|
Neural Stem Cells to the Rescue—Can Neuroreplacement Ever Become a Treatment for Alzheimer's?
|
|
|
Kiminobu Sugaya led this live discussion on 9 July 2002. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
|
 View Transcript of Live Discussion — Posted 29 August 2006
Background Text
By Kiminobu Sugaya
The discovery of multipotent neural stem cells (NSCs) in the adult brain (Gould, 1999) has brought revolutionary changes to the theory of neurogenesis. This theory now suggests that regeneration of neurons can occur throughout life. Recent advances in stem cell technologies are expanding our capability of eventually replacing many types of tissues throughout the body. In particular, the successful transplantation of human NSCs (HNSCs) into aged rats with subsequent improvement of cognitive function (Qu et al., 2001) reinforces the potential feasibility of HNSC transplantation therapy for neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's (Fricker, 1999; Snyder, 1997).
Parkinson's disease has been a good target for neuroreplacement therapy because of its specific loss of large projecting dopaminergic neurons in the substantia nigra. These neurons are sending dopaminergic projections to the striatum, hence conventional treatment for Parkinsons' augments the dopamine content in the striatum with L-dopa. Based on experience with L-dopa treatment, transplantation of fetal tissue producing dopamine to the striatum of PD has been tested for many years. Many of the clinical trials significantly ameliorated the behavioral deficit, though with significant side effects (see ARF news story). However, the use of human fetal neuronal tissue not only raises ethical concerns but also is impractical because neural tissue from multiple fetuses is required for each patient. Thus we must seek alternatives to fetal tissue.
Neural stem cells, capable of spontaneously differentiating into neurons and glia, are the most promising candidates. Stem cells are often defined as self-renewing and multipotent. They can be isolated from the embryonic and adult rodent central nervous system and propagated in vitro in a variety of culture systems (Brannen, 2000; Doetsch, 1999). Our inability to grow NSCs in serum-free culture media has long been a major obstacle in understanding their physiology. Now, however, NSCs can be maintained or expanded in serum-free medium containing basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) (Brannen, 2000, Fricker 1999). HNSCs differentiate into cells immuno-positive for the neuronal marker bIII-tubulin and the astrocyte marker glial fibrillary acidic protein in an unsupplemented medium, suggesting the genesis of neurons or astrocytes without exogenous differentiation factors. This capability to expand multipotent HNSCs in vitro offers a well-characterized and efficient source of transplantable cell types.
Even so, many researchers are still trying to differentiate dopaminergic cells in vitro and then transplant them into the basal ganglia as dopamine-release vehicles in the target area (Clarkson, 2001). This approach seems natural, just as we were transplanting the fetal dopaminergic tissue to the basal ganglia to increase its dopamine content, however, we must consider several issues. First, fully differentiated neuronal cells do not migrate, meaning they sit at the injection site. Second, a "cure" for PD is conceivable only if we replace degenerating dopaminergic neurons in the substantia nigra. Dopaminergic neurons transplanted to the basal ganglia may not be functionally regulated by the host brain, which may be a cause of side effects (Freed, 2001). Third, if the injection is made into the brain, the concomitant tissue destruction will cause monocyte recruitment, and the ensuing immune response will eliminate the transplanted cells. To avoid these problems, I suggest injecting undifferentiated stem cells into the brain ventricle.
Our group has succeeded in recovering cognitive function in aged rats by intraventricular injection of neural stem cells. Yet this work did not take into account the effect of pathological changes of the diseased brain, which may prevent regular differentiation or migration of the stem cells. For example in thinking about neuroreplacement therapy for AD, we must consider the following issues:
1. Can we replace long-projecting cholinergic neurons?
2. Does AD pathology affect stem cell biology? How?
In AD, memory deterioration involves degeneration of basal forebrain (BF) cholinergic neurons, so this neuron population should be replaced. Their long projections and expression of nerve growth factor receptor make cholinergic neurons phenotypically different from dopaminergic neurons. This has led some researchers to declare BF cholinergic neurons irreplaceable. However, it has since been shown that BF cholinergic neurons transplanted into striatum and nucleus basalis of Meynert (NBM, which provides major cholinergic input to the neocortex) of adult rat brain survived and expressed the cholinergic phenotype (Martinez-Serrano, 1996). Furthermore, engrafted cholinergic-rich (but not non-cholinergic) cell suspensions reversed the deficits in radial-arm maze performance previously caused by NBM excitotoxic lesion (Sinden, 1995). Although these results hint that it may be possible to replace BF cholinergic neurons, we have to prove that degenerating BF cholinergic neurons in AD can be replaced by HNSC transplantation.
