R+D CSIC

Antibodies against Alzheimer's disease

Scientists at the Centre for Molecular Biology (CBM), joint center of the CSIC and the UAM, have developed antibodies that neutralise the SFRP1 protein, which according to recent studies is a crucial player in the pathogenesis of Alzheimer's disease and a promising therapeutic target. The aim is to obtain a drug that can delay the progression of the disease. Now they are searching for partners to scale-up the trial for clinical use.

Research by a team led by Paola Bovolenta of the Centre for Molecular Biology (CBM), a joint center of the CSIC and the Universidad Autónoma de Madrid, has revealed that SFRP1 (Secreted Frizzled protein 1) protein is overexpressed in the cerebrospinal fluid of Alzheimer's patients.

The increase in this protein appears to have three effects. One is that it accumulates in amyloid plaques, one of the hallmarks of the disease, where it promotes the formation and aggregation of toxic peptides. Secondly, it would also increase neuroinflammation and, as a third effect, it appears to interfere with synaptic activity, which in turn affects cognitive ability.

A preclinical trial in a murine model developed by the same team has shown that neutralizing the activity of SFRP1 protein counteracts all three effects. To do this, the researchers designed two monoclonal antibodies against the protein. This was the basis of an assay that has already been validated.

The results, published in Nature Neuroscience, showed that the overexpression of SFRP1 in rodents anticipated the appearance of amyloid plaques and dystrophic neurites. But when SFRP1 is genetically inactivated or neutralized with antibodies, the formation of amyloid plaques is reduced. This, the inactivation or neutralization of SFRP1, can also improve histopathological features associated with Alzheimer's disease, and prevent the loss of long-term potentiation – which is one of the neural mechanisms that make learning and memory possible – as well as cognitive deficits.
"Our study," the researchers said in the paper, "reveals that SFRP1 is a crucial player in the pathogenesis of the disease and a promising therapeutic target".

Since the first paper on the involvement of SFRP1 in the pathogenesis of Alzheimer's disease, the team has moved on. "On the one hand, we have analysed in more detail how this protein influences neuroinflammation and synaptic plasticity. These are very important aspects as there is growing evidence that these processes are critical in the progression of the disease," explains Paola Bovolenta.

Scaling up the trial for clinical use

On the other hand, the team continues studying the therapeutic potential of neutralising SFRP1 with antibodies. "We are studying their capacity for stopping the disease at different times in the disease process, as well as the distribution of the antibodies throughout the body, and the development of possible adverse effects that we have not yet detected.”
As a next step, the researchers plan to scale up the trial for clinical use, for which they are looking for industry partners. "The development and validation of a potential drug is time-consuming and requires a large workload that an individual lab like ours cannot tackle alone - we need partners who believe in or see the potential of our results!”

The goal is to obtain a drug that can slow the progression of Alzheimer's disease. "We believe that SFRP1 is a therapeutic target with a lot of potential because it has multiple functions, just as AD has multiple pathological aspects," concludes the researcher.

Reference article:
Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer's disease pathogenesis. Pilar Esteve et al.  Nat Neuroscience, 2019. doi: 10.1038/s41593-019-0432-1.

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