Understanding the mechanisms of amyloid-β protein (Aβ) production and clearance in the brain has been essential to elucidating the etiology of Alzheimer disease (AD). Chronically decreasing brain Aβ levels is an emerging therapeutic approach for AD, but no such disease-modifying agents have achieved clinical validation. Certain proteases are responsible for the catabolism of brain Aβ in vivo, and some experimental evidence suggests they could be used as therapeutic tools to reduce Aβ levels in AD. The objective of this study was to determine if enhancing the clearance of Aβ in the brain by ex vivo gene delivery of an Aβ-degrading protease can reduce amyloid plaque burden.
Methods and Findings
We generated a secreted form of the Aβ-degrading protease neprilysin, which significantly lowers the levels of naturally secreted Aβ in cell culture. We then used an ex vivo gene delivery approach utilizing primary fibroblasts to introduce this soluble protease into the brains of β-amyloid precursor protein (APP) transgenic mice with advanced plaque deposition. Brain examination after cell implantation revealed robust clearance of plaques at the site of engraftment (72% reduction, p = 0.0269), as well as significant reductions in plaque burden in both the medial and lateral hippocampus distal to the implantation site (34% reduction, p = 0.0020; and 55% reduction, p = 0.0081, respectively).
Ex vivo gene delivery of an Aβ-degrading protease reduces amyloid plaque burden in transgenic mice expressing human APP. These results support the use of Aβ-degrading proteases as a means to therapeutically lower Aβ levels and encourage further exploration of ex vivo gene delivery for the treatment of Alzheimer disease.
Matthew Hemming and colleagues describe the ex vivo gene delivery of an Aβ-degrading protease that reduces amyloid plaque burden in transgenic mice expressing human amyloid precursor protein.
Alzheimer disease is the most common form of dementia and is increasingly common as people age. It may affect up to half of the population in people over 85 years of age. The classic pathological features of Alzheimer disease in the brain were described 100 years ago by a German neuropathologist, Alois Alzheimer. They consist of plaques, which are made up of a protein called amyloid-β protein (shortened to Aβ); and tangles of another protein, called tau. These proteins accumulate especially in areas of the brain where memory and thought are processed and are believed to be toxic to neurons. There are a number of inherited forms of Alzheimer disease which are caused by mutations either in the protein from which Aβ is derived, called beta-amyloid precursor protein (shortened to APP) or in other proteins that act to release the Aβ protein from APP. Research on these inherited forms of Alzheimer disease has helped in the understanding of how plaques accumulate, which has subsequently led to new potential approaches to the treatment of Alzheimer disease such as lowering the production of Aβ from APP or enhancing clearance of the plaques.
Why Was This Study Done?
The researchers here wanted to investigate the use of a type of gene therapy called ex vivo (which means out of body) gene therapy, in which cells are taken from an individual, genetically altered, then put back into the individual they were taken from. This approach has already been studied in some human diseases and conditions including hemophilia, cancer, and spinal cord injury. The researchers here wanted to investigate whether they could use this approach to deliver to the brain one of the proteases that breaks down amyloid plaques.
What Did the Researchers Do and Find?
The researchers used a mouse model of Alzheimer disease in which, as the mice age, they develop plaques in the brain made of the same protein found in human Alzheimer disease. The researchers took a particular type of cell from the mice called a fibroblast, used a virus called a lentivirus to insert into the cells a protease called neprilysin that can degrade Aβ, and then injected these altered cells into the brains of the mice. They then compared results of these experiments with what happened when cells with a control (an inactive virus) were injected. They found that when the active protease was put into the brains of mice there was a substantial clearing of plaques especially in the areas close to the injection site, compared with the control mice.
What Do These Findings Mean?
These results suggest that this ex vivo gene therapy approach to Alzheimer disease is worth considering further. However, despite showing that the plaques were cleared the researchers did not show whether or not there was any effect on the behavior of the mice, i.e., whether there was any effect on the symptoms that the plaques cause. In addition, before this approach could be used in humans more work would need to be done, including showing that the lentivirus and the protease used were safe in humans, and the injection could be scaled up to the much larger human brain.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040262.
The slides from the original cases that Alois Alzheimer described are available online
Current research is discussed by the Alzheimer Research Forum
News and information for researchers, doctors, and patients, including a 24-hour help line, are available from the Alzheimer's Association
Medline Plus, the health information site for patients from the US National Library of Medicine, has a page of links on Alzheimer disease
The US National Institutes of Health National Institute of Aging has a fact sheet on Alzheimer disease, which is also available in Spanish
The UK's National Health Service online information site has information on Alzheimer disease