Longevity Briefs: Regenerating Lost Brain Cells With Antibodies

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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:

The adult brain has very limited ability to grow new neurons (brain cells), which means that cognitive function can only really change in one direction with increasing age: downhill. Beyond normal cognitive decline is Alzheimer’s disease, a devastating consequence of ageing in which large numbers of neurons die, resulting in the loss of memory and learning ability. Current treatments can only slow down the progression of Alzheimer’s but cannot stop or reverse it. Even if a treatment was developed that completely halted the progression of Alzheimer’s, there would be no way to restore the brain function that had already been lost.

As bleak as this sounds, there are ideas about how the brain could be rebuilt in the wake of neurodegenerative disease. One idea is to target the astrocytes – the star-shaped ‘support cells’ within the brain – to encourage them to turn into neurons. Astrocytes have a wide range of functions including metabolic regulation, maintaining the blood-brain barrier, influencing synaptic transmission and overseeing the repair process following injuries. Previous studies showed that removing a protein called PTBP1 (polypyrimidine tract-binding protein 1) could cause astrocytes to transform into neurons. Efforts were then made to suppress the gene responsible for producing PTBP1 using gene therapy (delivering genetic material that would ‘switch off’ the PTBP1 gene). However, these attempts ran into problems.

In order to reach the brain, gene therapies must be packaged into harmless (non disease-causing) viruses that can then enter the target cells and deliver the therapy. The delivery method (or vector) can’t be too large, or it won’t be able to cross the blood-brain barrier and reach the astrocytes. This also limits the available cargo space inside the vector, which restricts scientists’ ability to design gene therapies that target astrocytes specifically, as targeting specific cell types requires additional genetic code. Early attempts to target PTBP1 either failed to work effectively, produced inconsistent results, or couldn’t target astrocytes without damaging other brain cells. It looks as though researchers may finally have circumvented this problem by developing a treatment that relies not on gene therapy, but on antibodies targeting the PTBP1 protein itself.

The discovery:

Researchers developed a new delivery system called TN-PTBP1 – essentially a tiny engineered particle (about 128 nanometers in diameter, roughly 1/1000th the width of a human hair) loaded with antibodies designed to destroy PTBP1 protein. The particles incorporate molecules to enhance their uptake by astrocytes, where they release their antibodies. These antibodies then bind to PTBP1 and trigger its degradation through a cellular recycling mechanism called the proteasome, which can be likened to the cell’s ‘garbage disposal’ system.

Researchers first tested this method on human astrocytes, and found that the treatment successfully transformed them into neuron-like cells with long axons (nerve fibres that project out from the cell body). Importantly, these weren’t just changes in cell structure – the converted cells were capable of producing electrical signals like real neurons and formed functional networks with other cells.

Next, researchers tested TN-PTBP1 on miniature brain-like structures grown from human stem cells called organoids. They recreated Alzheimer’s-like conditions in these organoids, resulting in a loss of neuron density similar to that seen in Alzheimer’s disease. TN-PTBP1 treatment reversed these changes, with electrical recordings showing that the regenerated neurons were functionally active and integrated into neural circuits.

Finally, the team tested the treatment in a mouse model of Alzheimer’s disease in which mice develop cognitive decline by 8 months of age. Groups of 6 mice received two intravenous injections of either TN-PTBP1, a control treatment in which the particles contained a different antibody, free PTBP1 antibody without the delivery system, or a saline solution. They found TN-PTBP1-treated mice showed progressive improvement in nesting behaviour (an early indicator of cognitive dysfunction) and learnt the Morris water maze task faster (a test of whether mice can remember the location of a platform under the water). Brain tissue analysis showed a reduction of PTBP1 in astrocytes after TN-PTBP1 treatment, alongside increased markers of new neurons and reduced levels of inflammation (with inflammation being a key component of Alzheimer’s).

The implications:

This is perhaps the most promising research to date suggesting that astrocytes could be converted into functioning neurons as a way to reverse some of the cognitive decline that occurs in Alzheimer’s. It uses an entirely new approach – rather than trying to ‘silence’ the responsible gene, antibodies targeting the PTBP1 protein are delivered selectively to astocytes.

The fact that this treatment successfully turned astrocytes into neurons in human organoids is encouraging, but we still don’t know if this would result in any meaningful effects in human Alzheimer’s patients. Mouse models of Alzheimer’s are imperfect as they represent a greatly accelerated form of the disease (wild mice do not ordinarily develop Alzheimer’s). We shouldn’t get too excited about this approach just yet – more animal research will be required to confirm these results, and human clinical trials would take many years to complete. The best defence against Alzheimer’s remains prevention – fortunately, we may have more control over our risk of Alzheimer’s than was once believed.