draft - university of toronto t-space · 21 might lead to novel concept for the development of ad...

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Sortilin: a new player in dementia and Alzheimer-type

neuropathology

Journal: Biochemistry and Cell Biology

Manuscript ID bcb-2018-0023.R1

Manuscript Type: Mini Review

Date Submitted by the Author: 09-Apr-2018

Complete List of Authors: Xu, Shu-Yin; Central South University Jiang, Juan; Central South University Pan, Aihua; Central South University Cai, Yan; Central South University Yan, Xiao-Xin; Central South Universuty School of Basic Medicine, Anatomy and Neurobiology

Is the invited manuscript for consideration in a Special

Issue? : N/A

Keyword: brain aging, neurodegenerative diseases, Vps10p, amyloid plaques

https://mc06.manuscriptcentral.com/bcb-pubs

Biochemistry and Cell Biology

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Sortilin: a new player in dementia and Alzheimer-type neuropathology 1

2

Shu-Yin Xu1, Juan Jiang1, Aihua Pan1, Cai Yan1,2#, Xiao-Xin Yan1# 3

4

1Department of Anatomy and Neurobiology, and 2Department of Histology and Embryology, 5

Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China 6

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Abstract：：：：Age-related dementias are now a major mortality factor among most human 8

populations in the world, with Alzheimer's disease (AD) being the leading 9

dementia-causing neurodegenerative disease. The pathogenic mechanism underlying 10

dementia disorders, and AD in specific, remained largely unclear. Efforts to develop drugs 11

targeting the major disease hallmark lesions, such as amyloid and tangle pathologies, have 12

been unsuccessful so far. The vacuolar protein sorting 10p (Vps10p) family plays a 13

critical role in membrane signal transduction and protein sorting and trafficking between 14

intracellular compartments. Data emerging during the past few years point to an 15

involvement of this family in the development of AD. Specifically, the Vps10p member 16

sortilin has been shown to participate in amyloid plaque formation, tau phosphorylation, 17

abnormal protein sorting and apoptosis. In this article, we update some latest findings 18

from animal experiments and human brain studies that suggest abnormal sortilin 19

expression in association with AD-type neuropathology, warranting further research that 20

might lead to novel concept for the development of AD therapeutics. 21

22

Key words：：：：amyloid plaques, brain aging, neurodegenerative diseases, Vps10p 23

24

#Corresponding author: Yan Cai or Xiao-Xin Yan, Department of Anatomy and Neurobiology, 25

Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China. Email: 26

[email protected]; [email protected]. 27

28

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Introduction 30

As one of the most common neurodegenerative diseases, Alzheimer’s disease (AD) is 31

clinically manifested as memory loss, cognitive decline, personality change and various 32

neurological symptoms. The neuropathological hallmarks in the brain of AD subjects 33

include senile plaques containing extracellular β-amyloid peptide (Aβ) deposits, dystrophic 34

neurites filled with abnormal neuronal organelles and axonal proteins, and intraneuronal 35

tangle formation rich of aggregated hyperphosphorylated tau (p-tau) proteins. The 36

mechanisms underlying AD pathogenesis remain largely elusive to date. As denoted 37

previously, several competing etiological and pathogenic hypotheses have been proposed, 38

including the amyloid cascade hypothesis, tau protein theory, prion theory, oxidative 39

stress theory, genetic susceptibility, insulin signal transduction dysfunction, and 40

cholinergic hypothesis (Scheltens et al. 2016). Among the above, the amyloid hypothesis 41

has been mostly influential, which posits that Aβ products, either as extracellular deposits 42

or soluble forms, cause synaptic damage, inflammatory glial activation, neuritic dystrophy 43

and tauopathy, leading to synaptic and neuronal loss and ultimately cognitive and 44

neurological deficits (Mullard, 2016). However, this hypothesis has been somewhat 45

questioned lately, because various Aβ-targeting therapies developed so far have 46

consistently failed in clinical trials (Franco and Cedazo-Minguez, 2014; Gold, 2017; Tse 47

and Herrup, 2017). Thus, in order to develop effective mechanism-based medicine, it is 48

important to broaden the understanding of AD pathology and pathogenesis. 49

In the past decade especially the last few years, increasing evidence suggests that 50

alterations in the vacuolar protein sorting 10p (Vps10p) receptor family may relate to 51

the development of AD (Bagyinszky et al. 2014; Mufson et al. 2010; Nyborg et al. 2006). 52

