SMOC1 Colocalizes with Alzheimer's Disease Neuropathology and Delays Aβ Aggregation

Overview

Journal Acta Neuropathol

Specialty Neurology

Date 2024 Nov 25

PMID 39585417

Authors

Kaleah Balcomb

Caitlin Johnston

Tomas Kavanagh

Dominique Leitner

Julie Schneider

Glenda Halliday

Thomas Wisniewski

Margaret Sunde

Eleanor Drummond

Affiliations

Soon will be listed here.

Abstract

SMOC1 has emerged as one of the most significant and consistent new biomarkers of early Alzheimer's disease (AD). Recent studies show that SMOC1 is one of the earliest changing proteins in AD, with levels in the cerebrospinal fluid increasing many years before symptom onset. Despite this clear association with disease, little is known about the role of SMOC1 in AD or its function in the brain. Therefore, the aim of this study was to examine the distribution of SMOC1 in human AD brain tissue and to determine if SMOC1 influenced amyloid beta (Aβ) aggregation. The distribution of SMOC1 in human brain tissue was assessed in 3 brain regions (temporal cortex, hippocampus, and frontal cortex) using immunohistochemistry in a cohort of 73 cases encompassing advanced AD, mild cognitive impairment (MCI), preclinical AD, and cognitively normal controls. The Aβ- and phosphorylated tau-interaction with SMOC1 was assessed in control, MCI, and advanced AD human brain tissue using co-immunoprecipitation, and the influence of SMOC1 on Aβ aggregation kinetics was assessed using Thioflavin-T assays and electron microscopy. SMOC1 strongly colocalized with a subpopulation of amyloid plaques in AD (43.8 ± 2.4%), MCI (32.8 ± 5.4%), and preclinical AD (28.3 ± 6.4%). SMOC1 levels in the brain strongly correlated with plaque load, irrespective of disease stage. SMOC1 also colocalized with a subpopulation of phosphorylated tau aggregates in AD (9.6 ± 2.6%). Co-immunoprecipitation studies showed that SMOC1 strongly interacted with Aβ in human MCI and AD brain tissue and with phosphorylated tau in human AD brain tissue. Thioflavin-T aggregation assays showed that SMOC1 significantly delayed Aβ aggregation in a dose-dependent manner, and electron microscopy confirmed that the Aβ fibrils generated in the presence of SMOC1 had an altered morphology. Overall, our results emphasize the importance of SMOC1 in the onset and progression of AD and suggest that SMOC1 may influence pathology development in AD.

Citing Articles

Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer's disease, and late-onset Alzheimer's disease.

Marta-Ariza M, Leitner D, Kanshin E, Suazo J, Giusti Pedrosa A, Thierry M Acta Neuropathol. 2025; 149(1):9.

PMID: 39825890 PMC: 11742868. DOI: 10.1007/s00401-025-02844-z.

References

Iwamoto N, Nishiyama E, Ohwada J, Arai H . Demonstration of CRP immunoreactivity in brains of Alzheimer's disease: immunohistochemical study using formic acid pretreatment of tissue sections. Neurosci Lett. 1994; 177(1-2):23-6. DOI: 10.1016/0304-3940(94)90035-3. View

Kuo H, Yen C, Chang C, Kuo C, Chen J, Sorond F . Relation of C-reactive protein to stroke, cognitive disorders, and depression in the general population: systematic review and meta-analysis. Lancet Neurol. 2005; 4(6):371-80. DOI: 10.1016/S1474-4422(05)70099-5. View

Delgado Lagos F, Elgheznawy A, Kyselova A, Heringdorf D, Ratiu C, Randriamboavonjy V . Secreted modular calcium-binding protein 1 binds and activates thrombin to account for platelet hyperreactivity in diabetes. Blood. 2021; 137(12):1641-1651. DOI: 10.1182/blood.2020009405. View

Frick E, Emilsson V, Jonmundsson T, Steindorsdottir A, Johnson E, Puerta R . Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer's disease. Nat Aging. 2024; 4(10):1446-1464. PMC: 11485263. DOI: 10.1038/s43587-024-00693-1. View

Carlyle B, Kandigian S, Kreuzer J, Das S, Trombetta B, Kuo Y . Synaptic proteins associated with cognitive performance and neuropathology in older humans revealed by multiplexed fractionated proteomics. Neurobiol Aging. 2021; 105:99-114. PMC: 8338777. DOI: 10.1016/j.neurobiolaging.2021.04.012. View

