Low Density Lipoprotein Receptor-related Protein (LRP) Interacts with Presenilin 1 and Is a Competitive Substrate of the Amyloid Precursor Protein (APP) for γ-Secretase

Lleó, Alberto; Waldron, Elaine; Arnim, Christine A. F. Von; Herl, Lauren; Tangredi, Michele M.; Peltan, Ithan D.; Strickland, Dudley K.; Koo, Edward H.; Hyman, Bradley T.; Pietrzik, Claus U.; Berezovska, Oksana

doi:10.1074/jbc.m413969200

Cited by 61 publications

(41 citation statements)

References 57 publications

(83 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally we could show here that SorLA is, like the amyloidogenic protein APP, a substrate for the presenilin-containing ␥-secretase complex, which is necessary for the production of the A ␤ -peptide. Therefore, SorLA might be a competitive substrate of APP for ␥-secretase similar to notch (55) and LRP (49). This could explain why reduced SorLA levels in brain would lead to an increased production of A ␤ and finally to the development of Alzheimer disease.…”

Section: Discussionmentioning

confidence: 99%

SorLA Signaling by Regulated Intramembrane Proteolysis

Böhm

Seibel

Henkel

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

The single-transmembrane receptor SorLA/LR11 contains binding domains typical for lipoprotein receptors and a VPS10 domain, which binds the neuropeptide head-activator. This undecapeptide enhances proliferation of neuronal precursor cells in a SorLA-dependent manner. Using specific inhibitors we found previously that head activator activates shedding of SorLA by the metalloprotease TACE close to the transmembrane domain releasing the large extracellular part of the receptor. Here we show that the remaining COOH-terminal membrane fragment of SorLA is processed by ␥-secretase. Inhibition of ␥-secretase by specific inhibitors or overexpression of dominant negative presenilin mutants and knock out of the presenilin genes led to accumulation of the SorLA membrane fragment and also of full-length SorLA in the membrane. In an in vitro assay we observed the ␥-secretase-dependent release of the two soluble cleavage products, the SorLA cytoplasmic domain and the SorLA ␤-peptide. These processing steps are reminiscent of a novel signaling pathway that has been described for the notch receptor. Here, the notch cytoplasmic domain is released into the cytoplasm by the ␥-secretase and migrates to the nucleus where it acts as a transcriptional regulator. In parallel we found that a fusion protein of the released cytoplasmic tail of SorLA with EGFP located to the nucleus only if the nuclear localization signal of SorLA was intact. In a reporter gene assay the cytoplasmic domain of SorLA acted as a transcriptional activator indicating that SorLA might directly regulate transcription after activation by ␥-secretase.

show abstract

Section: Discussionmentioning

confidence: 99%

SorLA Signaling by Regulated Intramembrane Proteolysis

Böhm

Seibel

Henkel

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…CRB2 Is Not a Competitive Substrate for ␥-Secretase-It is still controversial whether ␥-secretase substrates competitively inhibit each others cleavage (25)(26)(27). CRB2 is a potential substrate for ␥-secretase, because CRB2 is a type I TM protein.…”

Section: Efficient Inhibition By Crb2 Requires Its Cytoplasmic Domainmentioning

confidence: 99%

Human CRB2 Inhibits γ-Secretase Cleavage of Amyloid Precursor Protein by Binding to the Presenilin Complex

Hasegawa

Matsuo

Araki

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Drosophila Crumbs has been reported to attenuate Notch signaling by inhibition of ␥-secretase cleavage at the wing margins. ␥-Secretase is an intramembrane protease that is responsible for the generation of amyloid-␤ (A␤) peptides from the ␤-amyloid precursor protein (APP). Here, we re-examined ␥-secretase inhibition by human CRB2, which is the most abundant Crumbs ortholog in the brain. Transfected CRB2 inhibited proteolytic production of A␤ and APP intracellular domains from APP C-terminal fragments in HEK293 and SH-SY5Y cells. Conversely, knockdown of endogenous CRB2 increased ␥-secretase cleavage products in SH-SY5Y cells. CRB2 inhibition of ␥-cleavage was also detected in cell-free assays. CRB2 interacted with the ␥-secretase complex, but was not a competitive substrate for ␥-cleavage. The transmembrane domain of CRB2 was indispensable for inhibition of A␤ generation and mediated CRB2 binding with the ␥-secretase complex. In addition, the cytoplasmic domain appeared to play a supportive role in ␥-secretase inhibition, whereas mutational disruption of the two protein-binding motifs involved in the formation of cell adhesion complexes did not affect ␥-secretase inhibition. Co-overexpression of presenilin-1 or APH-1 abrogated ␥-secretase inhibition probably through prevention of the incorporation of CRB2 into the ␥-secretase complex. Our results suggest that CRB2 functions as an inhibitory binding protein that is involved in the formation of a mature but inactive pool of the ␥-secretase complex.

show abstract

“…79 In other studies, Ab1À40 has been found to reduce cholesterol synthesis by inhibiting the enzyme 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase (involved in cholesterol synthesis), in a putative negative feedback loop, and Ab1À42 has been found to activate neutral sphingomyelinase, an enzyme that cleaves sphingomyelins to produce ceramides, thought to be primary effectors of apoptosis. 80 This latter finding is consistent with the fact that ceramide:sphingomyelin ratios are higher in vulnerable brain regions of AD patients.…”

mentioning

confidence: 99%

Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease

et al. 2006

View full text Add to dashboard Cite

High fat diets and sedentary lifestyles are becoming major concerns for Western countries. They have led to a growing incidence of obesity, dyslipidemia, high blood pressure, and a condition known as the insulin-resistance syndrome or metabolic syndrome. These health conditions are well known to develop along with, or be precursors to atherosclerosis, cardiovascular disease, and diabetes. Recent studies have found that most of these disorders can also be linked to an increased risk of Alzheimer's disease (AD). To complicate matters, possession of one or more apolipoprotein E e4 (APOE e4) alleles further increases the risk or severity of many of these conditions, including AD. ApoE has roles in cholesterol metabolism and Ab clearance, both of which are thought to be significant in AD pathogenesis. The apparent inadequacies of ApoE e4 in these roles may explain the increased risk of AD in subjects carrying one or more APOE e4 alleles. This review describes some of the physiological and biochemical changes that the above conditions cause, and how they are related to the risk of AD. A diversity of topics is covered, including cholesterol metabolism, glucose regulation, diabetes, insulin, ApoE function, amyloid precursor protein metabolism, and in particular their relevance to AD. It can be seen that abnormal lipid, cholesterol and glucose metabolism are consistently indicated as central in the pathophysiology, and possibly the pathogenesis of AD. As diagnosis of mild cognitive impairment and early AD are becoming more reliable, and as evidence is accumulating that health conditions such as diabetes, obesity, and coronary artery disease are risk factors for AD, appropriate changes to diets and lifestyles will likely reduce AD risk, and also improve the prognosis for people already suffering from such conditions.

show abstract

Low Density Lipoprotein Receptor-related Protein (LRP) Interacts with Presenilin 1 and Is a Competitive Substrate of the Amyloid Precursor Protein (APP) for γ-Secretase

Cited by 61 publications

References 57 publications

SorLA Signaling by Regulated Intramembrane Proteolysis

SorLA Signaling by Regulated Intramembrane Proteolysis

Human CRB2 Inhibits γ-Secretase Cleavage of Amyloid Precursor Protein by Binding to the Presenilin Complex

Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease

Contact Info

Product

Resources

About