The Vps10p members belong to the type I transmembrane proteins. Generally they 53

consist of a N-terminal extracellular sequence containing the Vps10p homology domain, 54

a transmembrane part and a short intracellular tail at the C-terminal (Quistgaard et al. 55

2014). There are five members in this protein family, including sortilin, sorting 56

protein-related receptor with A-type repeats (SorLA), and sortilin-related receptor CNS 57

(central nervous system) expressed 1 (SorCS 1), SorCS2 and SorCS3 (Hermey 2009) (Fig. 58

1). Comparing to other members, sortilin has the simplest structure, though likely the 59

widest range of ligand binding capability. As a membrane receptor or co-receptor, 60

sortilin plays important biological roles for signal transduction and protein sorting in 61

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cells. Relating to AD pathogenesis in specific, sortilin may participate in the development 62

of both the amyloid and the tau pathologies. In fact, sortilin itself appears to undergo 63

novel degradation process and could generate insoluble peptidic fragments that deposit 64

at neuritic plaques in the human brain (Hu et al. 2017). In this article, we will first 65

briefly review the structure and function of sortilin, and then update recent findings that 66

highlight a change in sortilin expression relative to AD-type amyloid and tau 67

pathologies. 68

69

Biochemical structure of sortilin protein 70

Sortilin was first identified from human brain tissue in 1997 (Petersen et al. 1997). 71

Full-length sortilin is a ~100 kDa transmembrane protein encoded by the SORT1 gene on 72

chromosome 1p13.3. The amino acid sequence of sortilin consists of a N-terminal signal 73

peptide (1-33a.a), a pro-peptide (34-78a.a), the Vps10p domain (133-741a.a), a 74

transmembrane helix (759-780a.a) and an intracellular C-terminal tail (781-831a.a). The 75

extracellular Vps10p domain and the intracellular tail are highly conserved in evolution. 76

The Vps10p domain is formed by folding of 10 cysteine-rich fragments（10CC） that 77

appear to arrange in a tunnel shape with a unique 10-bladed beta propeller, which may 78

serve as a channel for ligand binding (Quistgaard et al. 2009). The Vps10p domain 79

contains two lysosomal sorting motifs, MS1 (787-FLVHRY-792) and MS2 80

(823-HDDSDEDLL-831). The structure and function of those sorting motifs appear 81

similar to that of mannose 6-phosphate receptor (M6PR), which is involved in 82

transporting proteins from trans-Golgi network to endosomal-lysosome system (Petersen, 83

et al. 1997; Puertollano et al. 2001). The acidic-cluster-dileucine sequences within the 84

cytoplasmic tail can bind to the (Vps27p/Hrs/STAM) VHS domain of the Golgi-localizing, 85

γ -Adaptin Ear Homology Domain, ADP-ribosylation Factor-binding (GGA) sorting 86

proteins, which are key players in protein sorting at trans-Golgi network (Ghosh and 87

Kornfeld 2004; Nielsen et al. 2001). Overall, sortilin messenger and protein are expressed 88

widely in the CNS according to a rat study (Sarret et al. 2003). A recent study shows 89

expression of sortilin full-length protein in cortical and hippocampal neurons in rodent 90

and human cerebrum (Hu, et al. 2017). Individual studies have suggested that sortilin is 91

also expressed in various types of peripheral cells, including hepatocytes, adipocytes, 92

skeletal myocytes, and macrophages (Kjolby et al. 2015). 93

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Synthesis and maturation of sortilin protein 94

