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PubMed1993

Characterization of proteases with the specificity to cleave at the secretase-site of beta-APP.

The beta-amyloid precursor protein (APP) can be proteolytically processed in at least two different ways either in a secretory pathway or in a lysosomal pathway. The proposed sites for the 'secretase' cleavage are the Gln15-Lys16 and Lys16-Leu17 peptide bonds within the beta A4 domain. Using chromogenic peptide substrates derived from these APP sites, proteolytic enzymes were investigated in the brain of AD patients and control individuals. Mean differences in enzyme activity were observed between the two groups, although no statistical significance was reached. Further analysis in rat brain allowed identification of the lysosomal cathepsin B and the cytosolic proteasome as secretase-like enzymes. They are probably not involved in APP secretion but possibly in removal of amyloidogenic fragments.

Alzheimer Disease↗

PubMed2026

Development, feasibility, acceptability, and preliminary impact of NutriSOS®: A behavioral mobile app to promote sustainable diets.

The primary objective of this study was to describe the development of the NutriSOS® app and to evaluate its feasibility and acceptability for its use in the NutriSOS® Randomized Controlled Trial (RCT) to promote sustainable diets. A secondary objective was to explore preliminary changes in dietary and physical activity behaviors and environmental impact following app use. The NutriSOS® app integrates personalized dietary advice, educational content, self-monitoring, and social interaction features. A single-arm, pre-post pilot study was conducted in 37 young Mexican adults over four weeks. Feasibility, acceptability, quality, and usability were assessed using online surveys, alongside exploratory changes in dietary and physical activity behaviors, environmental indicators, and their association with perceived behavioral determinants. Feasibility and acceptability were high overall, with favorable responses reaching up to 100% in key components such as the nutritional guide and learning modules, and above 90% for messaging, registration, and design. Greater variability was observed in some sections, particularly the 24-h recall (41-86%). Reductions in red and processed meat and ultra-processed food consumption were observed (from 3 to 1 times/week, p < 0.01), with ∼60% decreases in their related environmental footprints (p < 0.01) and favorable self-reported behavioral determinants (p < 0.0001). Physical activity type and intensity changed (p < 0.05). These findings support NutriSOS® as a feasible and acceptable tool, while highlighting areas for refinement, particularly those related to the time and effort required for data entry, prior to its implementation in the NutriSOS® RCT, in which its effectiveness will be formally evaluated.

Humans↗

PubMed2006

ADAM19 is tightly associated with constitutive Alzheimer's disease APP alpha-secretase in A172 cells.

To elucidate whether new proteases are involved in the processing of amyloid precursor protein (APP), we examined catalytically active ADAM12 and ADAM19 as candidates alpha-secretases. The overexpression of ADAM19 in HEK293 cells resulted in an increase in sAPPalpha. Therefore, we suggest that ADAM19 has a constitutive alpha-secretase activity. We examined regulated alpha-secretase activity by adding phorbol 12-myristate 13-acetate (PMA), but no regulated activity was found. To verify that endogenous ADAM19 has an APP alpha-secretase activity, we examined whether the constitutive level of alpha-secretase activity was reduced by RNA interference with ADAM19 in A172 cells. The amount of secreted sAPPalpha decreased by about 21% following RNAi. These results suggest that ADAM19 has a constitutive alpha-secretase activity for APP.

ADAM Proteins↗

PubMed2006

A genome wide analysis of ubiquitin ligases in APP processing identifies a novel regulator of BACE1 mRNA levels.

Proteolysis of beta-amyloid precursor protein (APP) into amyloid beta peptide (Abeta) by beta- and gamma-secretases is a critical step in the pathogenesis of Alzheimer's Disease (AD), but the pathways regulating secretases are not fully characterized. Ubiquitinylation, which is dysregulated in AD, may affect APP processing. Here, we describe a screen for APP processing modulators using an siRNA library targeting 532 predicted ubiquitin ligases. Seven siRNA pools diminished Abeta production. Of these, siRNAs targeting PPIL2 (hCyp-60) suppressed beta-site cleavage. Knockdown of PPIL2 mRNA decreased BACE1 mRNA, while overexpression of PPIL2 cDNA enhanced BACE1 mRNA levels. Microarray analysis of PPIL2 or BACE1 knockdown indicated that genes affected by BACE1 knockdown are a subset of those dependent upon PPIL2; suggesting that BACE1 expression is downstream of PPIL2. The association of PPIL2 with BACE expression and its requirement for Abeta production suggests new approaches to discover disease modifying agents for AD.

Amyloid Precursor Protein Secretases↗

PubMed2005

Impaired Cu/Zn-SOD activity contributes to increased oxidative damage in APP transgenic mice.