How Does AβPP Enter the Picture?
While the physiological functions of AβPP remain unclear (join the other chats in this series!), prior work has generated a host of possibilities. The ones relevant to this discussion include AβPP's possible involvement in neurite outgrowth (Roch, 1993; Salinero, 2000); NSC proliferation (Hayashi, 1994; Ohsawa, 1999); epidermal basal cell proliferation (Hoffmann, 2000); neuronal migration (De Strooper, 2000); and neuronal differentiation (Ando, 1999). AβPP expression increases after brain injury, neuronal loss (Murakami, 1998) and axonal injury (Koszyca, 1998). AβPP potentiates the effect of neurotrophin (Wallace, 1997; Wang, 2000), and treatment with a monoclonal antibody to AβPP induces neuronal apoptosis, indicating the involvement of AβPP in cell survival (Rohn, 2000).
In our recent study (Society for Neuroscience 2000, http://sfn.ScholarOne.com/itin2001/; search by Sugaya), unsupplemented, serum-free differentiation causes HNSC apoptosis associated with an increase in AβPP expression. A monoclonal antibody recognizing the N'-terminal of AβPP inhibited this HNSC differentiation, but the addition of an exogenous a-secreted AβPP (sAβPP) to the culture media accelerated it. Furthermore, exogenous sAβPP induces gliogenesis rather than neurogenesis of HNSCs. These results indicate that apoptotic cells release AβPP fragment(s) to increase HNSC differentiation into glial cells, possibly contributing to gliogenesis seen in AD. Overexpression of AβPP in HNSCs by transfection with wild-type AβPP also induced glial differentiation.
Recently, Bahn et. al., reported that stem cells from people with Down's syndrome differentiated into astrocytes rather than neurons (see ARF news story. Since Downs' patients have inherited three copies of AβPP, (which resides on chromosome 21,) this abnormal differentiation may result from an overdose of AβPP. Down's patients develop AD by age 40. Given all this, transplantation therapy of AD with HNSCs may not be effective in an environment where AβPP metabolism is altered, since it might lead to excessive gliogenesis.
What are the implications of these findings for AD? It is not clear whether adult neurogenesis is essential for normal cognitive function in age. Yet it is tempting to speculate that pathologically altered AβPP metabolism could impair NSC migration and differentiation into the proper ratio of neurons and glia. Aged transgenic AβPP mice exhibit neuronal loss and extensive gliogenesis in the neocortex (Bondolfi, 2002). Although the rate of endogenous neuroregeneration in the adult brain may be minimal, in the long run a defect in this process might significantly harm normal brain function.
Incidentally, this possibility raises the question whether Aβ immunization, which may also reduce AβPP fragments, is helpful for maintaining stem cell function in AD? Here is why I say no to this question: HNSCs transplanted into AβPP knockout mice did not migrate or effectively differentiate into neurons in the cerebral cortex, where we have seen beautiful neural differentiation of transplanted HNSCs in wild-type mice (Society for Neuroscience, 2000). HNSCs may play important roles in neuroregeneration, and if AβPP is, indeed, involved in the regulation of HNSCs, as we propose, destruction of the AβPP system may jeopardize the maintenance of brain function.
Many in the field are talking about clinical trials of NSC transplantation for AD, though none are underway yet. This approach will take time to establish itself as a therapy for AD. We need to know what good NSCs can do in the AD brain and how the AD brain environment affects NSC biology. I hope our effort in stem cell and AD research will cut down the time needed to develop a better treatment for AD.
Reference:
Sinden, J., Hodges, H. and Gray, J., Neural transplantation and recovery of cognitive function, Behavioral and Brain Sciences, 18 (1995) 10-35.
|
|
|
|
Submit a Comment on this Live Discussion
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Home
Webinar: A Webinar is a seminar conducted remotely over the Web. Attendees view the slides through their Web browser and hear the presentations over their own telephones. 
