Anne-Sophie Carlo

Sortilin-related receptor with A-type repeats (SORLA) affects the amyloid precursor protein-dependent stimulation of ERK signaling and adult neurogenesis.

Sortilin-related receptor with A-type repeats (SORLA) is a sorting receptor that impairs processing of amyloid precursor protein (APP) to soluble (s) APP and to the amyloid β-peptide in cultured neurons and is poorly expressed in patients with Alzheimer disease (AD). Here, we evaluated the consequences of Sorla gene defects on brain anatomy and function using mouse models of receptor deficiency. In line with a protective role for SORLA in APP metabolism, lack of the receptor results in increased amyloidogenic processing of endogenous APP and in aggravated plaque deposition when introduced into PDAPP mice expressing mutant human APP. Surprisingly, increased levels of sAPP caused by receptor deficiency correlate with pro-found stimulation of neuronal ERK signaling and with enhanced neurogenesis, providing in vivo support for neurotrophic functions of sAPP. Our data document a role for SORLA not only in control of plaque burden but also in APP-dependent neuronal signaling and suggest a molecular explanation for increased neurogenesis observed in some AD patients.

Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer's disease mutation

A familial AD mutation in SORL1 disrupts the ability of the sorting receptor SORLA to mediate intracellular degradation of Aβ peptides. SORLA: Sorting Aβ for Destruction Alzheimer’s disease (AD) is a devastating neurodegenerative disorder. The principal cause of AD is neurotoxic amyloid-β (Aβ) peptides, derived by processing of an amyloid precursor protein, which impair neuronal viability and function. Current efforts are directed toward elucidating factors that determine the extent of Aβ production that could represent therapeutic targets to reduce Aβ buildup in the brain. In new work, Caglayan and colleagues focused on SORLA, a sorting receptor genetically associated with both sporadic and familial forms of AD. Because low SORLA levels coincide with high Aβ concentrations in AD patients, the authors tested whether and by what mechanism raising SORLA activity could protect from Aβ peptide accumulation. Using mouse models overexpressing human SORLA, the authors documented that boosting this receptor caused a marked reduction in brain Aβ. The underlying molecular mechanism was traced to the ability of SORLA to direct newly produced Aβ to lysosomes for degradation. The authors also demonstrated that this sorting function was lost in a SORLA receptor carrying a G511R mutation expressed in an autosomal dominant form of AD. This study substantiates the beneficial effects of raising SORLA activity for AD-related processes, and identifies lysosomal sorting of Aβ as a new pathway that may be amenable to therapeutic intervention. SORLA/SORL1 is a unique neuronal sorting receptor for the amyloid precursor protein that has been causally implicated in both sporadic and autosomal dominant familial forms of Alzheimer’s disease (AD). Brain concentrations of SORLA are inversely correlated with amyloid-β (Aβ) in mouse models and AD patients, suggesting that increasing expression of this receptor could be a therapeutic option for decreasing the amount of amyloidogenic products in affected individuals. We characterize a new mouse model in which SORLA is overexpressed, and show a decrease in Aβ concentrations in mouse brain. We trace the underlying molecular mechanism to the ability of this receptor to direct lysosomal targeting of nascent Aβ peptides. Aβ binds to the amino-terminal VPS10P domain of SORLA, and this binding is impaired by a familial AD mutation in SORL1. Thus, loss of SORLA’s Aβ sorting function is a potential cause of AD in patients, and SORLA may be a new therapeutic target for AD drug development.

Sorting receptor sortilin—a culprit in cardiovascular and neurological diseases

Sortilin is a sorting receptor that directs target proteins, such as growth factors, signaling receptors, and enzymes, to their destined location in secretory or endocytic compartments of cells. The activity of sortilin is essential for proper function of not only neurons but also non-neuronal cell types, and receptor (dys)function emerges as a major cause of malignancies, including hypercholesterolemia, retinal degeneration, neuronal cell loss in stroke and spinal cord injury, or Alzheimer’s disease and other neurodegenerative disorders. In this article, we describe the molecular mechanisms of sortilin action in protein sorting and signaling and how modulation of receptor function may offer novel therapeutic strategies for treatment of common diseases of the cardiovascular and nervous systems.

