Loss of Apolipoprotein E Receptor LR11 in Alzheimer Disease

Scherzer, Clemens R.; Offe, Katrin; Gearing, Marla; Rees, Howard D.; Fang, Guofu; Heilman, Craig J.; Schaller, Chica; Bujo, Hideaki; Levey, Aĺlan I.; Lah, James J.

doi:10.1001/archneur.61.8.1200

Cited by 295 publications

(257 citation statements)

References 38 publications

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“…Apparently, APP interacts with a number of neuronal proteins; the significance of such interactions for onset and progression of AD in patients remains to be established. The relevance of sorLA for APP processing and AD progression is supported by the observation that the receptor recognizes all APP variants as ligands and that patients with AD exhibit significantly reduced expression of the receptor in the brain (9). The reason for reduced sorLA expression in these individuals remains to be determined, but our findings strongly suggest that low levels of the receptor may be a primary cause of accelerated A␤ production and senile plaque formation.…”

Section: Discussionsupporting

confidence: 62%

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Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein

Andersen

Reiche

Schmidt

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

580

680

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sorLA (sorting protein-related receptor) is a type-1 membrane protein of unknown function that is expressed in neurons. Its homology to sorting receptors that shuttle between the plasma membrane, endosomes, and the Golgi suggests a related function in neuronal trafficking processes. Because expression of sorLA is reduced in the brain of patients with Alzheimer's disease (AD), we tested involvement of this receptor in intracellular transport and processing of the amyloid precursor protein (APP) to the amyloid ␤-peptide (A␤), the principal component of senile plaques. We demonstrate that sorLA interacts with APP in vitro and in living cells and that both proteins colocalize in endosomal and Golgi compartments. Overexpression of sorLA in neurons causes redistribution of APP to the Golgi and decreased processing to A␤, whereas ablation of sorLA expression in knockout mice results in increased levels of A␤ in the brain similar to the situation in AD patients. Thus, sorLA acts as a sorting receptor that protects APP from processing into A␤ and thereby reduces the burden of amyloidogenic peptide formation. Consequently, reduced receptor expression in the human brain may increase A␤ production and plaque formation and promote spontaneous AD.endocytic receptors ͉ knockout mouse ͉ neurodegeneration ͉ Vps10p-domain receptors S orting protein-related receptor (sorLA), also known as LR11, is a 250-kDa type-1 membrane protein of unknown function that is expressed in neurons of the central and peripheral nervous system (1-4). The protein is a member of a family of neuronal receptors that share structural similarity with the vacuolar protein sorting 10 protein (Vps10p), a sorting protein in yeast that transports carboxypeptidase Y from the Golgi to the vacuole (5). Other family members include the proneurotrophin receptor sortilin (6) and the head activator-binding protein in hydra (7). Because sorLA interacts with the family of GGA (Golgi-localizing, ␥-adaptin ear homology domain, ARFinteracting) adaptors that shuttle between the Golgi and endosomes͞lysosomes, the receptor was proposed to act in intracellular protein trafficking (8). The relevance of such sorLAmediated protein transport in neurons is unclear at present. However, expression profiling has demonstrated reduction of sorLA expression in the brain of patients suffering from Alzheimer's disease (AD), suggesting a causal role for the receptor in the pathogenesis of this disease (9).Central to the pathogenesis of AD is the proteolytic processing of a neuronal membrane protein called the amyloid precursor protein (APP). APP follows a complex intracellular trafficking pathway that influences processing to either a soluble fragment sAPP␣ (nonamyloidogenic) or to sAPP␤ and the insoluble amyloid ␤-peptide (A␤), the principal component of senile plaques (10). The rate of A␤ production is considered the major risk factor for onset of AD (10). En route through the secretory pathway to the cell surface, most newly synthesized APP molecules are cleaved into sAPP␣ by ␣-secretase;...

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Section: Discussionsupporting

confidence: 62%

“…The relevance of such sorLAmediated protein transport in neurons is unclear at present. However, expression profiling has demonstrated reduction of sorLA expression in the brain of patients suffering from Alzheimer's disease (AD), suggesting a causal role for the receptor in the pathogenesis of this disease (9).…”

mentioning

confidence: 99%

Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein

Andersen

Reiche

Schmidt

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

580

680

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“…To provide a completely independent confirmation of the association between AD and SORL1, SNPs 4,5,8,9,12,19, and 22-25 were genotyped and analyzed in an independent facility in three series of Caucasian cases and controls ascertained at the Mayo Clinic (n = 1400 late onset AD cases; 2113 controls, , and two of the three subdatasets individually gave highly significant results (0.003 < p < 0.007) for one or more of these SNPs (Table 5). Importantly, the alleles and haplotypes at SNPs 19, 22-25 that were associated with increased risk for AD in the Mayo datasets (black highlight in Tables 5 and 6) were the same as those associated with increased risk for AD in both the North European FAD dataset and in the North European case:control dataset (black highlight in Tables 3 and 4).…”

Section: Snps In Sorl1 Are Associated With Late-onset Admentioning

confidence: 99%

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

et al. 2007

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The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid β-peptide (Aβ) in Alzheimer's Disease (AD). We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset AD. These variants, which occur in at least two different clusters of intronic sequences may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways, and that when SORL1 is under-expressed, APP is sorted into Aβ-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing AD.

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“…However, in the absence of common ligands, Apoer2 increases the distribution of APP into lipid rafts and APP processing to Ab (Fuentealba et al 2007). A third apoE receptor that modulates APP trafficking and processing to Ab is sorLA/LR11 whose expression is significantly reduced in AD brains (Scherzer et al 2004). Cell biological studies show that sorLA in neurons shifts APP distribution to the Golgi compartment and decreases its processing to Ab (Andersen et al 2005).…”

Section: Lrp1: Effects On App Ab and Apoe Metabolism Regulation Of mentioning

confidence: 99%

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Holtzman

Herz²,

2012

Cold Spring Harbor Perspectives in Medicine

657

593

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Loss of Apolipoprotein E Receptor LR11 in Alzheimer Disease

Cited by 295 publications

References 38 publications

Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein

Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

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