Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-β secretion via deregulated lysosomal exocytosis
Open accessAbstract
Alzheimer's disease (AD) belongs to a category of adult neurodegenerative conditions, which are associated with intracellular and extracellular accumulation of neurotoxic protein aggregates. Understanding how these aggregates are formed, secreted and propagated by neurons has been the subject of intensive research, but so far no preventive or curative therapy for AD is available, and clinical trials have been largely unsuccessful. Here we show that deficiency of the lysosomal sialidase NEU1 leads to the spontaneous occurrence of an AD-like amyloidogenic process in mice. This involves two consecutive events linked to NEU1 loss-of-function--accumulation and amyloidogenic processing of an oversialylated amyloid precursor protein in lysosomes, and extracellular release of Aβ peptides by excessive lysosomal exocytosis. Furthermore, cerebral injection of NEU1 in an established AD mouse model substantially reduces β-amyloid plaques. Our findings identify an additional pathway for the secretion of Aβ and define NEU1 as a potential therapeutic molecule for AD.
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Neu1 deficiency leads to increased release of Aβ42.
“We also confirmed that Neu1 deficiency led to increased release of Ab42 (Figure 2H), a process facilitated by excessive lysosomal exocytosis in these mice 38 .”
From Targeting Lysosomal Dysfunction to Alleviate Plaque Deposition in an Alzheimer Disease Model (2025) · cites this paper as [38]
Lysosomal exocytosis secretes lysosomal contents, including Aβ peptides and active enzymes, into the extracellular space.
“Additionally, we find that Neu1 dysregulation leads to a marked increase in lysosomal exocytosis, a mechanism through which lysosomal contents, including Aβ peptides and active enzymes, are secreted into the extracellular space 35,38,39 .”
From Targeting Lysosomal Dysfunction to Alleviate Plaque Deposition in an Alzheimer Disease Model (2025) · cites this paper as [38]
The 5XFAD model has an early plaque development phenotype.
“The 5XFAD model, due to its early plaque development phenotype, has been investigated extensively to study the various aspects of early onset AD [20]–[24], [37].”
From Galantamine Slows Down Plaque Formation and Behavioral Decline in the 5XFAD Mouse Model of Alzheimer’s Disease (2014) · cites this paper as [37]
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References 63 · Cited by 146
- Authors
- Annunziata, I., Patterson, A., Helton, D., Hu, H., Moshiach, S., Gomero, E., Nixon, R., & d’Azzo, A.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Nathan Kline Institute for Psychiatric Research (US)
- Corresponding author
- d’Azzo, Alessandra
- Venue
- Nature Communications
- Published
- 2013-11-14
- Volume
- 4
- Issue
- 1
- Pages
- 2734-2734
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4015463
- OpenAlex
- W2110588674
- Cited by
- 146
- References
- 63
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 21 · 2023: 14 · 2022: 14 · 2021: 13 · 2020: 13 · 2019: 9 · 2018: 10 · 2017: 4 · 2016: 7 · 2015: 10 · 2014: 8 · 2013: 1
- FWCI
- 5.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Assisi Foundation of Memphis
- American Lebanese Syrian Associated Charities
- National Institutes of Health (1r13gm060905-01, DK-52025)
- National Institute of General Medical Sciences (R01GM104981, GM60905, R01GM060950)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-52025, Z01DK052025, R01DK052025)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- NEU1, lysosomal exocytosis, amyloid precursor protein, amyloid-beta secretion, Alzheimer's disease, amyloid plaques, AD mouse model
- MeSH terms
- Calcimycin, Dependovirus, Animals, Brain, Cell Line, Exocytosis, Hippocampus, Humans, Lysosomes, Mice, Transgenic, Mucolipidoses, Neuraminidase, Neurons, Risk Factors, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice
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