SORLA-Dependent and -Independent Functions for PACS1 in Control of Amyloidogenic Processes

ABSTRACT Sorting-related receptor with A-type repeats (SORLA) is a sorting receptor for the amyloid precursor protein (APP) that prevents breakdown of APP into Aβ peptides, a hallmark of Alzheimers disease (AD). Several cytosolic adaptors have been shown to interact with the cytoplasmic domain of SORLA, thereby controlling intracellular routing of SORLA/APP complexes in cell lines. However, the relevance of adaptor-mediated sorting of SORLA for amyloidogenic processes in vivo remained unexplored. We focused on the interaction of SORLA with phosphofurin acidic cluster sorting protein 1 (PACS1), an adaptor that shuttles proteins between the trans-Golgi network (TGN) and endosomes. By studying PACS1 knockdown in neuronal cell lines and investigating transgenic mice expressing a PACS1-binding-defective mutant form of SORLA, we found that disruption of SORLA and PACS1 interaction results in the inability of SORLA/APP complexes to sort to the TGN in neurons and in increased APP processing in the brain. Loss of PACS1 also impairs the proper expression of the cation-independent mannose 6-phosphate receptor and its target cathepsin B, a protease that breaks down Aβ. Thus, our data identified the importance of PACS1-dependent protein sorting for amyloidogenic-burden control via both SORLA-dependent and SORLA-independent mechanisms.

SorLA deficiency dissects amyloid pathology from tau and cholinergic neurodegeneration in a mouse model of Alzheimer's disease.

Sortilin-related receptor with A-type repeats (SorLA, also known as LR11) has been implicated in Alzheimers disease (AD). Thus, genetic studies associated SorLA gene variants with the risk of sporadic AD. Also, in vitro and in vivo studies showed that SorLA impairs processing of the amyloid-β protein precursor (AβPP) to amyloid-β. In particular, it has been found that loss of SorLA accelerates senile plaque deposition in mouse models overexpressing mutant forms of human AβPP and presenilin 1. Here we tested the possibility that SorLA deficiency also interferes with behavioral and neuropathological endpoints in an alternative murine AD model, the AD10 anti-nerve growth factor (NGF) mouse, in which amyloid-β accumulation derives from the altered processing of endogenous AβPP. In addition to alterations in AβPP processing, AD10 mice also show cholinergic deficit and tau hyperphosphorylation resulting in behavioral deficits in learning and memory paradigms. We found that the loss of SorLA not only exacerbates early amyloid pathology but, at the same time, protects from cholinergic deficit and from early phospho-tau mislocalization. The results show that in the AD10 anti-NGF mouse model the AβPP processing-related aspects of neurodegeneration can be dissociated from those related to tau posttranslational processing and to cholinergic phenotypic maintenance by modulation of SorLA expression. We suggest that SorLA regulates different aspects of neurodegeneration in a complex way, supporting the hypothesis that SorLA expression might be critical not only for amyloid-related pathology but also for other cellular processes altered in AD.

Apolipoprotein E receptor pathways in Alzheimer disease

Alzheimer disease (AD) is the most common neurodegenerative disease affecting millions of patients worldwide. According to the amyloid cascade hypothesis, the formation of neurotoxic oligomers composed of amyloid‐β (Aβ) peptides is the main mechanism that causes synaptic dysfunction and, eventually, neuronal cell death in this condition. Intriguingly, apolipoprotein E (apoE), the most important genetic risk factor for sporadic AD, emerges as a key factor that contributes to many aspects of the amyloid cascade including the clearance of Aβ from brain interstitial fluid and the ability of this peptide to form neurotoxic oligomers. Central to the activity of apoE in the healthy and in the diseased brain are apoE receptors that interact with this protein to mediate its multiple cellular and systemic effects. This review describes the molecular interactions that link apoE and its cellular receptors with neuronal viability and function, and how defects in these pathways in the brain promote neurodegeneration.