The N-terminal of sortilin is synthesized in the early endoplasmic reticulum system 95

and contains a 44-residue-long protein (named as spadin). Spadin not only can promote 96

adequate folding, but also prevent premature binding of sortilin to ligands during its 97

synthesis. Spadin is further hydrolyzed in trans-Golgi network (TGN) by a protease called 98

furin. At this stage, sortilin is converted into a mature form, which can sort proteins and 99

transport them to their destined intracellular organelles or compartments. Sortilin can be 100

secreted by the TGN as clathrin-coated vesicles, which may mediate bi-directional 101

protein transportation between the TGN and plasma membrane. There are at least three 102

trafficking routes for activated sortilin (Fig.2). Firstly, in the constitutive secretory 103

pathway, secretory vesicles transport sortilin to the cell surface and fuse with it 104

immediately. Then about 5-10% of sortilin’s extracellular domain is cleaved and degraded, 105

releasing the soluble ligand-binding domain to the extracellular space. The remaining 106

sortilin keeps intact and serves as the binding site for ligands. Sortilin binding with 107

ligands may exert different functions, such as signal transduction and receptor-mediated 108

endocytosis. Following endocytosis, sortilin associated with vesicles is transported from 109

the plasma membrane to the early endosome by adaptor protein 2 (AP2). Then the ligand 110

may be degraded in lysosomes, while sortilin is transported reversely to the TGN with the 111

retromer and AP2 complex. Secondly, anterograde transport of sortilin moves from the 112

TGN to early endosome by GGAs and AP1. While the ligand is degraded in the lysosome, 113

the majority of sortilin is palmitoylated and moves back to TGN for re-use (McCormick et 114

al. 2008). Upon successive rounds of transport, a portion of the receptor is ubiquitinated 115

and internalized into lysosomes for degradation (Dumaresq-Doiron et al. 2013). Thirdly, 116

in the regulated secretory pathway, sortilin assists ligands to be incorporated into 117

secretory granules after the cell is stimulated by extracellular signal. But this pathway 118

only exists in the cells that are capable of regulated secretion (Carlo et al. 2014). 119

Major biological function of sortilin 120

As an important membrane signaling protein, it is expected that there could be 121

numerous sortilin ligands in central and peripheral cells (Eggert et al., 2017; Strong, 122

2018). Most sortilin ligands identified so far are associated with lipid metabolism or 123

neurotrophin signal transduction. Ligands related to lipid metabolism include 124

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lipoproteinlipase, apolipoprotein A-V (ApoA-V) and ApoB100, which are generally 125

transported to the cell surface through constitutive secretion, and then degraded in 126

lysosomes. The neurotrophic signaling pathway appears fairly complex because sortilin 127

has been shown to participate in this system by three different ways (Nykjaer and 128

Willnow 2012). Thus, first, with the help of sortilin, mature neurotrophin (mNT) and 129

proneurotrophin (proNT) secreted by neurons and glial cells are released to the 130

extracellular space through regulatory secretory pathways. Second, sortilin can transport 131

the tyrosine kinase receptor (Trk) to axon terminals through anterograde trafficking. Trk 132

and p75 neurotrophin receptor (p75NTR) are involved in mNT signal transduction, which 133

help maintain the growth, development and differentiation of neurons (Bracci-Laudiero 134

and De Stefano, 2016). Third, on cell surface, sortilin and p75NTR work together as 135

partners in the transduction of proNT, which is responsible for mediating apoptosis 136

during differentiation, in aging and under certain pathological conditions (Lewin and 137

Nykjaer 2014; Liu et al. 2007). One of the first identified neuronal roles of sortilin is to 138

bind with neurotensin and regulate the signaling of this and other neuropeptides. In 139

addition, sortilin can bind to thyroglobulin and plays a role in the recycling of the latter. 140

