Gene therapy designed to target cause of Alzheimer's disease

A gene therapy that strengthens brain cell connections in mice may help protect memory in Alzheimer's disease patients, according to a new study.

Previously, researchers at the University of California San Diego found that a protein called caveolin-1 (cav-1), which helps organise parts of the cell membrane that are essential for healthy brain cell communication, is decreased in a mouse model of Alzheimer's disease. Hypothesising that increasing cav-1 expression could be a promising treatment for Alzheimer's disease, they developed a gene therapy, SynCav1, which uses an adeno-associated virus vector to deliver synapsin-cav-1 cDNA. Delivering the therapy to the hippocampus of pre-symptomatic mice demonstrated neuroprotective effects. Now, the researchers have demonstrated the therapeutic effect of the SynCav1 gene therapy at the symptomatic stage of Alzheimer's disease in mice.

'SynCav1 demonstrated a promising effect in preserving cognitive function despite being given at the symptomatic stage. While multiple newly FDA-approved treatments focus on targeting [amyloid plaque] clearance in [Alzheimer's disease] patients, the therapeutic value of SynCav1 lies in its ability to protect vulnerable neurons,' the authors wrote in Signal Transduction and Targeted Therapy.

Alzheimer's disease, characterised by progressive memory decline, is a neurodegenerative disease affecting millions of people worldwide. Currently, most treatments focus on removing amyloid plaques, toxic clumps of protein that build up in the brain and cause brain cell death. These treatments can slow disease progression in some patients but do not fully stop memory loss.

In this study, the scientists injected the SynCav1 gene therapy directly into the hippocampus, a brain area important for memory, in two types of mouse models of Alzheimer's disease, one of which carries three human amyloid precursor protein mutations.

Even after the mice had begun to show memory problems, the gene therapy helped preserve their ability to form and recall memories. Furthermore, the treatment did not cause problems with movement or anxiety, indicating its safety in mice.

Genetic analysis showed that the mice with symptomatic Alzheimer's disease treated with the gene therapy had similar gene expression patterns as healthy mice. The gene therapy also increased the expression of genes involved in learning, memory, and brain cell connections, while decreasing expression of genes linked to neurodegeneration. In particular, the researchers reported the increased expression of ADNP, a key gene that helps protect nerve cells and support brain structure, as well as PAC1R, which helps regulate ADNP.

The researchers note that, unlike drugs which target amyloid plaques directly, this approach works by protecting vulnerable brain cells and enhancing the brain's own protective responses, offering a potentially complementary way to treat Alzheimer's disease.

They suggest that combining their gene therapy approach with current amyloid-targeting drugs might one day offer even greater benefit: 'Due to the multitude of neurotoxicity in the [Alzheimer's disease] brain, further studies are warranted to investigate SynCav1's therapeutic role when combined with amyloid-targeted drugs to enhance clinical outcomes.'

While these results are promising, the therapy has only been tested in mice so far. The researchers acknowledge that more work is needed to test its safety and effectiveness in people.