Neuropathological and amyloid peptide differences between DS and familial AD with duplications and missense mutations in APP gene
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence of amyloid plaques mainly constituted of extracellular amyloid beta peptides (Abeta) deposits in brain parenchyma and intraneuronal neurofibrillary tangles consisting of hyperphosphorylated tau protein. Additionally Abeta can be found deposited in blood vessel walls as cerebral amyloid angiopathy (CAA), a major cause of intracerebral hemorrhage. While the presence of amyloid plaques in postmortem brains is common to all AD cases including sporadic, familial and Down syndrome (DS, trisomy of chromosome 21, with overdose of the Amyloid Precursor Protein (APP) gene on Hsa21), CAA is a more prominent phenotype in familial cases with either APP duplication or certain (but not all) point mutations. The nature and mechanisms underlying these pathological and clinical differences between APP causes of AD remain unclear. We propose a unique study specifically focusing on rare and poorly studied patient groups focusing on rare and poorly studied, but potentially very informative patient groups - those with APP mutations and duplications and DS - to elucidate differences that may provide important clues for treatment. We plan to investigate the diversity of clinical and neuropathological phenotypes associated with the diversity of alterations in the APP gene by studying endo-lysosomal alterations and Abeta species neuropathological differences in human cases, novel mouse models, and in several cell types derived from iPSC lines reproducing various diseases to unravel pathophysiological mechanisms involved in specific Abeta deposition.
Technical Summary
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence of amyloid plaques mainly constituted of extracellular amyloid beta peptides (Abeta) deposits in brain parenchyma and intraneuronal neurofibrillary tangles consisting of hyperphosphorylated tau protein. Additionally Abeta can be found deposited in blood vessel walls as cerebral amyloid angiopathy (CAA), a major cause of intracerebral hemorrhage. While the presence of amyloid plaques in postmortem brains is common to all AD cases including sporadic, familial and Down syndrome (DS, trisomy of chromosome 21, with overdose of the Amyloid Precursor Protein (APP) gene on Hsa21), CAA is a more prominent phenotype in familial cases with either APP duplication or certain (but not all) point mutations. The nature and mechanisms underlying these pathological and clinical differences between APP causes of AD remain unclear. We propose a unique study specifically focusing on rare and poorly studied patient groups focusing on rare and poorly studied, but potentially very informative patient groups - those with APP mutations and duplications and DS - to elucidate differences that may provide important clues for treatment. We plan to investigate the diversity of clinical and neuropathological phenotypes associated with the diversity of alterations in the APP gene by studying endo-lysosomal alterations and Abeta species neuropathological differences in human cases, novel mouse models, and in several cell types derived from iPSC lines reproducing various diseases to unravel pathophysiological mechanisms involved in specific Abeta deposition.
Planned Impact
Partners of this consortium (MC Potier Chair, A Strydom, E Fisher, Y Hérault) are members of European College of Neuropsycho Pharmacology (ECNP) Network (https://www.ecnp.eu/research-innovation/ECNP-networks/List-ECNP-Networks/Down-syndrome.aspx). ECNP will support the patient and public involvement (PPI) activities, helping to disseminate project results and recommendations to each of the relevant neurodegenerative stakeholder communities, including patients, care community, policy-makers, clinicians and researchers. ECNP will design a public-facing information strategy that is focused on patient and public collaboration and broad-scale distribution, mobilizing a variety of communications channels, including electronic bulletins, social media and press. The consortium has strong links with European or international consortia devoted to research on AD (Alzheimer Europe; AgedBrainSYSBIO, National Alzheimer associations, Dementia Table initiative), DS (Trisomy 21 Research Society (T21RS), the LonDownS consortium, European and national DS associations). The partners are very active in organizing symposia for caregivers/families of people with DS and dementia. Additionally, the data generated within the project will be relevant to industry to inform the design of future clinical trials.
Organisations
Publications
Aschenbrenner AJ
(2021)
Markers of early changes in cognition across cohorts of adults with Down syndrome at risk of Alzheimer's disease.
in Alzheimer's & dementia (Amsterdam, Netherlands)
Ashton NJ
(2021)
A multicentre validation study of the diagnostic value of plasma neurofilament light.
in Nature communications
Aslam AA
(2022)
Diabetes and Obesity in Down Syndrome Across the Lifespan: A Retrospective Cohort Study Using U.K. Electronic Health Records.
in Diabetes care
Baksh RA
(2022)
Susceptibility to COVID-19 Diagnosis in People with Down Syndrome Compared to the General Population: Matched-Cohort Study Using Primary Care Electronic Records in the UK.
in Journal of general internal medicine
Baksh RA
(2023)
Multiple morbidity across the lifespan in people with Down syndrome or intellectual disabilities: a population-based cohort study using electronic health records.
in The Lancet. Public health
Cannavo C
(2020)
Using mouse models to understand Alzheimer's disease mechanisms in the context of trisomy of chromosome 21.
in Progress in brain research
Cannavo C
(2022)
Endosomal structure and APP biology are not altered in a preclinical mouse cellular model of Down syndrome.
in PloS one
Carmona-Iragui M
(2021)
Diagnostic and prognostic performance and longitudinal changes in plasma neurofilament light chain concentrations in adults with Down syndrome: a cohort study.
in The Lancet. Neurology