Lack of human-like extracellular sortilin neuropathology in transgenic Alzheimer’s disease model mice and macaques

Zhou, Fangyuan; Jiang, Juan; Griffith, Chelsea M.; Patrylo, Peter R.; Cai, Huaibin; Chu, Yaping; Yan, Xiao‐Xin

doi:10.1186/s13195-018-0370-2

Cited by 19 publications

(21 citation statements)

References 86 publications

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“…This is the first demonstration of PGRN/PSAP interactions in human brain samples. These PGRN immunoprecipitated samples were negative for sortilin [67, 68]; this finding was unexpected as sortilin is enriched in plaques and regulates PGRN levels [53, 69]. Other proteins that did not interact with PGRN were TMEM106B [34, 70], cathepsin D [71], EphA2 [72] and BACE-1 [32].…”

Section: Discussionmentioning

confidence: 99%

Characterization of lysosomal proteins Progranulin and Prosaposin and their interactions in Alzheimer’s disease and aged brains: increased levels correlate with neuropathology

Mendsaikhan

Tooyama

Bellier

et al. 2019

acta neuropathol commun

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Progranulin (PGRN) is a protein encoded by the GRN gene with multiple identified functions including as a neurotrophic factor, tumorigenic growth factor, anti-inflammatory cytokine and regulator of lysosomal function. A single mutation in the human GRN gene resulting in reduced PGRN expression causes types of frontotemporal lobar degeneration resulting in frontotemporal dementia. Prosaposin (PSAP) is also a multifunctional neuroprotective secreted protein and regulator of lysosomal function. Interactions of PGRN and PSAP affect their functional properties. Their roles in Alzheimer’s disease (AD), the leading cause of dementia, have not been defined. In this report, we examined in detail the cellular expression of PGRN in middle temporal gyrus samples of a series of human brain cases (n = 45) staged for increasing plaque pathology. Immunohistochemistry showed PGRN expression in cortical neurons, microglia, cerebral vessels and amyloid beta (Aβ) plaques, while PSAP expression was mainly detected in neurons and Aβ plaques, and to a limited extent in astrocytes. We showed that there were increased levels of PGRN protein in AD cases and corresponding increased levels of PSAP. Levels of PGRN and PSAP protein positively correlated with amyloid beta (Aβ), with PGRN levels correlating with phosphorylated tau (serine 205) levels in these samples. Although PGRN colocalized with lysosomal-associated membrane protein-1 in neurons, most PGRN associated with Aβ plaques did not. Aβ plaques with PGRN and PSAP deposits were identified in the low plaque non-demented cases suggesting this was an early event in plaque formation. We did not observe PGRN-positive neurofibrillary tangles. Co-immunoprecipitation studies of PGRN from brain samples identified only PSAP associated with PGRN, not sortilin or other known PGRN-binding proteins, under conditions used. Most PGRN associated with Aβ plaques were immunoreactive for PSAP showing a high degree of colocalization of these proteins that did not change between disease groups. As PGRN supplementation has been considered as a therapeutic approach for AD, the possible involvement of PGRN and PSAP interactions in AD pathology needs to be further considered.

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Section: Discussionmentioning

confidence: 99%

Characterization of lysosomal proteins Progranulin and Prosaposin and their interactions in Alzheimer’s disease and aged brains: increased levels correlate with neuropathology

Mendsaikhan

Tooyama

Bellier

et al. 2019

acta neuropathol commun

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“…A recent paper demonstrated low amounts of sortilin expression by microglia in vitro, with increased amounts on intracellular membranes of Grn deletion microglia [10]. Immunohistochemistry for sortilin was confirmed in an AD mouse model, though extracellular sortilin bound to plaques was a feature only observed in human AD brains [133]. In contrast, EphA2 can be highly expressed in rodent microglia/macrophages and endothelial cells ( search term epha2).…”

Section: Role Of Pgrn In Alzheimer’s Diseasementioning

confidence: 99%

Microglial Progranulin: Involvement in Alzheimer’s Disease and Neurodegenerative Diseases

