SorLA has been recognized as a novel sorting receptor that regulates trafficking and processing of the amyloid precursor protein (APP) and that represents a significant risk factor for sporadic Alzheimer disease. Here, we investigated the cellular mechanisms that control intracellular trafficking of sorLA and their relevance for APP processing. We demonstrate that sorLA acts as a retention factor for APP in trans-Golgi compartments/ trans-Golgi network, preventing release of the precursor into regular processing pathways. Proper localization and activity of sorLA are dependent on functional interaction with GGA and PACS-1, adaptor proteins involved in protein transport to and from the trans-Golgi network. Aberrant targeting of sorLA to the recycling compartment or the plasma membrane causes faulty APP trafficking and imbalance in non-amyloidogenic and amyloidogenic processing fates. Thus, our findings identified altered routing of sorLA as a major cellular mechanism contributing to abnormal APP processing and enhanced amyloid ␤-peptide formation.

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. Still, the receptors involved in this process remain controversial. Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of 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 (e.g., accumulation of sulfatides) 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.

Sorting protein-related receptor with A-type repeats (SORLA) is a major risk factor in cellular processes leading to Alzheimer's disease (AD). It acts as sorting receptor for the amyloid precursor protein (APP) that regulates intracellular trafficking and processing into amyloidogenic-␤ peptides (A␤). Overexpression of SORLA in neurons reduces while inactivation of gene expression (as in knock-out mouse models) accelerates amyloidogenic processing and senile plaque formation. The current study aimed at identifying molecular pathways that control SORLA gene transcription in vivo and that may contribute to low levels of receptor expression in the brain of patients with AD. Using screening approaches in primary neurons, we identified brain-derived neurotrophic factor (BDNF) as a major inducer of Sorla that activates receptor gene transcription through the ERK (extracellular regulated kinase) pathway. In line with a physiological role as regulator of Sorla, expression of the receptor is significantly impaired in mouse models with genetic (Bdnf Ϫ/ Ϫ ) or disease-related loss of BDNF activity in the brain (Huntington's disease). Intriguingly, exogenous application of BDNF reduced A␤ production in primary neurons and in the brain of wild-type mice in vivo, but not in animals genetically deficient for Sorla. These findings demonstrate that the beneficial effects ascribed to BDNF in APP metabolism act through induction of Sorla that encodes a negative regulator of neuronal APP processing.

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...