Alzheimer’s
disease (AD) is a neurodegenerative disorder, clinically marked by
the onset of memory
disturbances progressively followed by cognitive deficits. The
cause of AD is unknown but
according to the “Amyloid Cascade Hypothesis” the accumulation
of the amyloid peptide Aβ1-42
in the brain could be at the origin of the neuronal
degeneration. Aβ1-42 is able to activate
a series of stress kinases in neurons leading to the
triggering of cellular toxic pathways. Among
these kinases C-Jun-N terminal kinases (JNK) are
implicated in various cell functions including
neuronal death especially for the JNK3 isoform mainly
expressed in the brain.
A
French Team led by Prof. Jacques Hugon from the Memory Center at
Lariboisiere Hospital in Paris,
University Paris Diderot and the Inserm Unit U942, has shown that
the protein JNK3 was increased
in the brains of 10 AD patients compared to 10 control subjects.
JNK3 concentrations correlated
with Aβ1-42 concentrations and both molecules we co-expressed
in senile plaques, a neuropathological
hallmark of AD.
In
addition, the cerebrospinal fluid (CSF) levels of JNK3 were
statistically increased in 30 AD patients compared to 27 non AD
control subjects. AD patients were followed for a period of 1 to 3
years and global cognitive assessment using MMSE was carried out at
various intervals. The results showed that JNK3 levels statistically
correlated with the cognitive decline of AD patients giving the
possibility to predict the rate of cognitive alteration The French
team has previously shown that another stress kinase, PKR, was also a
good diagnostic and prognostic CSF AD biomarker. This work emphasizes
the fact that stress kinases including PKR and JKN3 are new potential
diagnostic and prognostic biomarkers in AD. Especially, these findings
underline that these kinases are new therapeutic targets that could
afford neuroprotection and could alter the relentless cognitive
decline of AD patients. Preclinical evaluations with kinase inhibitors
are currently taking place. Increased levels of cerebrospinal fluid
JNK3 associated with amyloid pathology: links to cognitive decline.
Gourmaud et al. Journal of Psychiatry and Neurosciences (in press)
Alzheimer : une enzyme tueuse de mémoire identifiée.