deposits and the prevention of
Alzheimer's disease related pathology without causing toxic side
The discovery was made by researchers at New York University (NYU)
Langone Medical Center. The study entitled Induction of Toll-like
Receptor 9 Signaling as a Method for Ameliorating Alzheimer's Disease
Related Pathology was published in The Journal of Neuroscience.
NYU Langone researchers stimulated the innate immune system via the
Toll-like 9 receptor (TLR9) via treatment with cytosine-guanosine
containing DNA oligodeoxynucleotides (CpG ODNs) in Tg2576 AD model
This treatment produced a 66% and 80% reduction in the cortical and
vascular amyloid burden, when compared with non-treated AD mice. Also,
vaccinated Tg2576 mice performed similarly to non-treated mice on a
radial arm maze used in the study, showing improvements in behaviour and
reduced amyloid burden.
"Our results indicate that stimulation of the innate immune system
through TLR9 with CpG ODNs is an effective and apparently non-toxic
method to reduce the amyloid burden in the brain," said Thomas
Wisniewski, MD, professor of neurology, pathology and psychiatry at NYU
Langone Medical Center.
"Furthermore we found that amyloid reduction was associated with
significant cognitive benefits in an AD mouse model. This approach has
significant implications for future human immunomodulatory approaches to
prevent AD in humans."
The deposition of amyloid β (Aβ) in the central nervous system in the
form of amyloid plaques is a hallmark of Alzheimer's disease. Aβ
accumulation destroys neurons in the brain, leading to deficits in
Immunomodulation or vaccination for AD is emerging as an effective
means of shifting the equilibrium from Aβ accumulation to clearance;
however, excessive cell mediated inflammation and cerebral
microhemorrhages — two forms of toxicity ÿ were shown to occur in
previous vaccination studies targeting the adaptive immune system.
"This innate immune approach did not have any of the problems
previously reported with immunomodulation targeting the adaptive immune
system, such as encephalitis, hemorrhages or lack of an effect on
vascular amyloid, suggesting that this method has significant
advantages," said Dr. Wisniewski.
"The treatment with CpG ODNs has already been tested in normal human
volunteers and found to be safe — in studies where CpG ODNs was to be
used to treat chronic infections; hence this AD treatment has the
potential to be brought to clinical trial relatively quickly."
With injection of CpG ODNs used as a treatment to stimulate the
innate immune system in Tg2576 AD model mice, the animals were closely
monitored for signs of toxicity during behavioural testing and later for
any signs of pathology through dissection.
No toxicity was evident in the CpG ODN treated group. During
behavioural testing in a maze the mice differed significantly between
Tg2576 AD group and the CgP ODN treated group that better navigated the
maze. The mice were dissected at 17 months of age after behavioural
testing and the brains were processed for analysis. CpG ODN treated mice
had fewer plaques compared to Tg2576 AD mice.
In addition to the analysis of Aβ burden, researchers evaluated the
treatment effect of CpG ODNs on microglial (cells that act as the first
form of active immune defense in the central nervous system) in Tg2576
AD mice. CpG ODNs treatment resulted in overall cortical and hippocampal
brain reduction in immunoreactivity at 17 months.
"In evaluating the efficiency of CpG ODN treatment in the AD mice
model, we found that simulation of TLR9 signaling led to a remarkable
reduction of amyloid burden which was paralleled by a reduction in the
numbers of activated defensive immune responses in the central nervous
system (CNS)," said Dr. Wisniewski.
"Thus the effect of CpG ODNs on immune cells may induce heightened
levels of surveillance and activity by these cells and thus increased
influx into the brain and clearance of Aβ. Activation of immune cells
may elicit entrance of other cells into the CNS and induce either Aβ
clearance or induce CNS cell signaling leading to recruitment of cells
capable of clearing Aβ."
Researchers noted that the findings show administration of CpG ODNs
clearly was beneficial, leading to reductions in both amyloid deposition
and cognitive decline. This shows that modulation of the immune system
may be beneficial for human AD patients but the methods used must be
modified to prevent toxicity.
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