Alzheimer's, Dementia & Mental Health
Scientists See Potential of Alzheimer’s Magic Bullet
in TSPO Ligands
Diseased mice respond to new drug
- most severe
older mice see signs of disease improve rapidly
May 21, 2013 – Gerontology researchers think they
have discovered what may lead to a drug to prevent and treat Alzheimer’s
disease. Working with a class of drugs called TSPO ligands and they were
able to reduce AD pathology and improve memory in mice. They were most
surprised in their success with old mice, where they saw the
potential for a treatment of the disease.
Imagine a pharmaceutical prevention, treatment or
even cure for Alzheimer’s disease. It is almost impossible to overstate
how monumental a development that would be and how it would answer the
prayers of millions.
Though science isn’t there yet, this new study
published in The Journal of Neuroscience spearheaded by USC Davis
School of Gerontology researchers offers a tantalizing glimpse of
“Our data suggests the possibility of drugs that
can prevent and treat Alzheimer’s,” said lead author, professor and lab
principal Christian Pike of USC Davis. “It’s just mouse data but
extremely encouraging mouse data.”
The team studied the effects of a class of drugs
called TSPO ligands on male mice that were genetically engineered to
develop Alzheimer’s disease, known as 3xTg-AD mice.
Because a key mechanism of TSPO ligands is to
increase production of steroid hormones, it was important to ensure that
the mice had low levels of testosterone and related hormones before
treatment. Younger mice were castrated while, in older mice, the
decrease occurred as a normal consequence of aging.
“We looked at the effects of TSPO ligands in young
adult mice when pathology was at an early stage and in aged mice when
pathology was quite severe,” Pike said. “TSPO ligands reduced measures
of pathology and improved behavior at both ages.”
The most surprising finding for Pike and his team
was the effect of TSPO ligands in the aged mice. Four treatments — one
per week over four weeks — in aged 3xTg-AD mice resulted in significant
lowering of Alzheimer’s-related pathology and improvements in memory
behavior. This finding suggested the possibility that TSPO ligands can
reverse components of Alzheimer’s and thus have the potential to be
useful in treatment.
For humans, these findings may indeed be quite
“TSPO ligands are currently used in humans in
certain types of neuroimaging. Newer TSPO ligands are at the clinical
trials stage of development for treatment of anxiety and other
conditions,” Pike said. “There is a strong possibility that TSPO ligands
similar to the ones used in our study could be evaluated for therapeutic
efficacy in Alzheimer’s patients within the next few years.”
In light of the findings, the team will next focus
on understanding how TSPO ligands reduce Alzheimer’s pathology. Building
on the established knowledge that TSPO ligands can act protectively by
reducing inflammation, shielding nerve cells from injury and increasing
the production of neuroactive hormones in the brain, the team will study
which of these actions is the most significant in fighting Alzheimer’s
so it can develop newer TSPO ligands accordingly.
While Pike and his team acknowledged that the
findings represent an exciting possibility, the researchers also
stressed that it is by no means a given.
“From the optimistic perspective, our data provide
very promising findings with tangible potential benefits for both the
prevention and treatment of Alzheimer’s,” Pike said. “On the pessimistic
side, research scientists have developed many interventions that cured
Alzheimer’s in mice but have failed to show significant benefits in
humans. A critical direction we are currently pursuing is successfully
translating these findings into humans.”
Co-authors of the study were Anna Barron (former
USC Davis postdoctoral student and Molecular Imaging Center, National
Institute of Radiological Sciences, Japan); Luis Garcia Segura
(Instituto Cajal, Spain); Donatella Caruso and Roberto Melcangi
(Department of Pharmacological and Biomolecular Sciences, Centre of
Excellence on Neurodegenerative Diseases, University of Milan); and
Anusha Jayaraman and Joo Lee (USC Davis).
The research was funded by the National Institutes
of Health in support of the USC Alzheimer’s Disease Research Center,
directed by Helena Chui, professor of neurology and gerontology at USC.
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