Alzheimer’s disease (AD), Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) are the most frequent age-related neurodegenerative diseases and causes of dementia. As of 2022, 8,000 people were affected by dementia in Luxembourg alone. Neurodegenerative diseases have no cure, and with treatment windows and options, remains a growing challenge for healthcare.

A growing medical and economic challenge

Even though there are multimodal treatment possibilities, neurodegenerative disorders are incurable to this day. Patients show only mild symptomatic clinical improvement, and this within a very narrow therapeutic window. The associated healthcare management is a growing medical and economic challenge.

“The human brain is a very complex organ in which not all processes and functions are discovered. Between individual patients the pathology and the corresponding symptoms are different,” explain Félicia Jeannelle, Sophie Schreiner and Mónica Miranda, researchers at the National Center of Pathology (NCP) working with the FNR PEARL Chair Prof Dr Michel Mittelbronn and Dr David S. Bouvier.

“The main challenge of our field is to understand the neurodegenerative diseases in their entirety. It is known that they are multifactorial diseases and several hallmarks have been already identified, however, we still have to understand their roles in the development and progression of these disorders. Furthermore, it cannot be ruled out that other yet unknown factors may also play a part in the development of these diseases.”

Research limited by complexity of human brain

The researchers explain that while the research and diagnostics of neurodegenerative diseases improve every year, the complexity of the human brain and the limited availability of human post-mortem tissue limit the research.

Researchers also use animal models since they are a useful resource to understand these diseases, but as there are strong differences to humans, it is essential to validate research findings by looking at human brains. Thanks to the collaboration of Prof Dr Michel Mittelbronn and Dr David S. Bouvier, the three PhD candidates, Félicia Jeannelle, Sophie Schreiner and Mónica Miranda, have access to a large collection of post-mortem human brains.

“Our group is in process to uncover new knowledge. We have the advantage to base our research on primary mouse cell culture (in vitro), mouse models (in vivo) and human post-mortem tissue (in situ). Our in vitro work focuses on the three main cell types of the brain (neurons, astrocytes and microglia) which allow us investigating the fundamental mechanisms and interplays behind these diseases in a dish.

“Furthermore, we collaborate with several brain banks in Luxembourg, Montreal, Paris, and the Netherlands, which provide us with the access to healthy, Alzheimer’s, Parkinson’s and Dementia with Lewy Bodies donated brains for post-mortem analysis.”

Understanding what’s behind brain cell dysfunctions

Félicia Jeannelle – a neuroscientist and PhD researcher at LNCP – has a focus on characterising the impact of the alteration of the noradrenergic system in brain cell dysfunctions and neurodegeneration and understanding its involvement in memory decline across the conditions of Alzheimer’s (AD), Parkinson’s (PD) and Dementia with Lewy Bodies (DLB).

Alzheimer’s, Parkinson’s and Dementia with Lewy Bodies have something in common: degeneration of the noradrenergic system, which plays a role in initiating and maintaining limbic and cortical stimulation. Noradrenaline (NA), the product of this noradrenergic system, is involved in key processes such as awareness, attention and memory. Due to its modulatory role of neuronal and glial cell activity and responses, it also plays an important role in the regulation of neuroinflammation and neuronal survival.

“Therefore, my research is focused on the characterisation of the modulatory role of noradrenaline on neuron and glial cell physiology and responses. Such characterisation in pathological contexts (e.g. AD, PD, DLB) is essential to possibly explain the impact of noradrenergic system degeneration on the vulnerability of certain brain regions (e.g. hippocampus, amygdala). Therefore, it may help clarify the onset of cognitive and behavioural phenotypes, such as memory decline or depression.” Félicia explains.

This insight would provide new insights into the understanding of the physiopathology of Alzheimer’s, Parkinson’s and Dementia with Lewy Bodies. It would also help in advancing therapeutic efforts against dementia progression.

“To do so, I’m working with primary mouse cells to try to understand the mechanistic behind the NA modulation as well as with post-mortem brain tissues from AD, PD and DLB patients, and age-matched control subjects, to define the alterations of the noradrenergic system within those disorders.”

Towards neuroprotective strategies

Sophie Schreiner, biologist and PhD researcher at the NCP, is working to establish neuroprotective strategies, to prevent the untimely neuronal death and with the ultimate goal to prevent Alzheimer`s disease onset.

A main characteristic of Alzheimer’s, Parkinson’s and Dementia with Lewy Bodies is neurodegeneration that is caused by axonal instability, cellular dysfunction, and, ultimately, cell death.

“The identification of neuroprotective pathways is crucial for developing therapeutic strategies to reduce neuronal cell death and improve patients’ care,” Sophie explains.

By using human brain tissue and so-called “primary neurons” Sophie is able to study phenotypic discoveries in a cellular model, with the aim to identify genes and associated pathways exerting neuronal resilience in-vivo.

A close look at the immunological mechanisms at play in Alzheimer’s

Mónica Miranda de la Maza, biologist and PhD researcher at Luxembourg Institute of Health (LIH), studies the interplay between microglia, astrocytes and peripheral immune cells in neuroinflammatory conditions in Alzheimer’s.

Chronic brain inflammation and impaired immunity play an important role in the neurodegenerative deterioration found in Alzheimer’s (AD) and several other neurodegenerative diseases.

“My project aims to decipher the interplay of astrocytes with microglia s  and peripheral immune cells, such as, T-cells and perivascular macrophages, which will unveil how they regulate, or fail to regulate, together neuroinflammation in AD, new facets of neuroinflammation in AD and potentially open new therapeutic strategies to alleviate the progression of the disease.”

Thanks to a translational approach that combines mouse cell cultures, high-throughput technologies in single cell RNA sequencing, as well as high-resolution microscopy, it is possible to generate high-content data on the immunological mechanisms at play in Alzheimer’s.

“We hope that our applied research will help designing new treatments to alleviate disease progression in Alzheimer and related dementias.”