Sortilin is also involved in the formation of the glucose transporter-4 (Glut4) vesicles, 141

which regulate glucose transport in response to insulin (Hermey 2009). To sum up, 142

sortilin travels between the cell surface and the endoplasmic reticulum, Golgi apparatus 143

and lysosomes to mediate diverse signal transduction, secretion and degradation of 144

various partner proteins, thereby fundamentally affecting their biological functions. 145

146

Genetic evidence for sortilin involvement in dementias 147

Emerging data from genome-wide association study (GWAS) suggest that the Vps10p 148

family proteins are genetically related to the risk of developing AD in human (Reitz et al. 149

2013). For instance, a number of studies have shown that alterations of SorLA single 150

nucleotide polymorphism (SNPs) are associated with AD-type brain imaging phenotypes, 151

such as leukoencephalopathy and hippocampal atrophy (Assareh et al. 2014). Specifically 152

in regard to sortilin, some SORT1 SNPs such as rs646776, rs599839 and rs12740374, 153

can affect the expression of SORT1 (Musunuru et al. 2010). For example, the rs646776 154

can increase the levels of transcriptional SORT1 mRNA, while the G allele of rs599839 is 155

important to promote SORT1 messenger expression. The rs12740374 with a secondary T 156

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allele can activate the CCAAT/enhance binding protein, which can elevate SORT1 mRNA 157

expression by more than 12 fold. So far, no SORT1 variations have been reported to 158

enhance the risk of AD. For instance, a study in Chinese Han population suggest that no 159

SORT1 SNPs variants are related to the risk of AD (Zeng et al. 2013). It should be noted 160

that certain SORT1 variants are associated with some cardiovascular conditions, such as 161

high plasma LDL-C level and atherosclerosis (Kjolby, et al. 2015), which are known risk 162

factors for AD (Gottesman et al.2017). 163

Importantly, two late studies have extended evidence supporting a certain link 164

between genetic variants of sortilin and the risk of developing AD and frontotemporal 165

dementia. A study enrolled 620 AD patients and 1107 healthy controls shows that the 166

rs17646665 polymorphism in the non-coding region of the SORT1 gene is associated 167

with a reduced risk of AD (Andersson et al. 2016). During the revision of our manuscript, 168

a study on a Belgian cohort of 636 FTD patients and 1066 unaffected control individuals 169

reveals 5 patient-only nonsynonymous rare variants in SORT1 (Philtjens et al., 2018). The 170

rare coding variants in patients are related to the β-propeller domain, including two 171

variants that are predicted to be the binding site for GRN. Analyzing a total of three 172

independent patient/control cohorts including 1155 FTD patients and 1161 controls from 173

Spain, Italy, and Portugal, the authors find 7 additional patient-only nonsynonymous 174

variants in European population. Thus, SORT1 appears to be a newly identified genetic 175

risk factor for FTD (Philtjens et al., 2018). 176

177

Pathological evidence for sortilin change relative to AD-type pathology 178

A limited number of studies have addressed sortilin expression in human brain tissue. 179

Levels of full-length sortilin in the cerebral cortex have been shown to be maintained in 180

subjects with mild cognitive impairment (MCI) and AD in an earlier report (Mufson, et al. 181

2010), while other studies report elevation of the protein in the cerebrum of AD patients 182

relative to aged controls (Coulson and Nykjaer, 2013; Finan et al. 2011; Saadipour et al. 183

2013) (Table.1). A recent study by our group shows that the levels of full-length sortilin 184

tend to be increased in neocortical lysates from aged and AD individuals relative to 185

mid-age subjects (Hu, et al. 2017). Immunohistochemical and immunoblotting 186

characterizations reveal for the first time that putative sortilin C-terminal fragments can 187

deposit extracellularly at senile plaques in aged and AD human brain. The morphological 188