Jalal D, Sanford B, Renner B, Ten Eyck P, Laskowski J, Cooper J . Detection of pro angiogenic and inflammatory biomarkers in patients with CKD. Sci Rep. 2021; 11(1):8786. PMC: 8062467. DOI: 10.1038/s41598-021-87710-0. View

Bezprozvanny I . Calcium signaling and neurodegeneration. Acta Naturae. 2012; 2(1):72-82. PMC: 3347543. View

Aoki H, Yamamoto E, Takasawa A, Niinuma T, Yamano H, Harada T . Epigenetic silencing of in traditional serrated adenoma and colorectal cancer. Oncotarget. 2018; 9(4):4707-4721. PMC: 5797007. DOI: 10.18632/oncotarget.23523. View

Ping L, Kundinger S, Duong D, Yin L, Gearing M, Lah J . Global quantitative analysis of the human brain proteome and phosphoproteome in Alzheimer's disease. Sci Data. 2020; 7(1):315. PMC: 7522715. DOI: 10.1038/s41597-020-00650-8. View

10.

Chandran R, Kumar M, Kesavan L, Jacob R, Gunasekaran S, Lakshmi S . Cellular calcium signaling in the aging brain. J Chem Neuroanat. 2017; 95:95-114. DOI: 10.1016/j.jchemneu.2017.11.008. View

11.

Arai H, Emson P, Mountjoy C, Carassco L, Heizmann C . Loss of parvalbumin-immunoreactive neurones from cortex in Alzheimer-type dementia. Brain Res. 1987; 418(1):164-9. DOI: 10.1016/0006-8993(87)90974-7. View

12.

Higginbotham L, Ping L, Dammer E, Duong D, Zhou M, Gearing M . Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer's disease. Sci Adv. 2020; 6(43). PMC: 7577712. DOI: 10.1126/sciadv.aaz9360. View

13.

Zhang Y, Chen K, Sloan S, Bennett M, Scholze A, OKeeffe S . An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014; 34(36):11929-47. PMC: 4152602. DOI: 10.1523/JNEUROSCI.1860-14.2014. View

14.

Rainger J, van Beusekom E, Ramsay J, McKie L, Al-Gazali L, Pallotta R . Loss of the BMP antagonist, SMOC-1, causes Ophthalmo-acromelic (Waardenburg Anophthalmia) syndrome in humans and mice. PLoS Genet. 2011; 7(7):e1002114. PMC: 3131273. DOI: 10.1371/journal.pgen.1002114. View

15.

Guo Y, Chen S, You J, Huang S, Chen Y, Zhang Y . Multiplex cerebrospinal fluid proteomics identifies biomarkers for diagnosis and prediction of Alzheimer's disease. Nat Hum Behav. 2024; 8(10):2047-2066. DOI: 10.1038/s41562-024-01924-6. View

16.

Kawahara M, Kuroda Y, Arispe N, Rojas E . Alzheimer's beta-amyloid, human islet amylin, and prion protein fragment evoke intracellular free calcium elevations by a common mechanism in a hypothalamic GnRH neuronal cell line. J Biol Chem. 2000; 275(19):14077-83. DOI: 10.1074/jbc.275.19.14077. View

17.

Hondius D, Koopmans F, Leistner C, Pita-Illobre D, Peferoen-Baert R, Marbus F . The proteome of granulovacuolar degeneration and neurofibrillary tangles in Alzheimer's disease. Acta Neuropathol. 2021; 141(3):341-358. PMC: 7882576. DOI: 10.1007/s00401-020-02261-4. View

18.

Xie K, Liu Y, Hao W, Walter S, Penke B, Hartmann T . Tenascin-C deficiency ameliorates Alzheimer's disease-related pathology in mice. Neurobiol Aging. 2013; 34(10):2389-98. DOI: 10.1016/j.neurobiolaging.2013.04.013. View

19.

Johnson E, Carter E, Dammer E, Duong D, Gerasimov E, Liu Y . Large-scale deep multi-layer analysis of Alzheimer's disease brain reveals strong proteomic disease-related changes not observed at the RNA level. Nat Neurosci. 2022; 25(2):213-225. PMC: 8825285. DOI: 10.1038/s41593-021-00999-y. View

20.

Drummond E, Pires G, Macmurray C, Askenazi M, Nayak S, Bourdon M . Phosphorylated tau interactome in the human Alzheimer's disease brain. Brain. 2020; 143(9):2803-2817. PMC: 7526722. DOI: 10.1093/brain/awaa223. View