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PubMed2006

Effects of apoE on neuronal signaling and APP processing in rodent brain.

We previously reported that primary neuronal cells treated with apolipoprotein E (apoE) or an apoE-derived peptide (EP) increased ERK activation and decreased JNK activation via apoE receptors. Here, we examined if the effects observed in vitro were observed in vivo. Similar to our observations in primary neurons, in vivo we found that injections of 2muM EP into the rat hippocampus increased the levels of ERK activation and decreased JNK activation. However, the time course of these effects was slower in vivo. Immunohistochemical analysis of the tissue showed prominently increased ERK phosphorylation and decreased JNK phosphorylation in neuronal cells throughout the hippocampus, particularly in the CA3 regions. To determine if apoE was endocytosed by neurons, we conjugated fluorescent microspheres with the EP and injected them into the rat hippocampus. After 7 days, the microspheres were present in neurons. We also examined the in vivo effects of apoE on ApoEr2 and APP processing. EP and full-length apoE3 and apoE4 increased C-terminal fragments of ApoEr2 and APP after a single injection, multiple injections, and chronic infusion paradigms. ApoE3 produced higher levels of ApoEr2 and APP C-terminal fragments than apoE4. These results demonstrate that apoE alters ApoEr2 and APP processing in vivo. The increase in ERK activation is consistent with a role for apoE in a neuronal response to stress, and the decrease in JNK activation suggests that apoE may have anti-apoptotic effects, over several days.

Amyloid beta-Protein Precursor↗

PubMed2006

The repressive effect of green tea ingredients on amyloid precursor protein (APP) expression in oral carcinoma cells in vitro and in vivo.

In a hamster model of N-methyl-N-benzylnitrosamine (MBN)-induced oral carcinogenesis, the incidence of buccal pouch (HBP) carcinomas in MBN-treated hamsters (17.8+/-7.5) was significantly higher than MBN-treated hamsters given tea (10.8+/-3.9) (P<0.05). Amyloid precursor protein (APP) expression was also significantly increased in MBN-induced HBP carcinomas but was significantly reduced by tea intake (P<0.0001). Furthermore, APP expression and secretion by OECM-1 oral squamous cell carcinoma cells was inhibited by a major polyphenolic ingredient of green tea, (-)-epigallocatechin gallate, in a dose-dependent manner. Thus, APP might promote oral carcinogenesis, whereas green tea ingredients might diminish it by down-regulating APP.

Amyloid beta-Protein Precursor↗

PubMed2005

The amyloid-beta precursor-like protein APLP2 and its relative APP are differentially regulated during neuroendocrine cell activation.

The amyloid-beta precursor-like protein APLP2 is structurally and functionally related to the amyloid-beta precursor protein APP, the protein generally accepted to be involved in Alzheimer's disease. Since we previously observed that the levels of APP mRNA and protein were up-regulated threefold in the active intermediate pituitary melanotrope cells of black-adapted Xenopus laevis, we now decided to study the regulation of APLP2 in these physiologically inducible neuroendocrine cells. Interestingly, both the mRNA and protein levels of Xenopus APLP2 were similar in the melanotrope cells of black and white frogs. Newly synthesized APLP2 became glycosylated and sulfated, chondroitin sulfate glycosaminoglycan chains were added, and eventually the protein was proteolytically cleaved. Unlike for APP, no phosphorylated APLP2 was observed. Our results show that, although APP and APLP2 are thought to be functionally related, their responses to neuroendocrine cell activation differ, suggesting distinct roles for these proteins.

Amyloid beta-Protein Precursor↗

PubMed2004

APP intracellular domain is increased and soluble Abeta is reduced with diet-induced hypercholesterolemia in a transgenic mouse model of Alzheimer disease.

Cholesterol is one of multiple factors, other than familial genetic mutations, that can influence amyloid-beta peptide (Abeta) metabolism and accumulation in Alzheimer disease (AD). The effect of a high-cholesterol diet on amyloid precursor protein (APP) processing in brain has not been thoroughly studied. This study was designed to further investigate the role of cholesterol in the production of Abeta and APP intracellular domain (AICD) in 12-month-old Tg2576 transgenic mice. The mice were maintained on a high-cholesterol diet for 6 weeks. We found that diet-induced hypercholesterolemia increased the APP cytosolic fragment AICD and reduced sAPPalpha in the Tg2576 mice compared to the mice on a control basal diet. In addition, the levels of detergent-extracted Abeta40 were reduced, although no change in guanidine-extracted Abeta levels was observed. Full-length APP, alpha/betaC-terminal fragment (alpha/betaCTF), and beta-secretase (BACE) were not different in the cholesterol-fed mice compared to the control diet-fed mice. This study suggests that a high dietary cholesterol in aged mice may not only influence Abeta metabolism, but also regulate the AICD levels. AICD has a proposed role in signal transduction and apoptosis, hence modulation of AICD production could be an alternative mechanism by which cholesterol contributes to AD pathogenesis.

