JPND The locus coeruleus: at the crossroad of dementia syndromes
Award Number
MR/R024901/1Programme
Research grantStatus / Stage
ActiveDates
1 February 2018 -31 January 2021
Duration (calculated)
02 years 11 monthsFunder(s)
MRC (UKRI)Funding Amount
£378,233.37Funder/Grant study page
MRC UKRIContracted Centre
King's College LondonPrincipal Investigator
Andre StrydomPI Contact
andre.strydom@kcl.ac.ukPI ORCID
0000-0002-2502-6704WHO Catergories
Understanding risk factorsUnderstanding Underlying Disease
Disease Type
Alzheimer's Disease (AD)CPEC Review Info
| Reference ID | 244 |
|---|---|
| Researcher | Reside Team |
| Published | 12/06/2023 |
Data
| Award Number | MR/R024901/1 |
|---|---|
| Status / Stage | Active |
| Start Date | 20180201 |
| End Date | 20210131 |
| Duration (calculated) | 02 years 11 months |
| Funder/Grant study page | MRC UKRI |
| Contracted Centre | King's College London |
| Funding Amount | £378,233.37 |
Abstract
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).
Aims
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.