A novel role for SHARPIN in amyloid-β phagocytosis and inflammation by peripheral blood-derived macrophages in Alzheimer's disease
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Abstract
Defective immune cell-mediated clearance of amyloid-beta (Aβ) and Aβ-associated inflammatory activation of immune cells are key contributors in pathogenesis of Alzheimer's disease (AD). However, the underlying mechanisms remain elusive. Shank-associated RH domain-interacting protein (SHARPIN) is a critical regulator of inflammatory response. Using in vitro cultures of THP-1-derived macrophages exposed to Aβ and AD patient-derived macrophages, we demonstrate the role of SHARPIN as an obligate regulator of Aβ phagocytosis and inflammation in macrophages. Specifically, Aβ-stimulated SHARPIN in THP-1 macrophages promoted Aβ phagocytosis and expression of proinflammatory markers. In addition, Aβ-stimulated SHARPIN in macrophages promoted neuronal cell-death in differentiated SHSY5Y neurons. Furthermore, we report a novel regulatory link between SHARPIN and the NLRP3 inflammasome in response to Aβ in THP-1 macrophages. In line with our in vitro observations, a strong positive association was demonstrated between levels of Aβ 42 in blood plasma of mild cognitive impairment and AD patients with SHARPIN expression in macrophages obtained from respective patient-derived peripheral blood mononuclear cells. Together, our findings show SHARPIN as a critical determinant in mediating macrophage response to Aβ and pathogenesis of AD.
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SHARPIN influences peripheral macrophage-mediated Aβ degradation, linking systemic inflammation to central amyloid burden.
“Similarly, proteins such as Shank-associated RH domain interactor (SHARPIN) influence peripheral macrophage-mediated Aβ degradation, linking systemic inflammation to central amyloid burden [37].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [37]
Section 3.1 reports that SHARPIN knockdown reduced Aβ uptake by THP-1-derived macrophages, and the Discussion links SHARPIN to macrophage inflammation and Aβ clearance. The study measured phagocytosis, not Aβ degradation or central amyloid burden; those more specific parts of the claim are not established by its results. Page numbers are unavailable in our copy. (LLM, conf=0.87)
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Cites
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- Authors
- Krishnan, D., Menon, R. N., Mathuranath, P. S., & Gopala, S.
- Affiliations
- Sree Chitra Thirunal Institute for Medical Sciences and Technology (IN)
- National Institute of Mental Health and Neurosciences (IN)
- Corresponding author
- Gopala, Srinivas
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 93
- Pages
- 131-141
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2967810811
- Cited by
- 36
- References
- 4
- Citations by year
- 2026: 1 · 2025: 9 · 2024: 5 · 2023: 6 · 2022: 7 · 2021: 7 · 2020: 1
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Neurobiology of Aging (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- Indian Council of Medical Research
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- SHARPIN, amyloid-beta, phagocytosis, macrophages, Alzheimer's disease, neuroinflammation, NLRP3 inflammasome, M1 macrophage polarization, THP-1 cells, apoptosis
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, THP-1 Cells, Adult, Aged, Alzheimer Disease, Female, Humans, Inflammation, Macrophages, Male, Middle Aged, Neurons, Phagocytosis, Ubiquitins, Amyloid beta-Peptides, Cell Death, Inflammasomes, Cognitive Dysfunction
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