Alzheimer's research with potential: FWF funds 1000 Ideas project by Dr Manuel Hessenberger, MSc / Department of Physiology

Dr Hessenberger's recently funded project, which is dedicated to one of the greatest medical challenges of our time: Alzheimer's disease (AD), should also be seen in this context. The aim of the current project is to investigate the mechanisms by which amyloid beta (amyloid-β) deposits in the brain can be broken down more efficiently in order to prevent the onset of the disease or significantly influence its progression. Dr Hessenberger's research team is focusing on an innovative strategy: using specialised llama antibodies, so-called nanobodies, to specifically stimulate the breakdown of protein deposits in the brain and pave the way for a completely new possible therapeutic approach.

Alzheimer's: a global challenge

The social relevance of the project is enormous. "It is estimated that almost 50 million people worldwide suffer from dementia, with Alzheimer's accounting for 60 to 70 per cent of cases. This neurodegenerative disease leads to a gradual impairment of cognitive abilities such as memory, learning ability and orientation," explains Dr Hessenberger. "Alzheimer's is mainly caused by an increased accumulation or impaired removal of amyloid β proteins, which leads to the formation of amyloid β plaques and subsequently to increased inflammation of the nerve cells." Currently available drug therapies aim to slow down the progression of the disease, but a cure for Alzheimer's disease is not yet possible. Only recently, the US Food and Drug Administration (FDA) approved three monoclonal antibodies for clinical trials that specifically target amyloid-β to reduce these plaques. However, the treatment is only effective in the early stages of AD and is associated with a high risk of inflammation.

The key lies in microglia activation

Dr Hessenberger's project takes a promising approach by directly activating microglia to stimulate the uptake and removal of amyloid-β plaques. Microglia are considered the macrophages (scavenger cells) of the central nervous system and play a crucial role in the removal of protein aggregates and cellular debris in the brain. Over the years, two important risk genes for Alzheimer's disease have been identified that are located in microglia: TREM2 and CD33.

The latter is the focus of the KL project: originally investigated in connection with the diagnosis of acute myeloid leukaemia (AML), CD33 was identified in 2011 as one of the most relevant genetic risk factors for Alzheimer's disease. "This is where it gets really exciting, especially as CD33 was increasingly found in the cell membrane of microglia in brains affected by Alzheimer's disease," explains Hessenberger. Simply explained, CD33 can interact with amyloid-β. This inhibits the degradation process and subsequently leads to an increase in amyloid-β deposits in the brain. Surprisingly, animal models have shown that mice with a truncated variant of CD33 exhibit significantly increased uptake and digestion of amyloid-β by microglia. This makes CD33 a potential pharmacological target protein to prevent interaction with amyloid-ß.

Nanobodies as a therapeutic tool

This is where the innovative concept of the 1000-Ideas project comes in: The aim is to use identified CD33-specific single-domain antibodies (nanobodies) specifically against CD33 in order to block the interaction of CD33 with amyloid-β. "In total, more than 20 different nanobodies against CD33 have been described in the literature and have already been used as a diagnostic tool against AML. In the funded project, we are testing the hypothesis that some of these nanobodies bind with high affinity to CD33 and can therefore promote microglia-specific uptake and consequently also the degradation of amyloid-β," the project leader continues.

Scientific excellence promoted

The Austrian Science Fund is convinced of the project's innovative potential and is supporting the project with funding totalling 180,000 euros over a period of two years. The funding will enable the research team to carry out basic experiments on the effectiveness and specificity of the nanobodies and to investigate the effects on cell models and possibly in preclinical animal models.

Dr Manuel Hessenberger is optimistic about the future: "We hope that this project will enable us to take a decisive step towards developing new diagnostic and therapeutic options for Alzheimer's disease. The funding from the 1000 Ideas Programme is an important signal for creative and courageous research."