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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
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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
7
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
29
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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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