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pattern of sortilin deposition at senile plaques appears to be comparable to that of 189

extracellular Aβ fibrils (Fig. 3). Notably, this extracellular sortilin neuropathology does not 190

occur in several commonly used transgenic mouse models of AD and even in aged Macaca 191

monkeys with overt cerebral amyloid deposition (Zhou et al., 2018). Thus, in reference to 192

their human brain counterparts, neuritic plaques seen in transgenic AD model mouse 193

brains represent an incomplete form of this disease pathological hallmark. The species 194

difference in neuritic plaque constituents is in line with the notion that during aging and 195

in AD there exist more complex secondary proteopathies in the brain of human relative to 196

rodents and non-human primates. The precise cellular/molecular mechanism underlying 197

extracellular sortilin deposition remains to be elucidated in future studies. Given that a 198

unifying explanation for Aβ deposition is still not established (Li et al. 2017; Yan et al. 199

2014), the finding of extracellular sortilin deposition at senile plaques in the human brain 200

extends a new reference system to explore how and why particular protein fragments 201

accumulate and deposit in the brain extracellular space. 202

203

Experimental study on sortilin modulation of Aβ generation 204

Amyloid precursor protein (APP) can be cleaved by two secretase-mediated 205

pathways. In the non-amyloidogenic pathway, APP is first cleaved byα -secretase, 206

releasing secreted amyloid precursor protein α (sAPPα), and α-site cleaved APP 207

C-terminal fragments (αCTFs) that can not form full-sequence Aβ peptides. The 208

amyloidogenic APP proteolytic pathway is initiated by β-secretase mediated cleavage to 209

produce β-site cleaved CTFs (βCTFs) that further produce monomeric Aβ species via 210

ɤ-secretase processing (Cai et al., 2010; Zhang et al., 2010; Liu et al., 2013). Overall, Aβ is 211

removed from the brain parenchyma via enzymatic degradation and other clearance 212

mechanisms. In theory, increased expression of APP, enhanced activity of β- andγ213

-secretases or obstructed Aβ clearance can lead to abnormal elevation of Aβ in the brain, 214

which could potentially result in cerebral Aβ deposition (Yan et al., 2014; Li et al., 2017). 215

Using human embryonic kidney HEK293T cell line expressing SORT1 transgene, 216

Finan et al. (2011) show that sortilin and β-secretase interact with each other. sAPPβ and 217

Aβ can also interact with the expression of sortilin, suggestive of sortilin involvement in 218

β-secretase-mediated APP processing. Since sortilin and β-secretase both have 219

intracellular motifs with similar binding partners and intracellular transport pathways, 220

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the authors suggest that the C-terminal of sortilin binds to β-secretase, thereby guiding 221

its intracellular transport. In subsequent in vitro experiments using C-terminal truncated 222

sortilin constructs, these investigators report that sortilin could redistribute β-secretase 223

from the TGN to the endosome. Truncated sortilin loses the binding site of retromer, 224

resulting in a reduction of retrograde trafficking of β-secretase. Gustafsen et al. (2013) 225

demonstrate that levels of sAPPα are significantly increased, whereas levels of sAPPβ are 226

decreased in the cells expressing C-terminal truncated sortilin, relative to non-transfected 227

control cells. In addition, sAPP levels are increased after inhibition of lysosomal protease 228

activity relative to control. Together, these in vitro experimental results suggest that 229

sortilin affects APP processing by promoting the α-secretase pathway and the degradation 230

of sAPP in lysosomes. Thus, further studies are needed to consolidate that sortilin could 231

affect Aβ production by modulating APP trafficking and enzymatic processing in vivo. 232

233

Experimental study on sortilin regulation of APP and Aβ degradation 234

Yang et al. (2013) has reported that the C-terminal of sortilin can regulate 235

non-specific degradation of APP. Specifically, the MS1 part of the C-terminal can bind to 236

APP and direct it to the lysosome. Knockout of this segment reduces the quantity of APP 237

targeting to lysosomes. In a subsequent study (Ruan et al. 2017), they show that aged 238

