Secernin-1 is a novel phosphorylated tau binding protein that accumulates in Alzheimer\u2019s disease and not in other tauopathies

Geoffrey Pires,Thomas Wisniewski,Marie-Claude Potier,Glenda Halliday,Sacha Mcelligott,Shiron Drusinsky,Eleanor Drummond

doi:10.1186/s40478-019-0848-6

Abstract

We recently identified Secernin-1 (SCRN1) as a novel amyloid plaque associated protein using localized proteomics. Immunohistochemistry studies confirmed that SCRN1 was present in plaque-associated dystrophic neurites and also revealed distinct and abundant co-localization with neurofibrillary tangles (NFTs). Little is known about the physiological function of SCRN1 and its role in Alzheimer’s disease (AD) and other neurodegenerative diseases has not been studied. Therefore, we performed a comprehensive study of SCRN1 distribution in neurodegenerative diseases. Immunohistochemistry was used to map SCRN1 accumulation throughout the progression of AD in a cohort of 58 patients with a range of NFT pathology (Abundant NFT, n = 21; Moderate NFT, n = 22; Low/No NFT, n = 15), who were clinically diagnosed as having AD, mild cognitive impairment or normal cognition. SCRN1 accumulation was also examined in two cases with both Frontotemporal Lobar Degeneration (FTLD)-Tau and AD-related neuropathology, cases of Down Syndrome (DS) with AD (n = 5), one case of hereditary cerebral hemorrhage with amyloidosis – Dutch type (HCHWA-D) and other non-AD tauopathies including: primary age-related tauopathy (PART, [n = 5]), Corticobasal Degeneration (CBD, [n = 5]), Progressive Supranuclear Palsy (PSP, [n = 5]) and Pick’s disease (PiD, [n = 4]). Immunohistochemistry showed that SCRN1 was a neuronal protein that abundantly accumulated in NFTs and plaque-associated dystrophic neurites throughout the progression of AD. Quantification of SCRN1 immunohistochemistry confirmed that SCRN1 preferentially accumulated in NFTs in comparison to surrounding non-tangle containing neurons at both early and late stages of AD. Similar results were observed in DS with AD and PART. However, SCRN1 did not co-localize with phosphorylated tau inclusions in CBD, PSP or PiD. Co-immunoprecipitation revealed that SCRN1 interacted with phosphorylated tau in human AD brain tissue. Together, these results suggest that SCRN1 is uniquely associated with tau pathology in AD, DS and PART. As such, SCRN1 has potential as a novel therapeutic target and could serve as a useful biomarker to distinguish AD from other tauopathies.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia
We found that the SCRN1 distribution in Down Syndrome (DS) with AD and Primary age-related tauopathy (PART) was similar to that observed in AD; SCRN1 accumulated in neurofibrillary tangles (NFTs) in both types of disease and was present in the dystrophic neurites present in neuritic plaques in DS with AD (Fig. 4a, b, c)
Here, we present a comprehensive neuropathological study showing that SCRN1 is a novel protein that accumulates in AD, DS and PART, which are 3R/4R tauopathies, but not in other tauopathies that are either 3R or 4R tauopathies

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia. It is characterized by extracellular aggregation of the amyloid-β (Aβ) peptide into plaques and intraneuronal accumulation of aggregated and hyperphosphorylated tau (pTau) into neurofibrillary tangles (NFTs) [17, 49]. There are 6 tau isoforms derived from alternative splicing of exon 2, 3 and 10 of the MAPT gene [6, 30]. Tau is hyper-phosphorylated and undergoes important conformational changes, causing it to aggregate and form lesions in the brain [3, 31, 32, 35]. In other neuropathological conditions, dysfunction of tau alone is sufficient to cause dementia [29, 43] Together, these neurodegenerative diseases are referred to as tauopathies, a group of diseases that includes (but is not limited to) AD, Down Syndrome (DS), Pick’s Disease (PiD), Corticobasal Degeneration (CBD), Progressive Supranuclear Palsy (PSP) and Primary age-related tauopathy (PART) [10, 18, 23]. It has been proposed that the ratio of 3R:4R tau is of particular pathological importance as this ratio determines the conformation of pTau aggregates and the associated cofactors, which in turn determines mechanism of disease [5, 16, 66]

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Conclusion