Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling

Baki, Lia; Neve, Rachael L.; Shao, Zhiping; Shioi, Junichi; Georgakopoulos, Anastasios; Robakis, Nikolaos K.

doi:10.1523/jneurosci.4067-07.2008

Cited by 56 publications

(51 citation statements)

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“…28 A role of possible insulin dysfunction in AD has been suggested recently. 7,8 Binding of insulin to IR leads to its rapid autophosphorylation and activation of its tyrosine kinase activity, which recruits and phosphorylates different substrates, such as insulin receptor substrate-1. Tyrosinephosphorylated insulin receptor substrate-1 then displays binding sites for various downstream signaling partners, of which PI3K is the major one.…”

Section: Discussionmentioning

confidence: 99%

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Dysregulation of Insulin Signaling, Glucose Transporters, O-GlcNAcylation, and Phosphorylation of Tau and Neurofilaments in the Brain

Deng

Liu

et al. 2009

The American Journal of Pathology

208

146

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Recent studies have suggested a possible role of insulin dysfunction in the pathogenesis of sporadic Alzheimer's disease (AD). In AD, brain glucose metabolism is impaired, and this impairment appears to precede the pathology and clinical symptoms of the disease. However, the exact contribution of impaired insulin signaling to AD is not known. In this study, by using a nontransgenic rat model of sporadic AD generated by intracerebroventricular administration of streptozotocin , we investigated insulin signaling , glucose transporters, protein O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain. We found impaired insulin signaling, overactivation of glycogen synthase kinase-3␤, decreased levels of major brain glucose transporters , downregulated protein O-GlcNAcylation , increased phosphorylation of tau and neurofilaments, and decreased microtubule-binding activity of tau in the brains of streptozotocin-treated rats. These results suggest that impaired brain insulin signaling may lead to overactivation of glycogen synthase kinase-3␤ and down-regulation of O-GlcNAcylation , which, in turn, facilitate abnormal hyperphosphorylation of tau and neurofilaments and, consequently, neurofibrillary degeneration. Alzheimer's disease (AD), the most devastating chronic neurodegenerative disease in adults, causes dementia in, and eventually, death of the affected individuals. In less than 1% of cases, AD is caused by autosomal dominant mutations of presenilin-1, presenilin-2, or ␤-amyloid precursor protein. Most AD cases are sporadic and are believed to result from multiple etiologic factors including genetic susceptibility (such as the ApoE4 allele) and environmental and metabolic factors.1 One of these factors, impaired brain glucose metabolism, can be detected many years before the appearance of clinical symptoms of AD. 2 We recently found that altered OGlcNAcylation, an O-linked post-translational modification of nucleocytoplasmic proteins by a monosaccharide ␤-N-acetylglucosamine (O-GlcNAc), of the microtubuleassociated protein tau, links the impairment of brain glucose metabolism to hyperphosphorylation of tau.3,4 On the basis of these findings, we hypothesized that the impairment of brain glucose metabolism contributes to neurodegeneration via down-regulation of O-GlcNAcylation, which is regulated by glucose metabolism, and the resultant abnormal hyperphosphorylation of tau, which is crucial to neurodegeneration in AD. 5Peripheral glucose metabolism is mainly regulated by insulin. Recent studies have indicated that insulin signaling also regulates glucose metabolism in the brain and plays important roles in neural development and neuronal activities and affects learning and memory. 6 The role of possible insulin dysfunction in AD has been suggested

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Section: Discussionmentioning

confidence: 99%

“…[7][8][9][10] However, how the impaired insulin signaling contributes to the pathogenesis of AD is not known.…”

mentioning

confidence: 99%

Dysregulation of Insulin Signaling, Glucose Transporters, O-GlcNAcylation, and Phosphorylation of Tau and Neurofilaments in the Brain

Deng

Liu

et al. 2009

The American Journal of Pathology

208

146

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“…Primary Neuronal Culture and Transfection-Cortical neuronal cultures were prepared from embryonic brains of Wistar rats (embryonic day 17-18) as described (18). Briefly, neocortices and hippocampi were dissected out, treated with trypsin, and mechanically dissociated.…”

Section: Methodsmentioning

confidence: 99%

Peptide EphB2/CTF2 Generated by the γ-Secretase Processing of EphB2 Receptor Promotes Tyrosine Phosphorylation and Cell Surface Localization of N-Methyl-d-aspartate Receptors

