Dementia affects over 35 million people worldwide, with figures set to double by 2030 according to the World Health Organization. Alzheimer’s disease (AD) is the leading cause of dementia, however current treatments for this disease are unable to halt or reverse disease progression. The underlying pathology of AD is tied to the development of beta-amyloid plaques and the subsequent cascade of destructive events that this initiates, leading to nerve cell damage. Efforts to repair this damage have revealed that transplantation of neural stem cells can improve cognition in mouse models of the disease, however with no effect on the aggregation of beta-amyloid. In a recent study in Stem Cell Research & Therapy Mathew Blurton-Jones from the University of California Irvine, USA, and colleagues sought to combine the beneficial effects of neural stem cell transplantation with an enzymatic approach to target beta-amyloid degradation. Here Blurton-Jones discusses their results, which show that neural stem cells expressing the enzyme neprilysin can reduce beta-amyloid pathology in mouse models of AD, and how this approach may impact future treatment.
What are the current problems in the treatment of Alzheimer’s disease?
Currently approved drugs for Alzheimer’s (AD) are palliative and fail to modify the long term progression of the disease. Drug development and recent clinical trials have primarily focused on approaches that aim to decrease beta-amyloid production or increase its clearance from the brain. Unfortunately, these approaches have thus far failed and in some cases led to troubling side effects (Nature 2002, Jan 31, 415(6871):462 and N Engl J Med 2013; 369:341-350). There is therefore a clear need to study and develop novel therapeutic approaches.
What is the underlying pathology that causes Alzheimer’s disease?
The great majority of AD researchers believe that the most upstream cause of AD is the accumulation and aggregation of beta-amyloid within the brain. However, beta-amyloid in turn appears to drive several other key pathologies including neurofibrillary tangle formation, neuronal and synaptic loss, and inflammation. This schema is commonly referred to as the amyloid cascade hypothesis and is strongly supported by genetic and transgenic studies (Science 1992,10 April, 184-185).
However, recent imaging data suggest that beta-amyloid accumulation begins many years before cognitive dysfunction (reviewed in Lancet Neurol 2010, Jan, 9(1):119-28). This may therefore explain why anti-amyloid therapies have thus far failed in clinical trials. One additional important point regarding AD pathology is that synapse loss correlates more closely with cognitive dysfunction than beta-amyloid and tangle pathology (Ann Neurol 199, Oct, 30(4):572-80). This suggests that a combinatorial therapy that not only targets beta-amyloid but also increases synaptic plasticity could be beneficial.
What has been shown previously with neural stem cell transplantation and Alzheimer’s disease?
Our group previously examined neural stem cell (NSC) transplantation in 3xTg-AD mice (Proc Natl Acad Sci U S A 2009, Aug 11, 106(32)) and a transgenic model of hippocampal neuronal loss (J Neurosci 2007, Oct 31,27(44)). In both of these studies we found that murine NSCs could improve cognition. Interestingly, NSC transplantation had no effect on either beta-amyloid or tangle pathology in 3xTg-AD mice. Instead, transplanted NSCs increased hippocampal synaptic density and NSC-derived BDNF was necessary for these effects. Recently, other groups have reported similar data that NSCs can improve cognition without effecting beta-amyloid or tau pathology (J Neurosci 2010, Jul 28,30(30):9973-83; J Neurosci Res 2014 Vol 92, 2, 185–194; Mol Neurobiol 2014, Vol 49, 1, 66-77).
How else could neural stem cells be used in the treatment of Alzheimer’s disease?
A major advantage to neural stem cells (NSCs) is that they can migrate considerable distances toward areas of injury and inflammation (Proc Natl Acad Sci U S A 2004 Dec 28, 101(52):18117-22). This suggests that NSCs could be an ideal vehicle to deliver therapeutic proteins such as neprilysin to the brain. Given the extensive distribution of AD pathology, NSCs could likely provide more widespread delivery than current viral gene therapy approaches. As we’ve previously shown, NSCs can also produce high levels of neuroprotective proteins such as neurotrophins, potentially providing additional benefits (Proc Natl Acad Sci U S A 2009, Aug 11, 106(32):13594-9).
In your current study you express the proteolytic enzyme neprilysin in the transplanted neural stem cells. What role do you think this could play as a potential treatment in Alzheimer’s disease?
Neprilysin is one of a few key enzymes in the brain that can degrade beta-amyloid. Studies suggest that neprilysin decreases with age and may therefore influence the risk of AD (reviewed in Neuron 2001, 32, 177-180). If amyloid accumulation is the driving cause of AD, then therapies that either decrease beta-amyloid production or increase its degradation could be beneficial, especially if they are started early enough. A great deal of effort has already been put forward to develop drugs that could inhibit beta-amyloid production. However, many of these compounds appear to have significant side effects. The other side of the coin is to also develop drugs that can increase beta-amyloid degradation by increasing either the expression or activity of enzymes like neprilysin.
In your study, you used two different mouse models of Alzheimer’s disease to investigate the effect of neural stem cells expressing the enzyme neprilysin. Why was this?
Every mouse model of AD is different and develops varying amounts, distribution, and types of beta-amyloid pathology. By studying the same question in two independent transgenic models, we can increase our confidence that these results are meaningful and broadly applicable to AD.
What further research is needed?
There is clearly a great deal more research needed to determine whether this kind of approach could eventually be translated to the clinic. Probably the most important question is whether a clinical grade human neural stem cell line can be identified that can safely provide equivalent synaptic and behavioral benefits. Another key question is how best to modify that line to express neprilysin. One would likely need to target the neprilysin transgene into a single safe-harbor integration site and then confirm the safety of the cells. Given that neprilysin can degrade a handful of other substrates (i.e. enkephalin, substance P), it would also be important to determine whether neprilysin overexpression can produce any troubling side effects.
Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models
Stem Cell Research & Therapy 2014, 5:46
Go to article >>