1 October 2001. The deposition of Aβ has long been implicated in the cellular
damage and subsequent cognitive dysfunction of Alzheimer's disease, but the mechanism
for this remains unclear. Recently, evidence has accumulated linking Aβ to
neuronal apoptosis. In today's Journal of Neuroscience, researchers in Michael
Greenberg's lab at Children's Hospital in Boston show that Aβ-induced neuronal death
may be linked to the apoptotic factor Fas ligand (FasL).
The authors found that the fibrillar form of Aβ (Aβ25-35) caused apoptosis
of cortical neurons in culture, which was accompanied by a twofold increase
in Jun N-terminal kinase (JNK) activity and an increase in the phosphorylation
of its substrate c-Jun; these observations are consistent with earlier data
indicating that c-Jun is necessary for Aβ-induced neuronal cell death (
Kihiko et al 1999 ). In addition, Aβ-induced synthesis of FasL in neuronal
culture, but neurons that were negative for JNK3 not only failed to activate
as much c-Jun as did wildtype, but also failed to produce FasL.
The data suggests that amyloid-induced cell death is mediated by c-Jun, which
in turn leads to activation of FasL and the apoptotic pathway. In support of
this, cells carrying mutations in FasL, or its receptor Fas, were much less
likely to undergo apoptosis when challenged with Aβ25-35. In addition,
the researchers were able to show that inhibition of caspase 8, a downstream
target of FasL/Fas, attenuates the effects of Aβ.-Tom Fagan.
Reference:Morishima Y, Gotoh Y, Zieg J, Barrett T, Takano H, Flavell R, Davis RJ, Shirasaki Y, Greenberg ME. b-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand. J Neurosci. 2001 Oct 1;21(19):7551-60. Abstract