Longevity Briefs: Could We Reverse Cognitive Ageing With Gene Therapy?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Cognitive function gradually declines with increasing age, while age-related neurodegenerative diseases like Alzheimer’s disease become more likely. There are many different factors contributing to cognitive ageing, one being that neurons progressively lose support and die as we age. In both Alzheimer’s disease and general brain ageing, there is a decline in the level of a key survival protein called brain-derived neurotrophic factor (BDNF). Trophic means ‘relating to nutrition’, so neurotrophic means ‘neuron-nourishing’ or something that supports the growth of nervous tissue. BDNF is like a fertilizer for neurons: it helps them grow, survive, and form connections needed for memory.

Restoring BDNF in the ageing brain is therefore an attractive idea, but while introducing this protein into the blood might have some benefit on other organ systems, BDNF is too large to easily cross into the brain. Most of the neurological benefits come from BDNF that is produced locally within brain tissue. In this study, researchers developed a gene therapy that enhances BDNF protein production in the brain and show that it functions well in both mice and macaque monkeys.

The discovery:

Researchers developed a gene therapy based on an adeno‑associated virus called AAVT42 that efficiently delivers genetic material to neurons. They obtained this virus by directed evolution in the lab – essentially ‘shuffling’ the genes of an already existing virus, then screening and selecting the ones that were most capable of targeting neurons. They then loaded this virus with the human BDNF gene and injected it directly into the hippocampus (an area of the brain central to learning and memory) of three different Alzheimer’s mouse models (ranging from 7-9 animals per group) and into two macaque monkeys aged 11 and 14 (which could be considered ‘early middle-age’ in human terms). The BDNF gene was packaged with DNA encoding a fluorescent protein so that cells that had successfully incorporated the gene therapy could be identified. A virus containing only the DNA encoding the fluorescent protein was used as a control treatment.

Researchers found that AAVT42 was able to successfully deliver the gene therapy to hippocampal neurons in both mice and monkeys. What’s more, they found that the treatment significantly improved the performance of Alzheimer’s mice in maze tests (designed to test spatial memory) and the fear conditioning test (in which mice learn to associate a specific location or noise with a mild electric shock).

At the molecular level, researchers found that increased BDNF expression was associated with changes in the expression of key genes in the hippocampus related to neuron growth, survival and synaptic plasticity (the ability of neural connections to weaken or strengthen in response to stimuli).

The implications:

This research suggests that enhancing BDNF expression in the ageing hippocampus can slow or reverse cognitive decline in Alzheimer’s mouse models. While it is likely to be too invasive to be used for general cognitive ageing in humans, it is worthy of exploration for the treatment of debilitating neurodegenerative diseases. Some human clinical trials for BDNF gene therapies are already underway, but efficient delivery to the brain is still a major challenge.

While gene therapy has come a long way, the ability to ensure that this technology is delivered to the intended tissues is still the main ‘bottleneck’ preventing it from becoming more widespread. Advances in the development of gene therapy vectors (the component of the gene therapy – in this case the virus – that delivers the genetic material to the target) will gradually unlock more and more treatments that are currently being held back in this way.

Fortunately, there are multiple lifestyle interventions that have been shown to increase BDNF levels in the brain. Exercise increases BDNF production and may allow some BDNF to cross the blood-brain barrier for a time. Consumption of omega-3 fatty acids and plants rich in flavonoids is associated with higher BDNF levels, as is calorie restriction and fasting. Chronic sleep loss, on the other hand, is associated with lower BDNF levels.