APP and presenilin 1 double transgenic mice (about 9 months old) with silenced SORT1 239

gene develop increased amyloid plaques in the forebrain, with astrocytic activation in the 240

hippocampus and neuronal loss in the cortex. These pathological phenotypes could be 241

rescued by intra-hippocampal injection of a viral vector that mediate overexpression of 242

human sortilin. Therefore, it is suggested that sortilin plays a protective role in AD by 243

reducing amyloid pathogenesis. 244

Sortilin may also participate in Aβ degradation through receptor-mediated pathways. 245

Most of Aβ in brain may bind to ApoE, and then form ApoE/Aβ complex, which is 246

transported to the lysosome for degradation and then being released through the 247

extracellular fluid or the blood-brain barrier (BBB)(Fan et al. 2009). Low-density 248

lipoprotein receptor (LDLR) and LDL–related protein 1(LRP1) may serve as two major 249

receptors for transporting ApoE/Aβ through the BBB. Carlo et al. (2013) report that the 250

concentration of ApoE in the cortex and hippocampus of SORT1-/- mice increases 2 fold 251

relative to the wildtype controls. Thus, the capability for ApoE-assisted binding and 252

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degradation of Aβ appear to be both decreased without sortilin. However, it is also shown 253

that the levels of Aβ40 and the amount of senile plaques are higher in the SORT1-/- brain 254

as compared to control, possibly because the expression of LPR1 is not changed in the 255

knockouts (Carlo et al., 2013). 256

257

Experimental study on sortilin regulation of tau hyperphosphorylation 258

Neurofibrillary tangle is one of the pathological hallmarks of AD and is associated 259

with intraneuronal tau hyperphosphorylation. It is suggested that abnormally 260

phosphorylated tau proteins spread in the brain in a manner similar to prion propagation 261

(Fraser et al., 2014; Yin et al. 2014). Pathogenic prion PrPSc has virus-like infectivity 262

capable of inducing conformational transformation of the normal prion protein PrPC. 263

PrPSc can incessantly proliferate and damage brain tissue. Prion diseases, just like AD, 264

show neuronal tau hyperphosphorylation in the brain (Ballatore et al. 2007). Uchiyama et 265

al. ( 2017) demonstrate that sortilin can bind to both PrPC and PrPSc, and guide them to 266

lysosome for degradation. However, because proliferating PrPSc increases sortilin 267

degradation in the lysosome, the positive effect of sortilin on prion propagation becomes 268

limited. Overall, the authors propose that sortilin can protect brain from injury during 269

PrPSc transmission (Sakaguchi and Uchiyama, 2017). 270

Recently, Johnson et al. (2017) demonstrate that abnormal tau phosphorylation in 271

Tg2541 transgenic mice is mainly located in the hindbrain, although there is no 272

significant difference in the levels of tau mRNA and protein between the forebrain and 273

hindbrain. The expression of sortilin in the forebrain is significantly higher than in the 274

hindbrain. Therefore, it is suggested that sortilin can inhibit abnormal tau spreading in 275

the forebrain of the transgenic mice with enhanced human mutant tau transgene. 276

277

Experimental evidence for sortilin involvement in proNT-mediated apoptosis 278

In AD pathogenesis, it is suggested that neurons and glial cells release proNT to 279

potentiate cellular apoptosis and this effect may relate to the massive loss of neurons in 280

the brains of AD patients (Fahnestock et al. 2001). As increased release of proNT in the 281

brain is also found in other conditions such as epilepsy, spinal nerve injury, retinal 282

ischemia and prion disease, it is proposed that proNT plays a significant role in neuronal 283

death by a mechanism involving receptor-mediated apoptosis (Hempstead, 2014; Glerup 284

