Apoptosis -- or the lack of it -- has been implicated in anumber of disease states.
Many researchers, for example, now feel that cancer occurs notwhen the affected cells proliferate unchecked, but rather whenthey refuse to give in to the natural, programmed cell death ofapoptosis. Apoptosis also has been cited as a factor in AIDS, inthat HIV kills not only the T cells that it has infected, but alsoprompts uninfected ones to commit suicide.
Other studies have suggested that during a stroke, the oxygen-deprived neurons get so distressed that they choose to die. Andprogrammed cell death has been implicated in aging andAlzheimer's as well. In fact, the immense loss of certainpopulations of central nervous system neurons is ascharacteristic a hallmark of Alzheimer's as the neurofibrillarytangles and amyloid plaques.
Dale Bredesen and his colleagues at the University of California,Los Angeles, and the Stanford Research Institute in Palo Alto,Calif., reported in last week's Science that neuronal cell deathcan be induced constitutively by the expression of a particularnerve growth factor (NGF) receptor. Moreover, the highest levelof expression of this low-affinity NGF receptor, termedp75NGFR, "occurs in cholinergic neurons of the nucleus basalisof Meynert, the cells most severely affected in Alzheimer'sdisease," they reported.
"These cells continue to express normal or supranormalamounts of p75NGFR messenger RNA and protein during theneuronal degeneration associated with Alzheimer's disease,"they said.
These results may shine some light on the function of this low-affinity NGF receptor, which has remained elusive. (Thefunction of the high-affinity NGF receptor, TrkA, has beenshown to transduce NGF signals for survival anddifferentiation.)
Bredesen and his collaborators went after the low-affinityreceptor p75NGFR because it has some sequence similarities tofour other molecules that mediate cell death: tumor necrosisfactors (TNF) I and II, the human cell surface antigen Fas andthe B cell antigen CD40.
It's been shown that factors TNF I and Fas initiate cell deathafter they are bound by their ligand or a monoclonal;conversely, CD40 is prevented from killing cells when it isbound by a ligand or specific antibody. Moreover, theexpression of both CD40 and p75NGFR occurs on developingcells: central cholinergic, sympathetic and sensory neurons forp74NGFR; centroblasts and centrocytes for CD40.
The researchers reasoned that, given these similarities, thelow-affinity BGF receptor might serve as a constitutive celldeath-promoting molecule. And their results support thatthesis. They found that in immortalized p75NGFR-transfectedneural cells, expression of the receptor led to increased neuraldeath when those cells were deprived of serum in the culturemedium (a means of experimentally inducing apoptosis).
This effect could be suppressed if either the ligand NGF or aspecific monoclonal antibody were added to the cultures.
The researchers also showed that the type of cell death inducedby the low-affinity receptor was apoptosis rather than necrosisby expressing it in a cell line that does not ordinarily undergoapoptosis in serum-free medium. Not only did those cells thendie, but they exhibited "the nuclear fragmentation, chromatincondensation and homogeneous nuclear staining characteristicof apoptosis but not necrosis," the scientists said.
-- Jennifer Van Brunt Senior Editor
(c) 1997 American Health Consultants. All rights reserved.