Genetically Modified As a Potential Treatment of Alzheimer’s Disease

A neurobiology team from UC Irvine (full disclosure, my alma mater) has used genetically engineered neural stem cells to treat mice with a form of Alzheimer’s disease (AD). Such implanted neural stem cells ameliorated some of the symptoms and pathological consequences of this disease in affected mice.

Patients with AD show accumulation of the protein amyloid-beta in their brains. These amyloid-beta clusters form clear plaques in the brain that are also quite toxic to nearby neurons.

Amyloid beta plaques can be cleared with the protein in them is degraded. Fortunately, the enzyme neprilysin can degrade these plaques, but the brains of AD patients show low levels of this enzyme. Neprilysin levels decrease with age and this is probably one of the reasons AD tends to be a disease of the aged.

The UC Irvine group, under the direction of Mathew Blurton-Jones, tried to deliver neprilysin to the brains of afflicted mice and used neural stem cells to do it. The goal of this work was to determine if increased degradation of the amyloid plaques abated the pathological effects of AD.

In this work, two different AD model systems were used. Thy1-APP and 3xTg-AD mice both exhibit many of the pathological effects of AD, and both were used in this study. Neural stem cells were transfected in express 25 times more neprilysin that normal. Then these genetically modified neural stem cells were transplanted into two areas of the brain known to be affected by AD: the hippocampus and the subiculum, which lies just below the hippocampus. Other AD mice were transplanted with neural stem cells that had not been transformed with neprilysin.

Post-mortem examination of both groups of mice even up to three months after transfection of the neural stem cells showed that those mice that received injections of neprilysin-expressing neural stem cells had significant reductions in amyloid-beta plaques within their brains compared to control mice. The neprilysin-expressing cells even seemed to promote the growth of neurons and the establishment of connections between them.

A truly remarkable finding of this work was that numbers of amyloid-beta plaques were also reduced in area of the brain that were some distance from the areas where the stem cells were injected. This suggests that the injected stem cells migrates across the brain, reducing plaque formation as they went.

Future experiments will seek to see if the reduction in amyloid-beta plaques also leads to improvements in cognition. Also, before this protocol can make its transition from animal models of human trials, the UC Irvine group will need to determine if the neprilysin also degrades soluble forms of amyloid-beta.

Every AD mouse model varies as to the types of pathologies observed in the brains of the affected mice. For this reason, this group tested their treatment strategy in two distinct AD mouse models, and in both cases, the neprilysin-expressing neural stem cells reduced the incidence of amyloid beta plaques. This strengthens the conclusion and neprilysin-expressing neural stem cells can indeed degrade amyloid-beta plaques.

More work needs to be done before this work can be used to support a human trial, but this is certainly an encouraging start to something great.


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Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).