Overexpression of the Insulin-Like Growth Factor II Receptor Increases β-Amyloid Production and Affects Cell Viability

Abstract

dAmyloid ␤ (A␤) peptides originating from amyloid precursor protein (APP) in the endosomal-lysosomal compartments play a critical role in the development of Alzheimer's disease (AD), the most common type of senile dementia affecting the elderly. Since insulin-like growth factor II (IGF-II) receptors facilitate the delivery of nascent lysosomal enzymes from the trans-Golgi network to endosomes, we evaluated their role in APP metabolism and cell viability using mouse fibroblast MS cells deficient in the murine IGF-II receptor and corresponding MS9II cells overexpressing the human IGF-II receptors. Our results show that IGF-II receptor overexpression increases the protein levels of APP. This is accompanied by an increase of ␤-site APP-cleaving enzyme 1 levels and an increase of ␤-and ␥-secretase enzyme activities, leading to enhanced A␤ production. At the cellular level, IGF-II receptor overexpression causes localization of APP in perinuclear tubular structures, an increase of lipid raft components, and increased lipid raft partitioning of APP. Finally, MS9II cells are more susceptible to staurosporine-induced cytotoxicity, which can be attenuated by ␤-secretase inhibitor. Together, these results highlight the potential contribution of IGF-II receptor to AD pathology not only by regulating expression/processing of APP but also by its role in cellular vulnerability. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe memory loss followed by the deterioration of higher cognitive functions. Although most cases of AD occur sporadically after the age of 60 years, a small proportion of cases correspond to the early-onset (Ͻ60 years) autosomal dominant form of the disease. To date, mutations in three genes, the amyloid precursor protein (APP) gene on chromosome 21, the presenilin 1 (PSEN1) gene on chromosome 14, and the presenilin 2 (PSEN2) gene on chromosome 1, have been identified as the cause of a large proportion of early-onset familial AD (1-3). Additionally, inheritance of the ε4 allele of the apolipoprotein E (APOE) gene on chromosome 19 increases the risk of late-onset and sporadic AD. The neuropathological features associated with AD include the presence of extracellular ␤-amyloid (A␤) peptidecontaining neuritic plaques, intracellular tau-positive neurofibrillary tangles, and the loss of synapses and neurons in defined brain regions. Several lines of in vivo evidence suggest that A␤ peptides initiate or contribute to the neuronal loss and development of AD pathology (2, 4). A␤ peptides are generated from APP, a type I transmembrane protein, which can be processed either by nonamyloidogenic ␣-secretase or amyloidogenic ␤-secretase pathways (5, 6). The ␣-secretase cleaves APP within the A␤ domain, yielding soluble APP␣ and a 10-kDa C-terminal fragment (CTF-␣), which then can be processed by ␥-secretase to generate A␤ 17-40 /A␤ 17-42 fragments. The ␤-secretase, on the other hand, cleaves APP to generate soluble APP␤ and an A␤-containing Cterminal fragment (CTF-␤), which is fu...

Insulin-Like Growth Factor-II/Cation-Independent Mannose 6-Phosphate Receptor in Neurodegenerative Diseases

“…As for secretase, while BACE1 proteins were increased, the steady-state levels of PS1 and APH-1 were not altered in MS9II cells when compared to MS cells [219]. The activities of both β- and γ-secretases, as well as secretory Aβ 1-40 /Aβ 1-42 levels, were significantly higher in MS9II cells than MS cells [220]. Conversely, levels of the Aβ degrading enzyme IDE, but not neprilysin, were lower in MS9II cells indicating that overexpression of the IGF-II/M6P receptor may also influence clearance of Aβ-related peptides [220].…”

“…The activities of both β- and γ-secretases, as well as secretory Aβ 1-40 /Aβ 1-42 levels, were significantly higher in MS9II cells than MS cells [220]. Conversely, levels of the Aβ degrading enzyme IDE, but not neprilysin, were lower in MS9II cells indicating that overexpression of the IGF-II/M6P receptor may also influence clearance of Aβ-related peptides [220]. At the cellular level, subsets of APP, BACE1 and PS1 in the perinuclear region were found to be co-localized with IGF-II/M6P receptor in MS9II cells [220].…”

“…Conversely, levels of the Aβ degrading enzyme IDE, but not neprilysin, were lower in MS9II cells indicating that overexpression of the IGF-II/M6P receptor may also influence clearance of Aβ-related peptides [220]. At the cellular level, subsets of APP, BACE1 and PS1 in the perinuclear region were found to be co-localized with IGF-II/M6P receptor in MS9II cells [220]. Additionally, receptor overexpression promoted APP localization in certain tubular structures, whose exact nature remains unclear.…”

“…Additionally, receptor overexpression promoted APP localization in certain tubular structures, whose exact nature remains unclear. The significance of the IGF-II/M6P receptor overexpression on APP metabolism is highlighted by two lines of evidence i) siRNA-targeted decrease of the receptor level led to a concomitant reduction of APP, APP-CTFs and Aβ levels in MS9II cells and ii) activation of the receptor by its agonist Leu 27 IGF-II did not significantly affect the levels or processing of the APP in MS9II cells [220]. Notwithstanding these results, the functional implications of normal levels of the IGF-II/M6P receptor on neuronal Aβ metabolism remain to be evaluated.…”

“…A number of earlier studies have indicated that lipid-raft microdomains and non-raft regions of lipid bilayers play critical roles in the efficiency of amyloidogenic and non-amyloidogenic processing of APP, respectively [221–224]. Since the relative amount of full-length APP is found to be markedly higher in raft vs non-raft fractions in MS9II cells compared to MS cells, it is likely that IGF-II/M6P receptor overexpression may partly enhance Aβ production in MS9II cells by promoting raft microdomain association of APP [220]. Alternatively, given the evidence that IGF-II/M6P receptors are involved in the intracellular trafficking of lysosomal enzymes such as cathepsins B and D, which are known to regulate Aβ metabolism [59, 203, 225], it is possible that receptor overexpression can influence amyloidogenic processing of APP by altering the levels and/or redistribution of the enzymes within the EL compartments, as in the case of cation-dependent M6P receptor overexpression [214].…”