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
Ashton N
(2021)
A multicentre validation study of the diagnostic value of plasma neurofilament light
in Nature Communications
Hillerstrom H
(2024)
Adapting prescribing criteria for amyloid-targeted antibodies for adults with Down syndrome
in Alzheimer's & Dementia
Larsen F
(2024)
Age of Alzheimer's disease diagnosis in people with Down syndrome and associated factors: Results from the Horizon 21 European Down syndrome consortium
in Alzheimer's & Dementia
Strydom A
(2018)
Alzheimer's disease in Down syndrome: An overlooked population for prevention trials.
in Alzheimer's & dementia (New York, N. Y.)
Iulita M
(2023)
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in Brain Communications
Montoliu-Gaya L
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Blood Biomarkers for Alzheimer's Disease in Down Syndrome.
in Journal of clinical medicine
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in Brain communications
Idris M
(2023)
Common mental health disorders and cognitive decline in a longitudinal Down syndrome cohort.
in BJPsych open
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Complement dysregulation and Alzheimer's disease in Down syndrome
in Alzheimer's & Dementia
Emes D
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COVID-19 in Children with Down Syndrome: Data from the Trisomy 21 Research Society Survey.
in Journal of clinical medicine
Aslam A
(2022)
Diabetes and Obesity in Down Syndrome Across the Lifespan: A Retrospective Cohort Study Using U.K. Electronic Health Records
in Diabetes Care
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
Cannavo C
(2022)
Endosomal structure and APP biology are not altered in a preclinical mouse cellular model of Down syndrome.
in PloS one
Mgaieth F
(2023)
Exploring semantic verbal fluency patterns and their relationship to age and Alzheimer's disease in adults with Down syndrome.
in Alzheimer's & dementia : the journal of the Alzheimer's Association
Michno W
(2021)
Following spatial Aß aggregation dynamics in evolving Alzheimer's disease pathology by imaging stable isotope labeling kinetics.
in Science advances
Snyder HM
(2020)
Further understanding the connection between Alzheimer's disease and Down syndrome.
in Alzheimer's & dementia : the journal of the Alzheimer's Association
Mumford P
(2022)
Genetic Mapping of APP and Amyloid-ß Biology Modulation by Trisomy 21.
in The Journal of neuroscience : the official journal of the Society for Neuroscience
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)
Van Zalm P
(2023)
Meta-analysis of published cerebrospinal fluid proteomics data identifies and validates metabolic enzyme panel as Alzheimer's disease biomarkers
in Cell Reports Medicine
Michno W
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Molecular imaging mass spectrometry for probing protein dynamics in neurodegenerative disease pathology
in Journal of Neurochemistry
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