Alzheimer Disease↗

PubMed2004

Late onset loss of hippocampal 5-HT and NE is accompanied by increases in BDNF protein expression in mice co-expressing mutant APP and PS1.

Transgenic mice expressing both mutant amyloid precursor protein (APPswe) and presenilin-1 (PS1DeltaE9) develop amyloid deposits as early as 4 months of age and preliminary evidence suggests that this may be associated with degenerative changes in serotonin axons innervating the dentate gyrus of the hippocampus. In the present investigation, which focused on further delineating the effects of amyloid deposition on hippocampal neurochemistry, decreases in serotonin neurotransmitter levels (-25%) were discovered to be present at 18 months in APP+/PS1+ mice, while norepinephrine was reduced in the hippocampus of 12- (-30%) and 18-month-old (-45%) APP+/PS1+ double mutants. In addition, brain-derived neurotrophic factor (BDNF) protein levels were investigated since changes in BDNF are reported to occur in AD, and BDNF has been shown to have trophic effects on serotonin and norepinephrine neurons. In doubly, but not singly mutant mice, hippocampal BDNF levels were increased at 12 (+70%) and 18 months (+170%). Furthermore, in a different model of serotonergic and noradrenergic degeneration, BDNF protein levels were similarly increased in response to depletions in hippocampal serotonin and norepinephrine caused by the chemical neurotoxin 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP). These findings show that early amyloid deposition in mice expressing mutant human APP and PS-1 is associated with a progressive loss of serotonin and norepinephrine neurotransmitter levels in the hippocampus later in life. Furthermore, BDNF protein levels are increased in APP+/PS1+ and 2'-NH2-MPTP-treated mice, possibly as a compensatory response to serotonergic and noradrenergic neurodegeneration in a brain region important for learning and memory.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2006

Convergence of genes implicated in Alzheimer's disease on the cerebral cholesterol shuttle: APP, cholesterol, lipoproteins, and atherosclerosis.

Polymorphic genes associated with Alzheimer's disease (see ) delineate a clearly defined pathway related to cerebral and peripheral cholesterol and lipoprotein homoeostasis. They include all of the key components of a glia/neurone cholesterol shuttle including cholesterol binding lipoproteins APOA1, APOA4, APOC1, APOC2, APOC3, APOD, APOE and LPA, cholesterol transporters ABCA1, ABCA2, lipoprotein receptors LDLR, LRP1, LRP8 and VLDLR, and the cholesterol metabolising enzymes CYP46A1 and CH25H, whose oxysterol products activate the liver X receptor NR1H2 and are metabolised to esters by SOAT1. LIPA metabolises cholesterol esters, which are transported by the cholesteryl ester transport protein CETP. The transcription factor SREBF1 controls the expression of most enzymes of cholesterol synthesis. APP is involved in this shuttle as it metabolises cholesterol to 7-betahydroxycholesterol, a substrate of SOAT1 and HSD11B1, binds to APOE and is tethered to LRP1 via APPB1, APBB2 and APBB3 at the cytoplasmic domain and via LRPAP1 at the extracellular domain. APP cleavage products are also able to prevent cholesterol binding to APOE. BACE cleaves both APP and LRP1. Gamma-secretase (PSEN1, PSEN2, NCSTN) cleaves LRP1 and LRP8 as well as APP and their degradation products control transcription factor TFCP2, which regulates thymidylate synthase (TS) and GSK3B expression. GSK3B is known to phosphorylate the microtubule protein tau (MAPT). Dysfunction of this cascade, carved out by genes implicated in Alzheimer's disease, may play a major role in its pathology. Many other genes associated with Alzheimer's disease affect cholesterol or lipoprotein function and/or have also been implicated in atherosclerosis, a feature of Alzheimer's disease, and this duality may well explain the close links between vascular and cerebral pathology in Alzheimer's disease. The definition of many of these genes as risk factors is highly contested. However, when polymorphic susceptibility genes belong to the same signaling pathway, the risk associated with multigenic disease is better related to the integrated effects of multiple polymorphisms of genes within the same pathway than to variants in any single gene [Wu, X., Gu, J., Grossman, H.B., Amos, C.I., Etzel, C., Huang, M., Zhang, Q., Millikan, R.E., Lerner, S., Dinney, C.P., Spitz, M.R., 2006. Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes. Am. J. Hum. Genet. 78, 464-479.]. Thus, the fact that Alzheimer's disease susceptibility genes converge on a clearly defined signaling network has important implications for genetic association studies.

