CD33-specific nanobodies to treat Alzheimer´s disease

According to estimates, nearly 50 million people worldwide suffer from dementia, with 6070% of cases attributed to Alzheimer`s disease (AD). This neurodegenerative disorder impairs essential cognitive functions such as memory and learning. Alzheimer`s is primarily caused by the excessive accumulation or impaired clearance of amyloid-beta (Aß) peptides, leading to the formation of Aß plaques and, subsequently, increased inflammation of nerve cells. Recently, the FDA has approved three monoclonal antibodies for clinical trials that specifically target Aß to reduce plaque formation. However, the treatment is only effective in the early stages of AD and is associated with a high risk of inflammation. To date, no adequate cure or therapy for AD has been found. A promising approach involves the direct activation of microglia to enhance the uptake and clearance of Aß plaques. Microglia are considered the macrophages of the neural system, responsible for "uptake and digesting" protein aggregates and other cellular debris. Over the years, two major Alzheimer`s risk genes located on microglia have been identified: TREM2 and CD33. Interestingly, CD33 has already become a focus of research as it is an attractive target for the treatment of acute myeloid leukemia (AML). In 2011, CD33 was characterized as one of the highest-ranked risk factors for AD. It has been shown that CD33 expression is increased on microglia in AD brains. In short, CD33 can interact with Aß, which inhibits the digestion process and subsequently leads to an accumulation of Aß in the brain. Remarkably, mouse models expressing a truncated variant of CD33 show enhanced Aß degradation by microglia and consequently fewer Aß plaques in the brain. In summary, CD33 represents a potential pharmacological target to prevent interaction with Aß. In this project, we aim to use already identified CD33-specific single-domain antibodies (nanobodies) to specifically target CD33 and disrupt the Aß-CD33 interaction. In total, more than 20 different nanobodies against CD33 have been described in the literature, some of which have already been used as diagnostic tools for AML. We hypothesize that some of these nanobodies bind to CD33 with high affinity and can thereby promote microglia-specific Aß uptake and degradation.