Although neurodegenerative diseases have different causes, the dysfunction and loss of specific groups of neurons is common to all these disorders and may allow the development of similar therapeutic approaches to the treatment of diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD). The efforts to treat the neurodegenerative diseases by existing methods of cellular therapy are insufficiently effective. The modern methods do not provide correct restoration of cytoarchitecture and pattern of connections (the rewiring of specifically organized long-distance connections), which are essential to achieve a significant functional recovery. This article discusses existing methods of neural stem cell therapy and provides example of new approach to the treatment of various neurodegenerative diseases.

Neurodegenerative diseases are an assortment of central nervous system disorders characterized by neuronal loss and intraneuronal accumulation of fibrillary materials. Abnormal protein-protein interactions may allow the precipitation of these proteins, forming extracellular and intracellular aggregates. These abnormal interactions could play a role in the dysfunction and neuronal death that characterizes several common neurodegenerative diseases, such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD).

AD is the most common cause of dementia, with aging a major contributor to its onset. Currently, it is estimated that 40% of people over age 80 are afflicted with AD.  Autopsy examination of a patient’s brain reveals gross cerebral atrophy, signifying loss of neurons and the presence of large numbers of extracellular neuritic plaques and intracellular neurofibrillary tangles. Plaques and tangles are found predominantly in the frontal and temporal lobes, including the hippocampus. In more advance cases, the pathology extends to other regions of the cortex.  Similar plaques and tangles do occur in normal ageing brains.

PD is more common in people 60 years old and older. In the US, PD affects 1.5 million people. The degeneration and loss of dopaminergic neurons in PD causes akinesia, rigidity and tremor. Cell transplantation for the treatment of PD is the promising approach that has received most attention.

Cell therapy for PD

The potential of cell therapy for neurodegenerative diseases was demonstrated on implantation of different types of stem cells in the animals with PD (Kim J-H et al 2002, Parati EA et al 2003). Transplantation of stem cells into rat brain resulted in reinnervation of the striatal neurons and partial recovery of motor deficit associated with dopamine deficiency (Kim J-H et al 2002). The same results were obtained after transplantation of fetal dopaminergic neurons in clinical trials (Piccini P et al 2000, Freed CR et al 2001). It is possible to use different types of stem cells to generate dopaminergic neurons. Today the process of dopaminergic neurons differentiation from embryonic stem cells (ESC) in vitro is most effective and understandable (Kim J-H et al 2002, Isacson O, Ann Neurol 2003,  Isacson O, Lancet Neurol 2003, Barberi T et al 2003). Recent progress in human therapeutic cloning (Woo Suk Hwang et al 2004) makes this way to generate neurons more and more attractive. Differentiation of ESC in vitro and transplantation of dopaminergic neurons in the animal models of PD resulted in functional integration of implanted cells into recipient’s brain and partial recovery of motor functions (Kim J-H et al 2002, Barberi T et al 2003).

Although transplantation of neurons into striatum in PD model has a higher effectiveness in comparison with transplantation of neurons in other neurodegenerative disorders, it is too early to speak about full restoration of motor deficit associated with parkinsonism. In case of PD significant functional recovery requires cell replacement with, at least partial repair of original connections with neurons in the striatum. If such connections do not exist the full regress of motor deficit is impossible because dopamine release is under feedback control. This fact emphasizes the importance to develop effective methods to

The method to enhance accuracy of regeneration (Potential therapeutic strategy)

After transplantation stem cells make decisions regarding fate and patterning in response to external signals from extracellular environment and neighboring cells. The effectiveness of neural stem cell therapy may be facilitated by the ability to manipulate these signals in a temporal and spatially appropriate fashion (Liu CY et al 2003). The future methods of therapy could include in vitro processing of stem cells before implantation, supporting and guiding the cells after implantation with the help of nanorobots, as well as the in vivo creation of molecular scaffold (The Samuel I. Stupp Laboratory – sistagirl.ms.northwestern.edu, Silva GA et al 2004) for stimulating their growth in the correct direction.

During experiments on neonatal rats (Englund U et al 2002) the potential ability of neural stem cells to establish appropriate long-distance axonal projection after region-specific differentiation were shown. Unfortunately, adult brain, as compared to neonatal, has unfavorable conditions for axon growth in the correct direction. It is for this reason the stimulation of new neurons growth, for example along the surface of neurons in the zone of progressive degeneration, is necessary. The reconstruction of dysfunctional neural circuits may be facilitated in the following way . The proposed strategies are designed to increase accuracy of dysfunctional neurons regeneration.