Project Portugal 2030

Summary

Alzheimer's disease (AD) is the most common cause of dementia and is on the rise as the world's population ages, with a massive socio-economic burden. AD is characterized by the presence of amyloid beta (Aß) peptide, which aggregation triggers Tau neurofibrillary tangles (NTFs), being the soluble Aß oligomers the ultimate culprits in neuronal damage and subsequent memory loss. Unfortunately, current detection methods often result in late diagnosis with poor prognosis by detecting AD at late stages, we still lack the tools to detect the soluble oligomers. This goes against the current consensus among researchers that therapeutic strategies targeting Aß may be more effective at earlier stages, before the onset of symptoms and neurodegeneration. In addition, current anti-Aß therapies rely on expensive monoclonal antibodies (mAbs), which are not safe to use and have several side effects. Previous work from our group resorted to genetic manipulation of phages to engineer the filamentous phage M13 with amyloidogenic peptide motifs (from the Aß42 isoform), and our results have demonstrated the ability of the engineered phages to detect soluble oligomeric species of Aß and prevent Aß aggregation. Given our previous results, and recent exploratory data showing their therapeutic potential (Fig. 1), the main objective of HERCULES is to develop and validate a phage-based tool able to detect early soluble species of Aß and Tau, respect to its therapeutic efficacy. We will follow two main objectives: 1) Develop new phages against Aß and Tau in order to develop a multiplex phage-based tool to detect AD at different stages and monitor the disease progression. We will increase the repertoire of phages towards Aß (AB-phages) and develop new phages towards Tau (Tau-phages), resorting to the identification of new peptide motifs identified by Phage Display technology using as a target the plasma from non-demented and AD human donors. 2) Validate the therapeutic potential the synthetic phages We will validate the therapeutic potential of the already reported AB-phages (AB30-39 and AB33-42) able to detect Aß oligomers in brain tissue from mice and humans, and also the new phages towards Aß and Tau. Exploratory results from our group, using in vivo cognitive assays with one of the engineered phages (AB30-39), showed that the cognitive deficits of transgenic mice (AD-mice) are rescued, and these animals behave like the wild-type littermates (Fig. 1B). We will first use Aß and Tau pathology models of the nematode Caenorhabditis elegans (widely used by scientific community as a powerful tool to study disease mechanisms and drug screenings), and then a mice-model of AD expressing Aß and Tau pathology, to assess if the engineered phages have therapeutic action regarding their effect on synapses and prevention of memory deficits. HERCULES is a breakthrough technology based on phages displaying a molecule of interest at their surface, being commonly used for biomedical applications. One of HERCULES’s biggest advantage is the fact that it can be further expanded to tackle other neurodegenerative diseases, where misfolded proteins play a central role, such as Dementia with Lewy bodies (DLB), Parkinson's disease (PD), Huntington's disease and amyotrophic lateral sclerosis.