Sortilin-related Receptor with A-type Repeats (SORLA) Affects the Amyloid Precursor Protein-dependent Stimulation of ERK Signaling and Adult Neurogenesis

Abstract

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 ␤-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 profound 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.Sortilin-related receptor with A-type repeats (SORLA), 4 also known as LR11 or SORL1 is a sorting receptor that controls intracellular transport and processing of the amyloid precursor protein (APP) in cultured neurons (1-4). The receptor shuttles between Golgi, plasma membrane, and endosomes (5), and determines residence time of the precursor protein in the various intracellular compartments (3). Most importantly, the receptor promotes retention of APP in subcellular compartments less favorable for processing and thereby reduces the extent of proteolytic breakdown into both amyloidogenic and non-amyloidogenic products. Consistent with its protective role in APP catabolism, increasing SORLA expression in cells reduces conversion of APP to the amyloid ␤-peptide (A␤) and soluble (s) APP fragments, while low levels of receptor activity accelerate generation of these processing products (3,4,6).Recently, a possible role for SORLA as a risk factor for sporadic Alzheimer disease (AD) was supported by the association of inherited gene variants with the occurrence of this disease in several populations (7,8). These findings support earlier studies that reported low levels of Sorla gene expression in patients suffering from sporadic AD, but not in individuals with familial forms of the disease that are caused by defects in genes encoding APP or presenilin 1 and 2 (9, 10).A substantial amount of data correlate SORLA activity with APP processing and A␤ production rates in cell cultures. Still, the normal physiological role of SORLA-dependent regulation of APP processing in vivo and the pathophysiological consequences of insufficient receptor activity in the brain remain poorly understood.Here, we used alternative mouse models with targeted Sorla gene disruption to address the molecular and pathophysiological consequences of impaired SORLA activity for neuronal function and AD pathology in vivo. Our findings identified a distinct increase in A␤ production and amyloid pl...

SorLA Complement-type Repeat Domains Protect the Amyloid Precursor Protein against Processing

“…Using SorLA-deficient mice, we have found that in the absence of SorLA, AD pathology is strongly accelerated, suggesting a proximal role of SorLA in AD (18,19) that has led to the current model in which SorLA protects against AD (20).…”

“…Numerous studies have indicated that SorLA activity decreases APP processing in several cell lines (10,11,18,23). Although SorLA plays a direct role as a Golgi-localized retention factor that influences the amount of APP processed in sub- JOURNAL OF BIOLOGICAL CHEMISTRY 3363 sequent cellular compartments (22), it remains unknown whether SorLA overexpression per se affects the processing machinery, i.e.…”

Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex

“…GJA1 directly regulates excitatory amino acid transporter 2 (SLC1A2) expression and function and modulates the activity of intracellular signal molecules, which in turn leads to its downregulation (Morioka et al, 2015 Mitogen-activated protein kinase kinase 1 (MAP2K1) has an important role in neuron differentiation and projection (Mace et al, 2013). The activity of MAPK signaling is markedly increased in AD brains (Rohe et al, 2008). The carbohydrate metabolism-related proteins showed increased protein level in CCH rats.…”

Retromer Binds the FANSHY Sorting Motif in SorLA to Regulate Amyloid Precursor Protein Sorting and Processing

“…We and others have shown that sorLA binds APP and retains it in the Golgi compartment, thereby preventing processing of the precursor into A␤ (Andersen et al, 2005(Andersen et al, , 2006Offe et al, 2006;Schmidt et al, 2007;Dodson et al, 2008;Rohe et al, 2008). Accordingly, single nucleotide polymorphisms in SORL1, the gene encoding sorLA, are associated with late-onset AD, and sorLA expression is reduced in vulnerable brain regions of AD patients (Scherzer et al, 2004;Andersen et al, 2005;Dodson et al, 2006;Rogaeva et al, 2007).…”