Sortilin-Related Receptor Expression in Human Neural Stem Cells Derived from Alzheimer’s Disease Patients Carrying the APOE Epsilon 4 Allele

Abstract

Alzheimer's disease (AD) is the most common form of dementia in the elderly; important risk factors are old age and inheritance of the apolipoprotein E4 (APOE4) allele. Changes in amyloid precursor protein (APP) binding, trafficking, and sorting may be important AD causative factors. Secretase-mediated APP cleavage produces neurotoxic amyloid-beta (Aβ) peptides, which form lethal deposits in the brain. In vivo and in vitro studies have implicated sortilin-related receptor (SORL1) as an important factor in APP trafficking and processing. Recent in vitro evidence has associated the APOE4 allele and alterations in the SORL1 pathway with AD development and progression. Here, we analyzed SORL1 expression in neural stem cells (NSCs) from AD patients carrying null, one, or two copies of the APOE4 allele. We show reduced SORL1 expression only in NSCs of a patient carrying two copies of APOE4 allele with increased Aβ/SORL1 localization along the degenerated neurites. Interestingly, SORL1 binding to APP was largely compromised; this could be almost completely reversed by γ-secretase (but not β-secretase) inhibitor treatment. These findings may yield new insights into the complex interplay of SORL1 and AD pathology and point to NSCs as a valuable tool to address unsolved AD-related questions in vitro.

Fyn Tyrosine Kinase Elicits Amyloid Precursor Protein Tyr682 Phosphorylation in Neurons from Alzheimer’s Disease Patients

“…However, experiments were also replicated in #ax0015 and #ax0018, without detecting any relevant experimental differences between the three different neural cell lines. of 21 For immunofluorescence (IF) analysis and Aβ42 ELISA, we used neurons that were differentiated for at least 5 weeks in culture in Neurobasal/B27 medium (250,000 cells/well, well plate diameter 10 mm) following the procedure described by Zollo et al [33].…”

Human and Rodent Temporal Lobe Epilepsy is Characterized by Changes in O-GLCNAC Homeostasis that can be Reversed to Dampen Epileptiform Activity

“…SORL1 is a receptor that binds to LDL and transports it into the cells via endocytosis, a process that is subject to inhibition upon binding to the receptor-associated protein (RAP) [44]. SORL1 has also been implicated in APP trafficking to and from the Golgi apparatus and in Alzheimer’s disease [45, 46]. Tmod2 is an actin-binding protein that stabilizes ADP-bound actin monomers onto actin filaments and is downregulated in epilepsy [47, 48].…”

Sorting Out the Role of the Sortilin-Related Receptor 1 in Alzheimer’s Disease

“…Overexpression of SORL1 increases cellular uptake of APOE 4 and 3 (but not 2, which is protective for AD (reviewed in [115])) as shown by a cell culture study [113]. Additionally, neural stem cells isolated from an AD patient with genotype 4/4 had lower SORL1 expression after 5 weeks in culture than neural stem cells from AD and control subjects with the other possible APOE genotypes [116]. However, this study only analyzed one homozygous 4 patient.…”