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et al. 2014). Sortilin has been considered as a modulator in proNT-induced apoptosis in 285

neurons (Nykjaer et al. 2004). Thus, sortilin can bind to the proNT propeptides with high 286

affinity, while mature proNT binds to p75 NTR forming a receptor complex that initiates 287

apoptotic signaling (Nykjaer et al. 2004; Rogers et al. 2010). Structural analyses show 288

that proNT and p75NTR take the form of a 2:2 symmetrical configuration when forming a 289

trimmer. The binding affinity of this proNT/p75NTR complex to sortilin is 5 times higher 290

than proNT alone (Feng et al. 2010). NGF-deprived AD model mice exhibit typical 291

pathological characteristics of AD such as Aβ deposition and tau phosphorylation, along 292

with cholinergic deficit and working memory deficits. After crossbred with SORT1-/- 293

mice, their cholinergic function and working memory are improved, although Aβ and tau 294

phosphorylation are not changed in the descendants. These findings point to a specific 295

resistance of SORT1-/- mice to proNT-induced apoptosis (Capsoni et al. 2013). An in vitro 296

experiment shows that by silencing sortilin expression in neuroblastoma SH-SY5Y, Aβ 297

oligomers-induced cell death is significantly mitigated (Takamura et al. 2012). 298

299

Conclusions and perspectives 300

Increasing in vitro and in vivo studies during the past few years report that sortilin 301

may be related genetically to the risk of development of AD and frontotemporal dementia, 302

and pathologically to AD-type lesions via participation in Aβ production and clearance, tau 303

phosphorylation and neuronal death. Sortilin may also influence the progression of AD 304

pathology by mediating signal transduction and intracellular transportation of other 305

molecules in neurons and glial cells (Wang et al. 2017). The finding that sortilin itself can 306

yield fragment products to deposit at senile plaques provides clear pathological evidence 307

for its involvement in this AD hallmark lesion. Therefore, future studies should be carried 308

out to elucidate the cellular and molecular mechanism by which sortilin affects AD 309

pathogenesis. It is worth noting that the levels of sortilin in circulation may serve as a 310

biomarker for coronary atherosclerosis and diabetes (Oh et al. 2017). Other reports 311

suggest that SorL1 is a target for the development of new drugs for the treatment of AD 312

(Na et al. 2017). The genetic and pathological evidence for sortilin involvement in 313

dementia and AD-type neuropathology warrants further investigation of the role of 314

sortilin in AD etiology and pathogenesis, which might extend new cutting edge for the 315

development of novel AD diagnostic and therapeutic options. 316

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Financial and competing interest’s disclosure 317

Ms. Shu-Yin Xu was awarded a postgraduate studentship from Central South University 318

(#2017zzts820). Dr. Yan Cai was awarded a grant from the National Natural Science 319

Foundation (NNSF) of China (#81200837). Prof. Xiao-Xin Yan is funded by a NNSF grant 320

(#91632116). The sponsors have no role in the design of this work; collection, analysis, 321

and interpretation of the data; writing of manuscript; or the decision to submit this 322

manuscript. The authors have no other relevant affiliations or financial involvement with 323

any organization or entity with a financial interest/conflict in the subject matter. No 324

writing assistance was utilized in the production of this manuscript. 325

326

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533

534

535

536

537

Figure legends 538

Figure 1. Molecular architecture of the vacuolar protein sorting 10 (Vps10p) receptor 539

family proteins. The extracellular domains of all the receptors contain one Vps10p domain 540

(Vps10p-D). SorLA has the largest extracellular part. Its Vps10p-D is followed by an 541

epidermal growth factor-type repeat, a cluster of 11 complement-type repeats and 6 542

fibronectin-type III repeats. SorCS1, SorCS2 and SorCS3 are distributed in different areas 543

of cell, all of them contain a leucine-rich segment between the Vps10p-D and the 544

transmembrane. SorLA, sorting protein-related receptor with A-type repeats; SorCS, 545

sortilin-related receptor CNS expressed. 546

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547

Figure 2. Routes of sortilin trafficking. (a) via constitutive secretory pathway that is 548

responsible for translating ligands to the cell surface directly; (b) from cell surface, with 549

ligands being targeted for lysosomal degradation; (c) via GGA anterograde transport and 550

retromer recycling path, after transporting ligands to endosomes, most of sortilin return 551

to the TGN for re-use; (d) via regulatory secretory pathway that exists in cells to regulate 552

secretion. TGN; trans Golgi network; E: endosome; L: Lysosome. 553

554

Figure 3. Extracellular deposition of putative C-terminal sortilin fragments (Sort-CFTs) as 555

senile plaque-like lesions in the temporal lobe neocortex and dentate gyrus (DG) of 556

