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Cited by 167Alzheimer's disease research and treatmentsAutophagy in Disease and TherapyDown syndrome and intellectual disability research

Dysfunction of autophagy and endosomal-lysosomal pathways: Roles in pathogenesis of Down syndrome and Alzheimer’s Disease

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Colacurcio, Daniel J., Pensalfini, Anna, Jiang, Ying, Nixon, Ralph A.·2018·Free Radical Biology and Medicine
DOI 10.1016/j.freeradbiomed.2017.10.001PMC PMC5748263
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Abstract

Individuals with Down syndrome (DS) have an increased risk of early-onset Alzheimer's Disease (AD), largely owing to a triplication of the APP gene, located on chromosome 21. In DS and AD, defects in endocytosis and lysosomal function appear at the earliest stages of disease development and progress to widespread failure of intraneuronal waste clearance, neuritic dystrophy and neuronal cell death. The same genetic factors that cause or increase AD risk are also direct causes of endosomal-lysosomal dysfunction, underscoring the essential partnership between this dysfunction and APP metabolites in AD pathogenesis. The appearance of APP-dependent endosome anomalies in DS beginning in infancy and evolving into the full range of AD-related endosomal-lysosomal deficits provides a unique opportunity to characterize the earliest pathobiology of AD preceding the classical neuropathological hallmarks. Facilitating this characterization is the authentic recapitulation of this endosomal pathobiology in peripheral cells from people with DS and in trisomy mouse models. Here, we review current research on endocytic-lysosomal dysfunction in DS and AD, the emerging importance of APP/βCTF in initiating this dysfunction, and the potential roles of additional trisomy 21 genes in accelerating endosomal-lysosomal impairment in DS. Collectively, these studies underscore the growing value of investigating DS to probe the biological origins of AD as well as to understand and ameliorate the developmental disability of DS.

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Cited by

Sorted by citations

Authors
Colacurcio, D. J., Pensalfini, A., Jiang, Y., & Nixon, R. A.
Affiliations
Nathan Kline Institute for Psychiatric Research (US)
Corresponding author
Nixon, Ralph A.
ORCID
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2018-01
Volume
114
Pages
40-51
ISSN
0891-5849 (ISSN-L)
DOI
10.1016/j.freeradbiomed.2017.10.001
PMC
PMC5748263
OpenAlex
W2761329528
Cited by
167
References
29
Citations by year
2026: 8 · 2025: 13 · 2024: 15 · 2023: 8 · 2022: 25 · 2021: 32 · 2020: 27 · 2019: 22 · 2018: 15 · 2017: 2
FWCI
2.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Free Radical Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Aging (NIA) (P01AG017617-16)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
Keywords
Down syndrome, Alzheimer's disease, autophagy, APP, amyloid precursor protein, lysosomal acidification, lysosomal proteolysis, endocytosis, cholinergic degeneration, neuronal cell death
MeSH terms
Alzheimer Disease, Animals, Autophagy, Down Syndrome, Humans, Lysosomes, Endosomes

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