Alzheimer Disease↗

PubMed2005

Estradiol regulates APP mRNA alternative splicing in the mice brain cortex.

Alternative splicing of amyloid precursor protein (APP), one of the candidate genes for Alzheimer's disease, yields three major mRNAs, which give rise to APP770, APP751 and APP695 protein isoforms. Out of these three isoforms, APP695 is expressed most predominantly in the brain. The splicing and processing of APP are shown to be influenced by several factors including hormones. In this study, we report the effect of withdrawal and administration of sex steroid hormones on the alternative splicing of APP mRNA during aging in the brain cortex of mice of both sexes. The level of APP695 mRNA isoform was higher in intact adult as compared to old mice of both sexes. Gonadectomy upregulated the APP695 mRNA isoform levels in all groups except in adult female where the level was downregulated. Estradiol supplementation upregulated the level of APP695 mRNA isoform in all groups except in old male where the level was downregulated. Thus these results show that the level of APP695 mRNA changes with age and estradiol may play a key role in the development of Alzheimer's disease by modulating the level of APP mRNA isoforms.

Aging↗

PubMed2002

A secreted form of human ADAM9 has an alpha-secretase activity for APP.

ADAM9 (MDC9, meltrin gamma) is a member of the ADAM family of metalloproteases, which play important roles in cell-cell fusion, intracellular signaling, and other cellular functions. Here we cloned a novel form of human ADAM9, designated hADAM9s (s for short), which lacks the carboxyl-terminus. Human ADAM9s was found to be secreted from transfected COS cells. RT-PCR analysis demonstrated that the mRNA for hADAM9s is expressed in human brain, liver, heart, kidney, lung, and trachea. When hADAM9s was co-expressed in COS cells with APP and treated with phorbol ester, the APP was digested exclusively at the alpha-secretory site. These results suggest that hADAM9s has an alpha-secretase-like activity for APP. Non-amyloidgenic cleavage of APP may occur at the plasma membrane. Our new results support a new therapeutic strategy to decrease in the Abeta content by directly activating ADAM9 in the extracellular space.

ADAM Proteins↗

PubMed2002

Presence of hydroxysteroid dehydrogenase type 10 in amyloid plaques (APs) of Hsiao's APP-Sw transgenic mouse brains, but absence in APs of Alzheimer's disease brains.

This immunocytochemical study using two anti-amyloid beta-protein (Abeta) monoclonal antibodies, 4G8 and 6E10, revealed the presence of Abeta in both amyloid plaques (APs) and blood vessels of brains of Hsiao's APP-Sw transgenic mice (also known as Tg2576) and human Alzheimer's disease (AD) brains. Further study using both monoclonal (5F3) and polyclonal (R-228) antibodies to hydroxysteroid dehydrogenase type 10 (HSD-10) [formerly called SCHAD (short-chain L-3-hydroxyacyl-CoA dehydrogenase); also called ERAB (endoplasmic-reticulum-associated amyloid beta-peptide-binding protein)] indicated that HSD-10 was present in the APs of Tg2576 mice but was absent or immunocytochemically undetectable in the APs of AD brains. Our observations also revealed that HSD-10 was present in the blood vessels of both Tg2576 mice and AD brains. Immunogold electron microscopy also indicated that HSD-10 was present in the amyloid fibers (AFs), mitochondria, nuclear heterochromatin, and nucleolus of Tg2576 mouse brains but was absent in APs of AD brains. These results suggest that the human APP gene transferred to mice may induce overexpression of HSD-10 in mouse APs and in various other cellular components of mouse brains. It is also possible that the human APP gene responsible for HSD-10 deposition in APs of these Tg2576 mice brains is different from that of AD brains. Alternatively, the HSD-10 gene and APP gene may function independently in AD brains. Despite these differences, the Tg2576 mouse, as shown in this study, is a proper animal model for the study of AD and also for the investigation of HSD-10.

3-Hydroxyacyl CoA Dehydrogenases↗

PubMed2000

A survey of adenine and 4-aminopyrazolo[3,4-d]pyrimidine (4-APP) as inhibitors of ribosome-inactivating proteins (RIPs).

