Alzheimer's disease (AD) is a neurodegenerative disorder mainly characterized by the progressive and irreversible loss of neurons located in central nervous system that results in impaired memory, thinking, and behavior. During the development of the disease most parts of the cortical brain and subcortical region are filled with amyloid plaques and neurofibrillary tangles. Amyloid-~ plaques are derived from amyloid-~ precursor protein (APP) after its sequential cleavage by~- and y-secretase. The neurofibrillary tangles are intraneuronal lesions made of 10-nm helical filaments. The main component of the filament is the hyperphosphorylated form of microtubulebinding protein Tau. Thus, amyloid-~ plaques and neurofibrillary tangles can serve as a diagnostic tool for AD.
On the other hand, Down's Syndrome patients, having trisomy of chromosome 21, develop Alzheimer's-like neuropathology by age 30-40 years. Three copies of APP gene on chromosome 21 cause overproduction of APP in Down Syndrome patients. Stem cells have the remarkable potential to develop into many different cell types in the body. There are several types of stem cells. First type is totipotent stem cells; they have the potential to become any type of cell in the body and even whole organism. Second type of stem cells is pluripotent. They can become almost any kind of cell in the body. Third type of stem cell is multipotent and those cells can differentiate into a limited variety of cells. During these experiments human neural stem cells (HNSCs), which are multipotent, will be used.
Stem cells serve as a sort of repair system for the body; they can theoretically divide without limit to replenish other cells. Hence, stem cells transplantation could become a treatment for many diseases. Recently multipotent neural stem cells (NSCs) were discovered in adult brain and were shown to differentiate into ~III-tubulin and glial fibrillary acidic protein(GFAP) immunopositive cells, neurons and glia respectively, which gave hope for the treatment of AD. Human neural stem cells (HNSCs) were successfully transplanted into the aged rats with subsequent improvement of cognitive function. As a consequence HNSCs transplantation could be used as a treatment to replace degenerating neurons in AD brain.
In our previous study HNSCs transplanted into the APP transgenic mouse mostly differentiated into glial cells. Another study shows HNSCs from Down syndrome patients differentiated into astrocytes, not neurons. Thus, overexpression of APP may cause glial differentiation of HNSCs, which may reduce neurogenesis. Therefore, transplantation of HNSCs, as a treatment of AD, could be problematic. Current Food and Drug Administration (FDA) approved treatments for Alzheimer's disease are cholinesterase inhibitors (Donepezil, Exelon, Galantamine), acetylcholinesterase inhibitors (Tacrine), and NMDA receptor antagonist (Namenda). Cholinesterases are the major target for treatment of AD because of their ability to reduce the hydrolysis of the neurotransmitter acetylcholine from the presynaptic clef, and thus prolong and amplify the action of the neurotransmitter.
A novel drug treatment, phenserine, a phenylcarbamate derivative of physostigmine, has been shown to reduce cholinesterase activity. Phenserine has two forms(+) and(-). The(-) form was shown to have anticholinesterase activity; however, the(+) and(-) forms have been shown to reduce the levels of APP in neuronal cells in vivo via reduction of translation through repression of iron regulatory element in the 5'-untranslated region of APPmRNA.
In the earlier study we showed that neuroprogenitor cells (NT2/D 1) treated with phenserine at the concentrations of 50uM, l00uM showed significant reduction of APP protein level while its mRNA level was not changed.
At the same time treatment with conditional media from NT2/D 1 cells, transfected with APP, indicating secreted APP produced by NT2, induced glial differentiation of HNSCs into mainly GF AP positive cells.
In this study we are using only(+) phenserine, which does not have an anticholinesterase activity. Those findings could be very promising for the treatment of AD because (+) form of phenserine could reduce the levels of APP in the AD brain, promote neurogenesis, thus, transplantation with HNSCs could be possible.
Choumkina, Elena Alexandrovna, "Phenserine and possible outcomes of treatment" (2005). HIM 1990-2015. 500.