A nanogel carrying an anti-PTBP1 antibody improved learning and memory test performance in a mouse model of Alzheimer’s disease

A nanogel carrying an anti-PTBP1 antibody improved learning and memory test performance in a mouse model of Alzheimer’s disease

On August 26, Cell Biomaterials published a paper on TN-PTBP1, a nanogel that delivers an anti-PTBP1 antibody to astrocytes. The authors detected neuronal markers and synchronized electrical activity in cells and human organoids. In 5XFAD mice, a model of Alzheimer’s disease, they observed changes in brain tissue and better performance on learning and memory tests.

In Alzheimer’s disease, the brain loses neurons and the connections between them, while the adult brain has little capacity to replace this loss. Astrocytes, which support neuronal function, could provide a source of cells for repair. PTBP1 regulates RNA processing in astrocytes and helps them maintain their cell identity. When PTBP1 levels fall, a neuronal program may become active in these cells.

PTBP1 has therefore been at the center of a long-running debate. Early studies reported that glial cells converted into neurons, but lineage-tracing studies that genetically labeled the cells of origin cast doubt on this conclusion. The authors of the current paper propose the following explanation:

“PTBP1 may simply not have been reduced below the threshold at which astrocytes can change their state.”

The authors use plasticity to mean the ability of astrocytes to change their cell type. They developed TN-PTBP1 to test this hypothesis. The nanogel carries an anti-PTBP1 antibody. Molecules on its surface help it cross the blood-brain barrier and enter astrocytes. Inside the cell, the antibody binds PTBP1, and TRIM21 directs the pair to the proteasome, the cellular machinery that breaks down proteins. The authors compared the result with a free antibody and a nanogel carrying a control antibody, allowing them to distinguish the effect of the antibody from that of the carrier.

Two weeks after primary human astrocytes were treated with TN-PTBP1, PTBP1 levels were less than 40% of the control level, while levels of DCX, a marker of immature neurons, increased. Using a microelectrode array that records cellular activity, the researchers detected synchronized electrical impulses. In human brain organoids, which are three-dimensional models of brain tissue, reduced PTBP1 was also accompanied by neuronal markers and electrical activity. These experiments examined the sequence from antibody delivery and target degradation to the function of the cellular network.

The researchers then gave eight-month-old 5XFAD mice two intravenous doses on days 0 and 8, each containing 4 mg of antibody per kilogram. Each group included six animals in the nest-building and learning tests. The test that counted crossings over the former location of the hidden platform included three animals per group. Mice treated with TN-PTBP1 built better nests and performed better in the Morris water maze, which requires them to find a hidden platform. In the hippocampus, the authors found lower levels of PTBP1 and GFAP, an astrocyte marker, and more cells positive for DCX and NeuN, markers of immature and mature neurons.

In 5XFAD mice, these findings associate reduced PTBP1 with a larger number of cells carrying neuronal markers and with changes in behavior. The authors add the following qualification:

“Markers alone cannot conclusively distinguish direct conversion of astrocytes into neurons from stimulation of endogenous neural progenitor cells.”

The authors examined each step in this sequence: antibody delivery into the cell, reduction of PTBP1, electrical activity in organoids, and behavior in mice.