Xu¹,

Litterst²,

Georgakopoulos

et al. 2009

Journal of Biological Chemistry

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N-Methyl-D-aspartate receptor (NMDAR)5 is a subtype of ionotropic glutamate receptors expressed in the mammalian central nervous system. Because of its high calcium permeability, this receptor plays crucial roles in the development of the central nervous system, neuroplasticity, and excitotoxicity. In the adult forebrain NMDAR consists mainly of NR1, NR2A, and NR2B subunits, and its functions are regulated by tyrosine phosphorylation events in these subunits. For example, upregulation of NMDAR channel functions following subunit phosphorylation by the Src family of nonreceptor tyrosine kinases plays crucial roles in cellular signaling, learning, and memory. In addition, tyrosine phosphorylation of NMDAR is important in pathological conditions including stroke, epilepsy, and chronic pain (for review see Ref. 2).Eph receptors constitute the largest family of transmembrane receptor tyrosine kinases. This family is divided into EphA and EphB subclasses based on their ability to be activated by ephrinA and ephrinB ligands, respectively. EphB-ephrinB interactions have been implicated in brain ontogenesis, repulsive axonal guidance, and dendritic spine morphogenesis (reviewed in Refs. 3 and 4). Mounting evidence suggests that interactions between EphB receptors and NMDARs regulate synapse formation, maturation, and plasticity. For example, activation of EphB2 receptor (EphB2R) by ephrinB ligand leads to the formation of complexes between EphB2R and NMDAR, resulting in increased synaptogenesis (5). In contrast, EphB2R knock-out mice show reduced current activity of synaptic NMDAR and a decreased number of glutamate receptors in excitatory synapses (6, 7). Synaptic plasticity, e.g. long term potentiation and depression, is also impaired in these mice (6,8). Other evidence suggests that the NR2B subunit is tyrosinephosphorylated by Src kinases in response to EphB2R activation (9, 10).PS1, a protein involved in the development of familial Alzheimer disease (FAD), is expressed in embryonic and adult brains where it is enriched in neurons (11,12). Previous work revealed that PS1 is a necessary component of the proteolytic ␥-secretase complex that promotes production of the A␤ peptides of Alzheimer disease amyloid by processing APP at the ␥-cleavage sites (13,14). Recent evidence, however, revealed that in addition to APP, the PS/␥-secretase system facilitates the proteolytic processing and signaling of many cell surface transmembrane proteins. Almost all ␥-secretase substrates are first processed through a pathway that involves extracellular cleavages, usually by a metalloproteinase (MP), and shedding of their ectodomain, whereas the remaining membrane-associated fragments are cleaved at the epsilon site (⑀-site) by the PS1/␥-

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“…In the hippocampus of AD patients, cytoplasmic phospho-Akt Ser 473 levels decrease (23). Presenilins bearing familial AD mutations increase neuronal susceptibility to cell death by down-regulating the pro-survival Akt pathway (24,25). Additionally, A␤42 oligomers bind to the insulin receptor (26,27) and the brain-derived neurotrophic factor receptor (28) and modify their signaling properties, suggesting that Akt deregulation might be central to AD.…”

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confidence: 99%

Low Density Lipoprotein Receptor-related Protein 1 Promotes Anti-apoptotic Signaling in Neurons by Activating Akt Survival Pathway

Fuentealba

Liu

Kanekiyo

et al. 2009

Journal of Biological Chemistry

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The low density lipoprotein receptor-related protein 1 (LRP1) is a multi-ligand receptor abundantly expressed in neurons. Previous work has shown that brain LRP1 levels are decreased during aging and in Alzheimer disease. Although mounting evidence has demonstrated a role for LRP1 in the metabolism of apolipoprotein E/lipoprotein and amyloid-␤ peptide, whether LRP1 also plays a direct role in neuronal survival is not clear. Here, we show that LRP1 expression is critical for the survival of primary neurons under stress conditions including trophic withdrawal, the presence of apoptosis inducers, or amyloid-␤-induced neurotoxicity. Using lentiviral short hairpin RNA to knock down endogenous LRP1 expression, we showed that a depletion of LRP1 leads to an activation of caspase-3 and increased neuronal apoptosis, an effect that was rescued by a caspase-3 inhibitor. A correlation between decreased Akt phosphorylation and the activation of caspase-3 was demonstrated in LRP1 knocked down neurons. Notably, LRP1 knockdown decreased insulin receptor levels in primary neurons, suggesting that decreased neuronal survival might be a consequence of an impaired insulin receptor signaling pathway. Correspondingly, both insulin receptor and phospho-Akt levels were decreased in LRP1 forebrain knock-out mice. These results demonstrate that LRP1 mediates anti-apoptotic function in neurons by regulating insulin receptor and the Akt survival pathway and suggest that restoring LRP1 expression in Alzheimer disease brain might be beneficial to inhibiting neurodegeneration.Originally described as a clearance receptor for lipoproteins in the liver, the low density lipoprotein receptor-related protein 1 (LRP1) 2 plays essential roles in development and mediates important tissue-specific functions throughout adulthood. These include regulation of glutamatergic synaptic transmission in the nervous system, prevention of vascular smooth muscle cell proliferation and atherosclerosis development, catabolism of activated coagulation factor VIII in hepatocytes, and regulation of body energy by adipocytes (1, 2). Mounting evidence suggests an important role for LRP1 in the pathogenesis of Alzheimer disease (AD). LRP1 regulates the production and clearance of amyloid-␤ (A␤) peptide and the metabolism of several AD-associated ligands, including apolipoprotein E (apoE), which has three isoforms in humans with apoE4 being a major risk factor for late onset AD (3). LRP1 is abundantly expressed in the cell body and proximal processes of cortical and hippocampal neurons in the brain (4 -6). It consists of an extracellular 515-kDa subunit (LRP1-515) that binds more than 30 different ligands and a transmembrane 85-kDa chain (LRP1-85) that interacts with several adaptor proteins for efficient endocytic trafficking and signaling (7). LRP1 binds to A␤ either directly or via A␤ chaperones, such as apoE, to mediate A␤ clearance (3,8,9). In AD patients and in the elderly, brain LRP1 levels are significantly decreased and inversely correlate with the age of onset of...

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Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling

Cited by 56 publications

References 54 publications

Dysregulation of Insulin Signaling, Glucose Transporters, O-GlcNAcylation, and Phosphorylation of Tau and Neurofilaments in the Brain

Dysregulation of Insulin Signaling, Glucose Transporters, O-GlcNAcylation, and Phosphorylation of Tau and Neurofilaments in the Brain

Peptide EphB2/CTF2 Generated by the γ-Secretase Processing of EphB2 Receptor Promotes Tyrosine Phosphorylation and Cell Surface Localization of N-Methyl-d-aspartate Receptors

Low Density Lipoprotein Receptor-related Protein 1 Promotes Anti-apoptotic Signaling in Neurons by Activating Akt Survival Pathway

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