Sortilin: a new player in dementia and Alzheimer-type neuropathology

Xu, Shuyin; Jiang, Juan; Pan, Aihua; Cai, Yan; Yan, Xiao‐Xin

doi:10.1139/bcb-2018-0023

Cited by 15 publications

(18 citation statements)

References 65 publications

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“…Amyloid-beta A4 protein (APP), which is a major component of the amyloid plaques in the brain of Alzheimer’s patients [73], is 1.43× down-regulated. Extracellular SORT1, which has been reported to be involved in plaque formation [74], is 5.13× down-regulated in our study. PTGDS was 3.67× up-regulated due to GR plus RF.…”

Section: Discussionsupporting

confidence: 51%

Glucose Restriction Plus Refeeding in Vitro Induce Changes of the Human Adipocyte Secretome with an Impact on Complement Factors and Cathepsins

Qiao

Bouwman

Baak

et al. 2019

IJMS

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Adipose tissue is a major endocrine organ capable of secreting adipokines with a role in whole-body metabolism. Changes in the secretome profile during the development of obesity is suspected to contribute to the risk of health complications such as those associated with weight regain after weight loss. However, the number of studies on weight regain is limited and secretome changes during weight regain have hardly been investigated. In an attempt to generate leads for in vivo studies, we have subjected human Simpson Golabi Behmel Syndrome adipocytes to glucose restriction (GR) followed by refeeding (RF) as an in vitro surrogate for weight regain after weight loss. Using LC-MS/MS, we compared the secreted protein profile after GR plus RF with that of normal feeding (NF) to assess the consequences of GR plus RF. We identified 338 secreted proteins of which 49 were described for the first time as being secreted by adipocytes. In addition, comparison between NF and GR plus RF showed 39 differentially secreted proteins. Functional classification revealed GR plus RF-induced changes of enzymes for extracellular matrix modification, complement system factors, cathepsins, and several proteins related to Alzheimer’s disease. These observations can be used as clues to investigate metabolic consequences of weight regain, weight cycling or intermittent fasting.

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Section: Discussionsupporting

confidence: 51%

Glucose Restriction Plus Refeeding in Vitro Induce Changes of the Human Adipocyte Secretome with an Impact on Complement Factors and Cathepsins

Qiao

Bouwman

Baak

et al. 2019

IJMS

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“…In fact, sortilin has a fairly high affinity (Kd = 0.1–0.3 nM) to NT, comparable to that of NTR1 (Alexander and Leeman, 1998), and thus could be sensitively affected by NTR3 agonization or antagonization. More recent studies show sortilin involvement in many neurobiological and neuropathological events, such as regulation of neuronal/synaptic viability and activity via its binding and trafficking of neurotrophic factors, mood disorders, dementia and AD-type neuropathology (Hu et al, 2010; Nykjaer and Willnow, 2012; Capsoni et al, 2013; Johnson et al, 2017; Ruan et al, 2018; Xu et al, 2018). This has also raised discussion of pharmacological manipulation of sortilin as a disease modifying strategy, regardless whether it involves neurotensin signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Sortilin was originally purified via receptor-associated affinity chromatography from human brain extracts and characterized as a type I transmembrane protein belonging to the vacuolar protein sorting 10 protein (VPS10P) domain receptor family (Petersen et al, 1997). Many signaling proteins have been identified as sortilin ligands in the central and peripheral systems (Mazella et al, 1998; Nykjaer and Willnow, 2012; Quistgaard et al, 2014; Xu et al, 2018). Thus, sortilin serves as an ApoE receptor on neuronal and non-neuronal cells, which may involve in the development of some cardiovascular, metabolic and neurological diseases (Carlo et al, 2013; Coutinho et al, 2013; Kjolby et al, 2015; Strong, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Sortilin can bind to nerve growth factors especially their preforms, thereby modulating neuronal viability and function critical for brain health and disease (Nykjaer et al, 2004; Chen et al, 2005; Arnett et al, 2007; Capsoni et al, 2013). Sortilin may involve in mood disorders (Buttenschøn et al, 2015; Devader et al, 2017; Moreno et al, 2018), and in brain aging and Alzheimer’s disease (AD) pathogenesis by interplaying with β-amyloid precursor protein (APP), β-secretase-1 (BACE1) and tau (Finan et al, 2011; Gustafsen et al, 2013; Yang et al, 2013; Andersson et al, 2016; Johnson et al, 2017; Xu et al, 2018). In fact, sortilin can form novel C-terminal fragments to deposit as senile plaque-like lesions in aged and AD human brains (Hu et al, 2017; Zhou F.Q.…”

Section: Introductionmentioning

confidence: 99%

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Regional and Cellular Mapping of Sortilin Immunoreactivity in Adult Human Brain

Zhang

et al. 2019

Front. Neuroanat.

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Sortilin is a member of the vacuolar protein sorting 10 protein (VPS10P) domain receptor family, which carries out signal transduction and protein transport in cells. Sortilin serves as the third, G-protein uncoupled, receptor of neurotensin that can modulate various brain functions. More recent data indicate an involvement of sortilin in mood disorders, dementia and Alzheimer-type neuropathology. However, data regarding the normal pattern of regional and cellular expression of sortilin in the human brain are not available to date. Using postmortem adult human brains free of neuropathology, the current study determined sortilin immunoreactivity (IR) across the entire brain. Sortilin IR was broadly present in the cerebrum and subcortical structures, localizing to neurons in the somatodendritic compartment, but not to glial cells. In the cerebrum, sortilin IR exhibited differential regional and laminar patterns, with pyramidal, multipolar and polymorphic neurons in cortical layers II–VI, hippocampal formation and amygdaloid complex more distinctly labeled relative to GABAergic interneurons. In the striatum and thalamus, numerous small-to-medium sized neurons showed light IR, with a small group of large sized neurons heavily labeled. In the midbrain and brainstem, sortilin IR was distinct in neurons at the relay centers of descending and ascending neuroanatomical pathways. Dopaminergic neurons in the substantia nigra, cholinergic neurons in the basal nuclei of Meynert and noradrenergic neurons in the locus coeruleus co-expressed strong sortilin IR in double immunofluorescence. In comparison, sortilin IR was weak in the olfactory bulb and cerebellar cortex, with the mitral and Purkinje cells barely visualized. A quantitative analysis was carried out in the lateral, basolateral, and basomedial nuclei of the amygdaloid complex, as well as cortical layers II–VI, which established a positive correlation between the somal size and the intensity of sortilin IR among labeled neurons. Together, the present study demonstrates a predominantly neuronal expression of sortilin in the human brain with substantial regional and cell-type variability. The enriched expression of sortilin in pyramidal, dopaminergic, noradrenergic and cholinergic neurons suggests that this protein may be particularly required for signal transduction, protein trafficking and metabolic homeostasis in populations of relatively large-sized projective neurons.

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“…Recently, we reported extracellular deposition of sortilinderived C-terminal fragments in aged and AD human cerebrum (Hu et al, 2017;Xu et al, 2018). Given that they can form microscopically prominent extracellular proteopathy, we here name these sortilin fragments as "sorfra(s)."…”

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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Sortilin: a new player in dementia and Alzheimer-type neuropathology

Cited by 15 publications

References 65 publications

Glucose Restriction Plus Refeeding in Vitro Induce Changes of the Human Adipocyte Secretome with an Impact on Complement Factors and Cathepsins

Glucose Restriction Plus Refeeding in Vitro Induce Changes of the Human Adipocyte Secretome with an Impact on Complement Factors and Cathepsins

Regional and Cellular Mapping of Sortilin Immunoreactivity in Adult Human Brain

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

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