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Nizetic D, Chen CL, Hong W, et al. Inter-Dependent Mechanisms Behind Cognitive Dysfunction, Vascular Biology and Alzheimer's Dementia in Down Syndrome: Multi-Faceted Roles of APP. Front Behav Neurosci. 2015;9:299doi: 10.3389/fnbeh.2015.00299.
Nizetic, D., Chen, C. L., Hong, W., & Koo, E. H. (2015). Inter-Dependent Mechanisms Behind Cognitive Dysfunction, Vascular Biology and Alzheimer's Dementia in Down Syndrome: Multi-Faceted Roles of APP. Frontiers in behavioral neuroscience, 9299. https://doi.org/10.3389/fnbeh.2015.00299
Nizetic, Dean, et al. "Inter-Dependent Mechanisms Behind Cognitive Dysfunction, Vascular Biology and Alzheimer's Dementia in Down Syndrome: Multi-Faceted Roles of APP." Frontiers in behavioral neuroscience vol. 9 (2015): 299. doi: https://doi.org/10.3389/fnbeh.2015.00299
Nizetic D, Chen CL, Hong W, Koo EH. Inter-Dependent Mechanisms Behind Cognitive Dysfunction, Vascular Biology and Alzheimer's Dementia in Down Syndrome: Multi-Faceted Roles of APP. Front Behav Neurosci. 2015 Dec 01;9:299. doi: 10.3389/fnbeh.2015.00299. eCollection 2015. PMID: 26648852; PMCID: PMC4664698.
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Front Behav Neurosci. 2015 Dec 01;9:299. doi: 10.3389/fnbeh.2015.00299. eCollection 2015.

Inter-Dependent Mechanisms Behind Cognitive Dysfunction, Vascular Biology and Alzheimer's Dementia in Down Syndrome: Multi-Faceted Roles of APP.

Frontiers in behavioral neuroscience

Dean Nizetic, Christopher L Chen, Wanjin Hong, Edward H Koo

Affiliations

  1. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore Singapore ; The LonDownS Consortium, Wellcome Trust London, UK ; The Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London London, UK.
  2. Department of Psychological Medicine and Memory Aging and Cognition Centre, National University Health System, Singapore Singapore ; Department of Pharmacology, National University of Singapore, Singapore Singapore.
  3. Agency for Science, Technology and Research (AStar), Institute of Molecular Cell Biology, Singapore Singapore.
  4. Departments of Medicine and Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Singapore ; Department of Neurosciences, University of California, San Diego San Diego, CA, USA.

PMID: 26648852 PMCID: PMC4664698 DOI: 10.3389/fnbeh.2015.00299

Abstract

People with Down syndrome (DS) virtually all develop intellectual disability (ID) of varying degree of severity, and also have a high risk of early Alzheimer's disease (AD). ID prior to the onset of dementia, and its relationship to the onset of dementia in DS is a complex phenomenon influenced by many factors, and scarcely understood. Unraveling the causative factors and modulators of these processes remains a challenge, with potential to be informative for both ID and AD, for the development of early biomarkers and/or therapeutic approaches. We review the potential relative and inter-connected roles of the chromosome 21 gene for amyloid precursor protein (APP), in both pathological conditions. Rare non-DS people with duplication of APP (dupAPP) get familial early onset AD (FEOAD) with virtually 100% penetrance and prominent cerebrovascular pathology, but don't suffer from ID before dementia onset. All of these features appear to be radically different in DS. On the other hand, rare individuals with partial trisomy 21 (T21) (with APP, but not DS-critical region in trisomy) have been described having ID. Likewise, partial T21 DS (without APP trisomy) show a range of ID, but no AD pathology. We review the multi-faceted roles of APP that might affect cognitive functioning. Given the fact that both Aβ secretion and synaptic maturation/plasticity are dependent on neuronal activity, we explore how this conflicting inter-dependency might affect cognitive pathogenesis in a dynamic way in DS, throughout the lifespan of an individual.

Keywords: Down syndrome; amyloid beta-peptides; amyloid beta-protein precursor; cognitive dysfunction; neuron activity-dependent; vascular dementia

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