Alzheimer’s disease human brain. Sortilin immunolabeling is visualized with a rabbit 557

antibody against the C-terminal domain (Hu et al., 2017). Cortical layers are indicated by 558

Arabic numbers. WM: white matter; ML: molecular layer; GCL: granule cell layer. Scale bar 559

= 200 µm in A applying to B, equivalent to 20 µm in C-F. 560

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Figure 1: Molecular architecture of the vacuolar protein sorting 10 (Vps10p) receptor family proteins. The extracellular domains of all the receptors contain one Vps10p domain (Vps10p-D). SorLA has the largest extracellular part. Its Vps10p-D is followed by an epidermal growth factor-type repeat, a cluster of 11

complement-type repeats and 6 fibronectin-type III repeats. SorCS1, SorCS2 and SorCS3 are distributed in different areas of cell, all of them contain a leucine-rich segment between the Vps10p-D and the

transmembrane. SorLA, sorting protein-related receptor with A-type repeats; SorCS, sortilin-related receptor CNS expressed.

112x123mm (300 x 300 DPI)

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Figure 2. Routes of sortilin trafficking. (a) via constitutive secretory pathway that is responsible for translating ligands to the cell surface directly; (b) from cell surface, with ligands being targeted for

lysosomal degradation; (c) via GGA anterograde transport and retromer recycling path, after transporting

ligands to endosomes, most of sortilin return to the TGN for re-use; (d) via regulatory secretory pathway that exists in cells to regulate secretion. TGN; trans Golgi network; E: endosome; L: Lysosome.

98x96mm (300 x 300 DPI)

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Figure 3. Extracellular deposition of putative C-terminal sortilin fragments (Sort-CFTs) as senile plaque-like lesions in the temporal lobe neocortex and dentate gyrus (DG) of Alzheimer’s disease human brain. Sortilin

immunolabeling is visualized with a rabbit antibody against the C-terminal domain (Hu et al., 2017). Cortical layers are indicated by Arabic numbers. WM: white matter; ML: molecular layer; GCL: granule cell layer.

Scale bar = 200 µm in A applying to B, equivalent to 20 µm in C-F.

77x58mm (300 x 300 DPI)

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Sample size and

mean age at death

(years)

Areas examined Mean

PMD(hours)

Sortilin change relative

to control

Tissue resource Reference

AD(n=8,76.0)

NC(n=7,75.0)

basic forebrain

nuclei hippocampus

Not indicated no difference London

Neurodegenerative

Diseases Brain Bank, UK

Al-Shawi et

al.(2008)

MCI(n=20,83.6)

AD(n=21,86.3)

NC(n=17, 82.8)

frontal cortex

temporal cortex

MCI(6.3)

AD(6.5)

NC(5.0)

no difference Rush University Medical

Center, USA

Mufson et

al.(2010)

AD(n=12,76.6)

NC(n=12,79.9)

temporal cortex AD(4.9)

NC(4.3)

elevated New York Brain Bank at

Columbia University,

USA

Finan et

al.(2011)

AD(n=4,81.0)

NC(n=4,85.6)

cortex Not indicated elevated South Australia Brain at

Flinders University,

Australia

Saadipour et

al.(2013)

AD(n=9,87.1)

aged NC(n=9,80.0)

mid-age

NC(n=9,56.4)

middle temporal

gyrus

AD(6.9) aged

NC(8.8) mid-

age NC(11.1)

elevated in AD and aged

relative to mid-age

groups

Central South University,

China

Hu et al.(2017)

MCI: mild cognitive impairment; AD: Alzheimer's disease; NC: normal control; PMD: postmortem delay.

Table 1. Sortilin protein levels reported in Alzheimer's disease and control human brains

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