The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain

Sortilin is a member of the VPS10P domain receptor gene family, a class of sorting and signalling receptors in neurons. This gene family also includes SORLA/LR11, the neuronal sorting factor for APP. Sortilin has been shown to constitute an essential component of the receptor complex that transmits pro-neurotrophin-dependent death signals in neurons. In previous studies, sortilin-dependent pro-neurotrophin signalling has been implicated in regulation of neuronal viability during normal development and aging. Also, sortilin activity has been shown to control neuronal cell death and survival in spinal cord injury. Remarkably, up-regulation of pro-neurotrophins has been observed under conditions of neurodegeneration. These findings led us to hypothesize that sortilin signaling may not only control neuronal viability during acute but also during chronic distress of the nervous system as in Alzheimer’s disease (AD). Here, we have used mice with targeted sortilin gene disruption to address the consequences of impaired receptor activity for APP processing, structural and functional integrity of the brain, as well as AD pathology in vivo. When crossed with two different AD models (PDAPP, 5xFAD), sortilin-deficient mice showed a robust increase in Aβ levels in brain compared with control animals. Surprisingly, the levels of soluble APP products were not altered in sortilin-deficient mice, nor were the levels of Aβ-degrading enzymes, neprilysin and insulin-degrading enzyme, suggesting an impairment of Aβ clearance pathways. Apolipoprotein (APO) E is the major risk factor for sporadic Alzheimer disease. Among other functions, APOE is proposed to sequester neurotoxic amyloid-β peptides (Aβ) in the brain, delivering them to cellular catabolism via neuronal APOE receptors. In this study, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of apoliporotein E (APOE)/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain, and in aggravated plaque burden. Also, primary neurons lacking sortilin exhibit significantly impaired uptake of APOE/Aβ complexes despite proper expression of other APOE receptors. In spite of higher than normal brain APOE levels, sortilin-deficient animals display anomalies in brain lipid metabolism seen in APOE-deficient mice, indicating functional deficiency in cellular APOE uptake pathways. Taken together, our findings identified sortilin as an essential neuronal pathway for APOE-containing lipoproteins in vivo and suggest an intriguing link between Aβ catabolism and pro-neurotrophin signaling converging on this receptor.

Pro-neurotrophin receptor sortilin in neurodegenerative processes and Alzheimer's disease

Background: Sortilin is a member of the VPS10P domain receptor gene family, a novel class of sorting and signalling receptors in neurons. This gene family also includes SORLA/LR11, the neuronal sorting receptor for APP. Sortilin has been shown to constitute an essential component of the receptor complex that transmits pro-neurotrophin-dependent death signals in neurons. In previous studies, sortilin-dependent pro-neurotrophin signalling has been implicated in regulation of neuronal viability during normal development and aging. Also, sortilin activity has been shown to control neuronal death and survival in spinal cord injury. Remarkably, up-regulation of proneurotrophins has been observed under conditions of neurodegeneration. These findings led us to hypothesize that sortilin signaling may not only control neuronal viability during acute but also during chronic distress of the nervous system as in Alzheimer’s disease (AD). Methods: Here, we have used mice with targeted sortilin gene disruption to address the consequences of impaired sortilin activity for APP processing, structural and functional integrity of the brain, as well as AD pathology in vivo. Results: Mice lacking sortilin were characterized by accelerated APP processing and a concomitant change in several neuronal signaling pathways including ERK1/2, PKBa, JNK, and PKA. Alterations in neuronal signaling did not affect viability of neurons as determined by stereological counting. However, loss of sortilin activity was accompanied by distinct changes in cognitive performance of affected mice. Conclusions: Ongoing experiments aim at further elucidating possible roles for sortilin in the progression and outcome of neurodegenerative processes in AD.

Regulation of Transport and Processing of Amyloid Precursor Protein by the Sorting Receptor SORLA

Trafficking of the amyloid precursor protein (APP) through intracellular compartments where the various secretase activities reside is a regulatory step that determines APP processing fates and is likely to play a role in pathological processes leading to Alzheimers disease (AD). SORLA is a member of a novel class of intracellular sorting proteins and acts as a neuronal receptor for APP, controlling transport and proteolytic processing of the precursor protein into amyloidogenic and non-amyloidogenic products. Substantial experimental evidence from epidemi-ological, cell biological and animal studies points to a model whereby SORLA determines trafficking of APP into cellular compartments less favorable for processing. Consequently, high levels of SORLA expression are associated with reduced APP processing rates, whereas low levels of the protein, as in patients with sporadic AD, may predispose to accelerated APP breakdown and enhanced senile plaque formation. This article discusses the molecular mechanisms that govern SORLA-mediated APP transport and processing and their potential relevance for neurodegenerative processes.