Another mechanism of neuronal death in Alzheimer's disease
The culprit of neuronal death in Alzheimer's disease is astrocyte apoptosis
LifeSciencesToday based on materials from Georgia Health Sciences University: Neuron-nourishing cells appear to retaliate in Alzheimer'sOur own brain cells kill neurons when the latter begin to secrete too many amyloid proteins, which is a characteristic sign of Alzheimer's disease.
Astrocytes, which usually provide neurons with nutrition and oxygen, become the involuntary culprits of their death, since high levels of amyloid peptides induce their apoptosis. Deprived of nutrition, neurons degenerate.
This conclusion is supported by the results of a new study conducted at the Georgia Health Sciences University. They are published in The Journal of Biological Chemistry: Astrocytes secret exosomes enriched with pro-apoptotic ceramide and prostate apoptosis response 4 (PAR-4): a potential mechanism of apoptosis induction in Alzheimer's disease (AD).
Alzheimer's disease is the most common form of dementia. This neurodegenerative disease occupies the sixth line in the list of diseases that claim the greatest number of lives in the United States, where about 5.4 million people suffer from it.
Amyloid is secreted by all neurons, but the level of its secretion increases with age and, especially sharply, in Alzheimer's disease. Astrocytes that deliver oxygen and nutrients to neurons, along with cleaning up a certain part of the biochemical "garbage" they emit, are activated and respond to excessive levels of amyloid with inflammation.
However, American scientists have discovered another reaction of astrocytes to elevated levels of amyloid.
"If a neuron produced something toxic and dumped it at your door, what would you do?" asks one of the study participants, a chemist Erhard Bieberich, PhD, from the Medical College of Georgia. "You probably would have done something to protect yourself."
Astrocytes that find themselves in such a situation are also "protected". Contact with amyloid leads to an increase in the synthesis of ceramide lipid in them, which induces the formation of exosomes and the association of exosomes with the PAR-4 protein. Secreted PAR-4/ceramide-associated exosomes accumulate in the intercellular medium until they reach a proapoptotic concentration. Proapoptotic exosomes (apoxosomes) bind to astrocytes and cause their apoptosis by activating caspase 3.
It is well known that amyloid protein induces the death of neurons. However, very little is known about its effect on astrocytes. Scientists have found that amyloid peptides activate caspase 3 and induce apoptosis in primary astrocyte culture, prevented by inhibition of caspase 3. Apoptosis is also prevented by shRNA-mediated suppression of expression of PAR-4, a protein sensitizing cells to sphingolipid ceramide. Apoptosis is not observed in astrocytes deficient in neutral sphingomyelinase 2 (nSMase2), indicating that ceramide, whose synthesis is catalyzed by nSMase2, plays a crucial role in amyloid-induced apoptosis. Antibodies against PAR-4 and ceramide prevent amyloid-induced apoptosis in vitro and in vivo, suggesting that apoptosis is mediated by exogenous PAR-4 and ceramide, possibly associated with secreted lipid vesicles. This was confirmed by the analysis of lipid vesicles from the conditioned medium, which showed that the amyloid peptide induces the secretion of exosomes rich in PAR-4 and ceramide C18. Exosomes are not secreted by nSMase2-deficient astrocytes, showing that ceramide plays a key role in the secretion of exosomes. Exogenously added ceramide C18 restores the secretion of PAR-4-containing exosomes by nSMase2-deficient astrocytes. Moreover, isolated exosomes with a high content of PAR-4 and ceramide are absorbed by astrocytes and induce apoptosis in the absence of an amyloid peptide. Scientists believe that they have discovered a new mechanism for the induction of apoptosis, mediated by protein-rich PAR-4 and ceramide exosomes, which can make a decisive contribution to the development of Alzheimer's disease.
In the picture from the website stanmed.stanford.edu – neuron and glial brain cells.
As a rule, ceramide and PAR-4 are not found in exosomes. Rather, in two different parts of the cell. Probably, ceramide takes the initiative to unite them when meeting with amyloid. Both ceramide and PAR-4 can cause harm even independently of each other, but their combination is a particularly dangerous duet.
In 2003 Erhard Biberich and his colleagues from the University of Georgia reported that this deadly duo helps to destroy duplicate brain cells that exist in the early stages of its development, when their survival can lead to disruption of the structure of the emerging organ. Then they suspected that this pair could play an important role in the development of Alzheimer's disease.
According to the assumption of American researchers, the lipid-coated "package" eventually kills both the astrocyte and the neuron. This hypothesis may explain the death of brain cells and a decrease in its volume in Alzheimer's disease.
"If astrocytes die, neurons die," Dr. Biberich continues. Previous studies have shown that excessive amyloid as such does not kill brain cells, and recent work has shown that the cause of their death is the reaction of the cell to amyloid.
"There must be a secondary process that makes amyloid toxic; otherwise, the neuron would die as a result of self-poisoning even before the formation of large plaques. The neuron would die first," Biberich believes.
One of the many directions in future research is to find out whether an antibody against ceramide can become a real remedy for the treatment of Alzheimer's disease. In experiments on brain cells of patients with this disease, as well as on animal model cells, antibodies to ceramide and PAR-4 prevented amyloid-induced astrocyte apoptosis.
Portal "Eternal youth" http://vechnayamolodost.ru25.05.2012