Alzheimer’s Could be Treated With Gene Therapy: Mouse Study

Summary: Researchers report they have successfully prevented the development of Alzheimer’s in mice by using gene therapy delivered by a virus to the brain.

Source: Imperial College London.

Researchers have prevented the development of Alzheimer’s disease in mice by using a virus to deliver a specific gene into the brain.

Researchers have prevented the development of Alzheimer’s disease in mice by using a virus to deliver a specific gene into the brain.

The early-stage findings, by scientists from Imperial College London, open avenues for potential new treatments for the disease.

In the study, published in the journal Proceedings of the National Academy of Sciences, the team used a type of modified virus to deliver a gene to brain cells.

The research was funded by Alzheimer’s Research UK and the European Research Council.

Previous studies by the same team suggest this gene, called PGC1 – alpha, may prevent the formation of a protein called amyloid-beta peptide in cells in the lab.

Amyloid-beta peptide is the main component of amyloid plaques, the sticky clumps of protein found in the brains of people with Alzheimer’s disease. These plaques are thought to trigger the death of brain cells.

Alzheimer’s disease affects around 520,000 people in the UK. Symptoms include memory loss, confusion, and change in mood or personality. Worldwide 47.5 million people are affected by dementia – of which Alzheimer’s is the most common form.

There is no cure, although current drugs can help treat the symptoms of the disease.

Dr Magdalena Sastre, senior author of the research from the Department of Medicine at Imperial, hopes the new findings may one day provide a method of preventing the disease, or halting it in the early stages.

She explained: “Although these findings are very early they suggest this gene therapy may have potential therapeutic use for patients. There are many hurdles to overcome, and at the moment the only way to deliver the gene is via an injection directly into the brain. However this proof of concept study shows this approach warrants further investigation.”

The modified virus used in the experiments was called a lentivirus vector, and is commonly used in gene therapy explained Professor Nicholas Mazarakis, co-author of the study from the Department of Medicine: “Scientists harness the way lentivirus infects cells to produce a modified version of the virus, that delivers genes into specific cells. It is being used in experiments to treat a range of conditions from arthritis to cancer. We have previously successfully used the lentivirus vector in clinical trials to deliver genes into the brains of Parkinson’s disease patients.”

Image shows brain cells from a mouse cortex.

Image 1 shows brain cells from a mouse cortex that didn’t receive the gene therapy. The amyloid plaques are shown in green, and the glial cells, which surround the plaques, are shown in red (microglia) and magenta (astrocytes). Image 2 shows a mouse cortex that received the gene therapy, and so had fewer amyloid plaques. NeuroscienceNews.com image is credited to Imperial College London.

In the new study, the team injected the virus, containing the gene PGC-1 – alpha, into two areas of the brain in mice susceptible to Alzheimer’s disease.

The areas targeted were the hippocampus and the cortex, as these are the first regions to develop amyloid plaques in Alzheimer’s disease.

Damage to the hippocampus affects short-term memory, and leads to a person forgetting recent events, such as a conversation or what they ate for breakfast. The hippocampus is also responsible for orientation, and damage results in a person becoming lost on familiar journeys, such as driving home from the shops.

The cortex, meanwhile, is responsible for long-term memory, reasoning, thinking and mood. Damage can trigger symptoms such as depression, struggling to work out how much money to give at a checkout, how to get dressed or how to cook a familiar recipe.

The animals were treated at the early stages of Alzheimer’s disease, when they still had not developed amyloid plaques. After four months, the team found that mice who received the gene had very few amyloid plaques, compared with the untreated mice, who had multiple plaques in their brain.

Furthermore, the treated mice performed as well in memory tasks as healthy mice. The tasks included challenges such as replacing a familiar object in the mouse’s cage with a new one. If the mice had a healthy memory, they would explore the new object for longer.

The team also discovered there was no loss of brain cells in the hippocampus of the mice who received the gene treatment. In addition to this, the treated mice had a reduction in the number of glial cells, which in Alzheimer’s disease can release toxic inflammatory substances that cause further cell damage.

The protein PGC-1 – alpha, which is coded by the gene, is involved in metabolic processes in the body, including regulation of sugar and fat metabolism.

Dr Sastre added that other studies from different institutions suggest physical exercise and the compound resveratrol, found in red wine, may increase levels of PGC-1 – alpha protein. However, resveratrol has only been found to have benefits as a pill, rather than in wine, as the alcohol counteracts any benefit.

The team suggest injections of the gene would be most beneficial in the early stages of the disease, when the first symptoms appear.

They now hope to explore translating their findings into human treatments, said Dr Sastre. “We are still years from using this in the clinic. However, in a disease that urgently needs new options for patients, this work provides hope for future therapies.”

Dr David Reynolds, Chief Scientific Officer at Alzheimer’s Research UK, said: “There are currently no treatments able to halt the progression of damage in Alzheimer’s, so studies like this are important for highlighting new and innovative approaches to take us towards that goal. This research sets a foundation for exploring gene therapy as a treatment strategy for Alzheimer’s disease, but further studies are needed to establish whether gene therapy would be safe, effective and practical to use in people with the disease. The findings support PGC-1-alpha as a potential target for the development of new medicines, which is a promising step on the road towards developing treatments for this devastating condition.”

About this Alzheimer’s disease research article

Funding: The research was funded by Alzheimer’s Research UK and the European Research Council.

Source: Kate Wighton – Imperial College London
Image Source: NeuroscienceNews.com image is credited to Imperial College London.
Original Research: Full open access research for “PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model” by Loukia Katsouri, Yau M. Lim, Katrin Blondrath, Ioanna Eleftheriadou, Laura Lombardero, Amy M. Birch, Nazanin Mirzaei, Elaine E. Irvine, Nicholas D. Mazarakis, and Magdalena Sastre in PNAS. Published online October 10 2016 doi:10.1073/pnas.1606171113

Cite This NeuroscienceNews.com Article
Imperial College London “Alzheimer’s Could be Treated With Gene Therapy: Mouse Study.” NeuroscienceNews. NeuroscienceNews, 10 October 2016.
<http://neurosciencenews.com/genetics-alzheimers-neurology-5257/>.
Imperial College London (2016, October 10). Alzheimer’s Could be Treated With Gene Therapy: Mouse Study. NeuroscienceNew. Retrieved October 10, 2016 from http://neurosciencenews.com/genetics-alzheimers-neurology-5257/
Imperial College London “Alzheimer’s Could be Treated With Gene Therapy: Mouse Study.” http://neurosciencenews.com/genetics-alzheimers-neurology-5257/ (accessed October 10, 2016).

Abstract

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

Current therapies for Alzheimer’s disease (AD) are symptomatic and do not target the underlying Aβ pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aβ pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.

“PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model” by Loukia Katsouri, Yau M. Lim, Katrin Blondrath, Ioanna Eleftheriadou, Laura Lombardero, Amy M. Birch, Nazanin Mirzaei, Elaine E. Irvine, Nicholas D. Mazarakis, and Magdalena Sastre in PNAS. Published online October 10 2016 doi:10.1073/pnas.1606171113

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