The inhibitory power of adenine and 4-aminopyrazolo[3,4-d]pyrimidine (4-APP) on the RNA-N-glycosidase activity catalyzed by bacterial (Shiga toxin 1) and plant (ricin, gelonin, momordin, bryodin-R, PAP-S, luffin, trichosantin, saporin 6 and barley) RIPs has been compared. The behavior of the two inhibitors is largely variable. While Shiga toxin 1 is preferentially inhibited by 4-APP, plant RIPs are either preferentially inhibited by adenine, or equally inhibited by the two compounds or, finally, only slightly more by 4-APP. Sequence variabilities involved in these different behaviors are discussed. The experimental data clearly indicate that, in spite of the same mechanism of action, RIPs differ widely in the ability to fit small ring molecules in the active cleft. While the strong inhibitory power of 4-APP on Shiga toxin 1 opens perspectives of therapeutic interventions, the ineffectiveness of the compound on ricin precludes its use as a suitable antidote in poisoning.

Adenine↗

PubMed2002

A role for APP in motility and transcription?

Recent studies suggest two novel roles for the amyloid precursor protein (APP): APP accelerates wound healing in MDCK cells and acts in a notch-like manner to activate transcription. Both of these putative functions are dependent on the interaction of APP with the APP-binding protein FE65. Future studies are required to understand the full implications of these new findings and to determine whether therapeutic strategies for Alzheimer's disease should take these putative functions into account.

Amyloid beta-Protein Precursor↗

PubMed2003

Effect of PPF and ALCAR on the induction of NGF- and p75-mRNA and on APP processing in Tg2576 brain.

Amyloidogenic processing of beta-amyloid precursor protein (APP) leading to Abeta accumulation is critical in Alzheimer's disease (AD). Abeta leads to pre-synaptic molecular changes in hippocampus of the AD mutant transgenic mouse model Tg2576 prior to plaque formation. Since NGF is critical to neuronal growth and is involved in regulating APP processing, we tested the hypothesis that NGF expression is altered early in this model of AD. We measured APP products and mRNAs for NGF and its low-affinity receptor p75 in 10-month-old Tg2576 whole brain after dietary propentofylline (PPF) or acetyl-L-carnitine (ALCAR) for 4 weeks to induce NGF- or p75-expression, respectively. The results (all P<0.0002) show that compared to wild-type or littermate controls, the transgene leads to decreases of 44% in NGF-mRNA, 25% in p75-mRNA, 64% in sAPPalpha, and 21-fold increases in Abeta40/42. PPF increased NGF-mRNA by 20% and sAPPalpha by 42% while decreasing Abeta40/42 by 45/48%, with no effect on p75-mRNA in Tg animals. ALCAR increased p75-mRNA by 16% and decreased Abeta40/42 by 46/26% with no significant effect on sAPPalpha or NGF-mRNA in Tg animals. The results indicate that NGF expression is reduced early in the Tg brain, that this reduction potentiates further Abeta formation in a vicious cycle, and that inducing NGF shifts the balance toward secretory processing of APP. To a lesser extent, p75 decreases Abeta peptides, possibly via peptidases since sAPPalpha level is not changed.

Acetylcarnitine↗

PubMedDate not supplied

FAD mutant PS-1 gene-targeted mice: increased A beta 42 and A beta deposition without APP overproduction.

To investigate the consequences of mutant presenilin-1 (PS-1) expression under the control of the normal PS-1 gene, a gene-targeted mouse bearing the FAD mutation P264L was made. Gene-targeted models are distinct from transgenic models because the mutant gene is expressed at normal levels, in the absence of the wild-type protein. PS-1(P264L/P264L) mice had normal expression of PS-1 mRNA, but levels of the N- and C-terminal protein fragments of PS-1 were reduced while levels of the holoprotein were increased. When crossed into Tg(HuAPP695.K670N/M671L)2576 mice, the PS-1(P264L) mutation accelerated the onset of amyloid (Abeta) deposition in a gene-dosage dependent manner. Tg2576/PS-1(P264L/P264L) mice also had Abeta deposition that was widely distributed throughout the brain and spinal cord. APP(NLh/NLh)/PS-1(P264L/P264L) double gene-targeted mice had elevated levels of Abeta42, sufficient to cause Abeta deposition beginning at 6 months of age. Abeta deposition increased linearly over time in APP(NLh/NLh)/PS-1(P264L/P264L) mice, whereas the increase in Tg2576 mice was exponential. The APP(NLh/NLh)/PS-1(P264L/P264L) double gene-targeted mouse represents an animal model that exhibits Abeta deposition without overexpression of APP.

