JPND The locus coeruleus: at the crossroad of dementia syndromes

The locus coeruleus (LC) is a brain area involved in important brain functions, including attention, memory, and wakefulness. It contains neurons (nerve cells) that use noradrenaline (Norepinephrine) as transmitter that are connected to other brain areas. These are often affected by brain diseases that result in neuronal loss, such as Alzheimer's disease, Down syndrome and Parkinson's disease. Loss of LC neurons may underlie similarities in symptoms between these diseases.

Our consortium have found that early markers of dementia in Down syndrome (which is due to an extra chromosome 21) and in other dementias may relate to LC cell loss.

Building on previous work, the goal of our project is now to uncover the common mechanisms and pathways associated with LC cell loss that is caused by dementias due to Down syndrome, Parkinson's disease, and Alzheimer's disease.

We will use state-of-the-art technologies to
(i) explore cell degeneration and cell function alterations in the LC of post-mortem brain material, stem cells derived from patients, and in mouse models of these diseases
(ii) Better understand the noradrenaline system in patients with and without dementia using blood and spinal fluid biomarkers and PET brain scan studies, and relate this to established biomarkers
(iii) analyze the involvement of specific genes on chromosome 21 in Alzheimer's disease, Parkinson's disease, and Down syndrome and explore their role as common risk or protective mechanisms for dementia.

The work will provide better knowledge of biomarkers related to LC degeneration, and their relationship to other dementia biomarkers and to dementia status across patient groups. This will help to improve clinical diagnosis, and also provide important information on biomarkers of dementia progression that will be valuable for prognosis and future clinical studies. The work will also provide improved knowledge of common causes and pathways of cell degeneration across patient groups, which could help to identify new treatment strategies.

Noradrenergic projection neurons from the locus coeruleus (LC) mediate attention, memory, and arousal and their loss occurs early in neurodegenerative conditions, such as Alzheimer's disease (AD), Down syndrome (DS) and even more in Parkinson's disease (PD). Consequently, LC neuronal loss affects the function of target areas such as the hippocampus and the cerebral cortex. Evidence from our consortium and others, suggests that AD, DS and PD may share key mechanisms of LC degeneration, affecting early onset and/or progression of neurodegenerative process.
Our consortium has been successful in identifying new biomarkers of AD in DS, some of which have already been validated in sporadic AD and are also common to PD. Specifically, alterations in the endo-lysosomal system (within which amyloid-beta processing occurs) and changes in noradrenaline and its main metabolite (3-methoxy-4-hydroxyphenylglycol, MHPG) due to LC degeneration were found to be early markers of dementia in DS and also in other dementias.
The goal of this project is now to uncover the common mechanisms and pathways related to dementia associated with LC degeneration among these three neurodegenerative diseases (AD, DS and PD). By using state-of-the-art technologies we will (i) characterize noradrenergic neurodegeneration and endo-lysosomal alterations in the LC of post-mortem brain material, iPSC-derived neurons/cerebral organoids from AD, DS and PD patients, and mouse models (WP1/2); (ii) characterize the noradrenergic system functionality in patients with and without dementia using biomarkers and PET studies (WP1); (iii) analyze the involvement of specific chromosome 21 genes (such as DYRK1A and APP) in AD, DS and PD pathways and their role as common risk or protective mechanisms for dementia (WP3); and (iv) identify common genes and pathways using transcriptomic studies (RNAseq) in the LC and validate new targets in post-mortem material from AD, DS and PD patients (WP4).

The main results expected by the project will fall mostly under the following categories:

New knowledge about common molecular, cellular and pathophysiological mechanisms in DS, AD and PD;
New molecular, neuroimaging and cognitive biomarkers across our target diseases;
Bio repositories (human samples and iPSCs) for further research;
New molecular targets for common therapy for patients affected by DS, AD and PD.

Anticipated impacts include:

1. Improved knowledge of biomarkers related to locus coeruleus degeneration and their relationship to other dementia biomarkers and to dementia status across patient groups will impact on clinical diagnosis, and also provide important information on biomarkers of dementia progression that will be valuable for prognosis and future clinical studies.

2. Improved knowledge of common mechanisms and pathways of degeneration across patient groups, which could help to identify new treatment strategies.