Mendsaikhan

Tooyama

Walker

2019

Cells

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Neurodegenerative diseases such as Alzheimer’s disease have proven resistant to new treatments. The complexity of neurodegenerative disease mechanisms can be highlighted by accumulating evidence for a role for a growth factor, progranulin (PGRN). PGRN is a glycoprotein encoded by the GRN/Grn gene with multiple cellular functions, including neurotrophic, anti-inflammatory and lysosome regulatory properties. Mutations in the GRN gene can lead to frontotemporal lobar degeneration (FTLD), a cause of dementia, and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Both diseases are associated with loss of PGRN function resulting, amongst other features, in enhanced microglial neuroinflammation and lysosomal dysfunction. PGRN has also been implicated in Alzheimer’s disease (AD). Unlike FTLD, increased expression of PGRN occurs in brains of human AD cases and AD model mice, particularly in activated microglia. How microglial PGRN might be involved in AD and other neurodegenerative diseases will be discussed. A unifying feature of PGRN in diseases might be its modulation of lysosomal function in neurons and microglia. Many experimental models have focused on consequences of PGRN gene deletion: however, possible outcomes of increasing PGRN on microglial inflammation and neurodegeneration will be discussed. We will also suggest directions for future studies on PGRN and microglia in relation to neurodegenerative diseases.

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“…Our initial characterization suggests that this extracellular proteopathy is associated with neuritic-like Aβ plaques, but not with diffuse plaques or subpial and vascular amyloidosis. Notably, sorfra plaques are not detectable in some commonly used transgenic mouse models of AD (i.e., 2 × FAD, 3 × FAD, and 3 × Tg-AD) or in aged non-human primates (Zhou et al, 2018). To further understand the significance of this lesion in AD pathogenesis, it is important to determine whether sorfra deposition develops with its own characteristic spatiotemporal pattern relative to that of Aβ and pTau pathologies.…”

Section: Introductionmentioning

confidence: 99%

Extracellular Sortilin Proteopathy Relative to β-Amyloid and Tau in Aged and Alzheimer’s Disease Human Brains

Jiang

Zhang

et al. 2020

Front. Aging Neurosci.

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Amyloid plaques and neurofibrillary tangles (NFTs) are hallmark lesions of Alzheimer's disease (AD) related to β-amyloid (Aβ) deposition and intraneuronal phosphorylated tau (pTau) accumulation. Sortilin C-terminal fragments (shortened as "sorfra") can deposit as senile plaque-like lesions within AD brains. The course and pattern of sorfra plaque formation relative to Aβ and pTau pathogenesis remain unknown. In the present study, cerebral and subcortical sections in postmortem human brains (n = 46) from aged and AD subjects were stained using multiple markers (6E10, β-secretase 1, pTau, and sortilin antibodies, as well as Bielschowsky silver stain). The course and pattern of sorfra plaque formation relative to Thal Aβ and Braak NFT pathogenic stages were determined. Sorfra plaques occurred in the temporal, inferior frontal and occipital neocortices in cases with Thal 1 and Braak III stages. They were also found additionally in the hippocampal formation, amygdala, and associative neocortex in cases with Thal 2-4 and Braak IV-V. Lastly, they were also found in the primary motor, somatosensory, and visual cortices in cases with Thal 4-5 and Braak VI. Unlike Aβ and pTau pathologies, sorfra plaques did not occur in subcortical structures in cases with Aβ/pTau lesions in Thal 3-5/Braak IV-VI stages. We establish here that sorfra plaques are essentially a cerebral proteopathy. We believe that the development of sorfra plaques in both cortical and hippocampal regions proceeds in a typical spatiotemporal pattern, and the stages of cerebral sorfra plaque formation partially overlap with that of Aβ and pTau pathologies.

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Lack of human-like extracellular sortilin neuropathology in transgenic Alzheimer’s disease model mice and macaques

Cited by 19 publications

References 86 publications

Characterization of lysosomal proteins Progranulin and Prosaposin and their interactions in Alzheimer’s disease and aged brains: increased levels correlate with neuropathology

Characterization of lysosomal proteins Progranulin and Prosaposin and their interactions in Alzheimer’s disease and aged brains: increased levels correlate with neuropathology

Microglial Progranulin: Involvement in Alzheimer’s Disease and Neurodegenerative Diseases

Extracellular Sortilin Proteopathy Relative to β-Amyloid and Tau in Aged and Alzheimer’s Disease Human Brains

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