Researchers at
Bengaluru’s Indian Institute of Science (IISc) have identified a potential
biomarker for Alzheimer’s disease. The biomarker shows up very early in the
disease process and well before clinical and even pathological manifestation of
the disease. They also found that it is possible to reverse the disease process
if identified early.
Loss of
dendritic spines from the surface of a nerve cell is already recognised as an
early feature of Alzheimer’s. But the underlying mechanism behind this loss was
not known. Now, a team led by Vijayalakshmi Ravindranath from the Centre for
Neuroscience at IISc has deciphered it. The results were published in Journal
of Neuroscience.
Projections on
the dendrites called spines grow or shrink in response to activity-dependent
modification and correlates with normal memory or memory deficit in animal
models.
Filamentous
actin (F-actin) is a cytoskeletal protein which is responsible for maintaining
the shape of the spines. While F-actin is formed by polymerisation of monomeric
globular-actin (G-actin), depolymerisation leads to loss of F-actin and, in
turn, the loss of spines. F-actin is crucial for memory consolidation.
“In mice that
are genetically altered to have Alzheimer’s, there was decreased F-actin
protein level and increased G-actin protein level in animals as young as one
month,” says Reddy Peera Kommaddi, a DBT-Ramalingaswami Fellow, from the Centre
for Neuroscience at IISc and first author of the paper. The change in the ratio
of F-actin and G-actin led to loss of spines. The decrease in F-actin level and
loss of spine thereof translated into memory deficit when the animals turned
two months old.
In contrast, the
first signs of memory deficit in mice with Alzheimer’s is typically seen only
when the animals are seven-eight months old. This is because the formation of
protein clumps called amyloid plaques, which is one of the earliest clinical
symptoms, happens at this stage.
Testing memory
To test the role
of F-actin in behaviour response, two-month-old mice were exposed to mild foot
shocks when kept in a conditioning chamber to bring about contextual fear
conditioning. While normal mice placed in the chamber the next day they tend to
freeze in anticipation of a shock, mice with Alzheimer’s did not exhibit this
behaviour. “The Alzheimer mice did not associate the aversive event [electric
shock] with context but simply kept exploring the chamber,” says Smitha
Karunakaran from the Centre for Brain Research at IISc and a coauthor of the
paper.
To test if
decrease in F-actin protein and, in turn, the spine was responsible for deficit
in memory a chemical was injected into Alzheimer mice to stabilise the level of
F-actin. “A day after the injection, the F-actin level was restored to normal
level and the Alzheimer mice showed increased freezing response just like
healthy mice,” says Dr Karunakaran.
The researchers
went a step further to test the role of F-actin level in behaviour response by
injecting a chemical into four-month-old normal mice. Since the chemical
inhibits actin polymerisation, there was a decrease in the F-actin level. And
the mice, though healthy, displayed significant decrease in freezing response,
just like Alzheimer’s mice would behave.
“These two
experiments conclusively proved that loss in F-actin level leads to early
behavioural changes that would eventually lead to Alzheimer’s disease,” says
Dr. Kommaddi.
The team checked
the level of F-actin levels in cortical brain tissue samples of human subjects
who had Alzheimer’s, mild cognitive impairment and normal cognition. There was
“graded lowering” of F-actin levels from normal to mild cognitive to
Alzheimer’s tissue samples.
The correlation
seen between mouse model and human disease indicates the potential to use
F-actin levels as a biomarker.
http://www.thehindu.com/sci-tech/science/iisc-team-identifies-an-early-stage-biomarker-for-alzheimers/article22715264.ece