Alzheimer Disease↗

PubMed1997

NMDA induces apoptosis and necrosis in neuronal cultures. Increased APP immunoreactivity is linked to apoptotic cells.

In rat neuronal cultures exposed for a prolonged period (16 h) to a low concentration of N-methyl-D-aspartate (NMDA; 20 microM) two different types of neuronal death were observed, necrosis and apoptosis. The immunocytochemical study of necrotic neurons revealed the absence of amyloid precursor protein (APP) labeling in the cytoplasmic region. In contrast, neuronal apoptosis was associated with an increase in cytoplasmic APP immunoreactivity. In addition, the presence of extracellular APP was also detected around some apoptotic neurons, suggesting that apoptosis could contribute to the presence of extracellular APP.

Amyloid beta-Protein Precursor↗

PubMed2003

APP processing and synaptic function.

A large body of evidence has implicated Abeta peptides and other derivatives of the amyloid precursor protein (APP) as central to the pathogenesis of Alzheimer's disease (AD). However, the functional relationship of APP and its proteolytic derivatives to neuronal electrophysiology is not known. Here, we show that neuronal activity modulates the formation and secretion of Abeta peptides in hippocampal slice neurons that overexpress APP. In turn, Abeta selectively depresses excitatory synaptic transmission onto neurons that overexpress APP, as well as nearby neurons that do not. This depression depends on NMDA-R activity and can be reversed by blockade of neuronal activity. Synaptic depression from excessive Abeta could contribute to cognitive decline during early AD. In addition, we propose that activity-dependent modulation of endogenous Abeta production may normally participate in a negative feedback that could keep neuronal hyperactivity in check. Disruption of this feedback system could contribute to disease progression in AD.

Alzheimer Disease↗

PubMed1992

A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid.

Mutations at codon 717 in exon 17 of the beta-amyloid precursor protein (APP) gene have previously been shown to segregate with early onset Alzheimer's disease in some families. We have identified a double mutation at codons 670 and 671 (APP 770 transcript) in exon 16 which co-segregates with the disease in two large (probably related) early-onset Alzheimer's disease families from Sweden. Two base pair transversions (G to T, A to C) from the normal sequence predict Lys to Asn and Met to Leu amino acid substitutions at codons 670 and 671 of the APP transcript. This mutation occurs at the amino terminal of beta-amyloid and may be pathogenic because it occurs at or close to the endosomal/lysosomal cleavage site of the molecule. Thus, pathogenic mutations in APP frame the beta-amyloid sequence.

Alzheimer Disease↗

PubMed2004

Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members.

The Alzheimer's disease beta-amyloid precursor protein (APP) is a member of a larger gene family that includes the amyloid precursor-like proteins, termed APLP1 and APLP2. We previously documented that APLP2-/-APLP1-/- and APLP2-/-APP-/- mice die postnatally, while APLP1-/-APP-/- mice and single mutants were viable. We now report that mice lacking all three APP/APLP family members survive through embryonic development, and die shortly after birth. In contrast to double-mutant animals with perinatal lethality, 81% of triple mutants showed cranial abnormalities. In 68% of triple mutants, we observed cortical dysplasias characterized by focal ectopic neuroblasts that had migrated through the basal lamina and pial membrane, a phenotype that resembles human type II lissencephaly. Moreover, at E18.5 triple mutants showed a partial loss of cortical Cajal Retzius (CR) cells, suggesting that APP/APLPs play a crucial role in the survival of CR cells and neuronal adhesion. Collectively, our data reveal an essential role for APP family members in normal brain development and early postnatal survival.

Amyloid beta-Protein Precursor↗

PubMed2006

Evidence against the overexpression of APP in Down syndrome.

Down syndrome (DS) is the most common genetic disorder with mental retardation and is caused by trisomy 21. By the age of 40 years, virtually all adults with DS have sufficient neuropathology for a diagnosis of Alzheimer's disease (AD), which is characterized by accumulation of amyloid-beta in senile plaques and formation of neurofibrillary tangles. Amyloid-beta derives from a longer precursor protein, APP, whose gene maps to chromosome 21. In DS, the early appearance of senile plaques is commonly associated with the presence of a third copy of the APP gene. Here we show DS brains and trisomic fibroblasts in which APP is not overexpressed, compared to euploid controls, challenging the notion that the widespread amyloid-beta deposits, consistently found in DS individuals, result from an extra copy of APP.

Adult↗