Oxidative stress plays an important role in the pathogenesis of Alzheimer's disease. To determine which mechanisms cause the origin of oxidative damage, we analyzed enzymatic antioxidant defense (Cu/Zn-superoxide dismutase Cu/Zn-SOD, glutathione peroxidase GPx and glutathione reductase GR) and lipid peroxidation products malondialdehyde MDA and 4-hydroxynonenal HNE in two different APP transgenic mouse models at 3-4 and 12-15 months of age. No changes in any parameter were observed in brains from PDGF-APP695(SDL) mice, which have low levels of Abeta and no plaque load. In contrast, Thy1-APP751(SL) mice show high Abeta accumulation with aging and plaques from an age of 6 months. In brains of these mice, HNE levels were increased at 3 months (female transgenic mice) and at 12 months (both gender), that is, before and after plaque deposition, and the activity of Cu/Zn-SOD was reduced. Interestingly, beta-amyloidogenic cleavage of APP was increased in female Thy1-APP751(SL) mice, which also showed increased HNE levels with simultaneously reduced Cu/Zn-SOD activity earlier than male Thy1-APP751(SL) mice. Our results demonstrate that impaired Cu/Zn-SOD activity contributes to oxidative damage in Thy1-APP751(SL) transgenic mice, and these findings are closely linked to increased beta-amyloidogenic cleavage of APP.

Aging↗

PubMed2005

Interaction of Tau with Fe65 links tau to APP.

The beta-amyloid precursor protein APP and the microtubule-associated protein Tau play a crucial role in the pathogenesis of Alzheimer's disease (AD). However, the possible molecular events linking these two proteins are still unknown. Here, we show that Fe65, one of the ligands of the APP cytodomain, is associated with Tau in vivo and in vitro, as demonstrated by co-immunoprecipitation, co-localization, and FRET experiments. Deletion studies indicated that the N-terminal domain of Tau and the PTB1 domain of Fe65 are required for this association. This interaction is regulated by the phosphorylation of Tau at selected sites, by glycogen synthase kinase-3beta (GSK3beta) and cyclin-dependent kinase 5 (Cdk5), and requires an intact microtubule network. Furthermore, laser scanner microscopy and co-immunoprecipitation experiments provide preliminary evidence of possible complex(es) involving Tau, Fe65, APP. These findings open new perspectives for the study of the possible crosstalk between these proteins in the pathogenesis of AD.

Alzheimer Disease↗

PubMed2006

APP mRNA splicing is upregulated in the brain of biglycan transgenic mice.

Many of the risk factors for cerebrovascular disease and atherosclerosis also increase the risk of Alzheimer's disease, characterized by the cerebral deposition of beta-amyloid plaques resulting from the abnormal processing of the transmembrane amyloid precursor protein (APP). The initiating event of cholesterol-induced atherosclerosis is the retention and accumulation of atherogenic apolipoprotein B (apoB) together with low-density lipoproteins in the vascular intima. Biglycan, a member of the small leucine-rich protein family, was suspected of contributing to this process. The individual and combined overexpressions of biglycan and apoB-100 were therefore examined on the cortical APP mRNA levels of transgenic mice by means of semiquantitative PCR. As compared with the control littermates, transgenic biglycan mice had significantly increased cortical APP695 (122%) and APP770 (157%) mRNA levels, while the double transgenic (apoB(+/-)xbiglycan(+/-)) mice did not exhibit any changes. These results provide the first experimental evidence that the atherogenic risk factor biglycan alters APP splicing and may participate in the pathogenesis of both Alzheimer and vascular dementias.

Amyloid beta-Protein Precursor↗

PubMed2004

APP and PS-1 mutations induce brain oxidative stress independent of dietary cholesterol: implications for Alzheimer's disease.

Epidemiological and biochemical studies strongly implicate a role for cholesterol in the pathogenesis of Alzheimer's disease (AD). Mutation in the PS-1 and APP genes, which increases production of the highly amyloidogenic amyloid beta-peptide (Abeta42), is the major cause of familial AD. The AD brain is under significant oxidative stress, including protein oxidation and lipid peroxidation. In the present study, protein oxidation and lipid peroxidation were compared in the brain homogenates from knock-in mice expressing mutant human PS-1 and APP in relation to the intake of dietary cholesterol. The APP and PS-1 mice displayed increased oxidative stress as measured by protein oxidation and lipid peroxidation, independent of dietary cholesterol. These results are discussed with reference to proposed therapeutic strategies of AD.

Aldehydes↗

PubMed2005

Exploratory activity and spatial learning in 12-month-old APP(695)SWE/co+PS1/DeltaE9 mice with amyloid plaques.

APP(695)SWE/co+PS1/DeltaE9 mice with Abeta plaques in neocortex and hippocampus were evaluated in tests of exploratory activity and spatial learning. On the initial testing day, 12-month-old APP(695)SWE/co+PS1/DeltaE9 mice spent more time than non-transgenic controls in the open arms of the elevated plus-maze. The bigenic group also travelled farther in the central region of the open-field without spending more time there. Only the bigenic group alternated above chance in the T-maze. In the Morris water maze, APP(695)SWE/co+PS1/DeltaE9 mice were impaired during acquisition of the hidden platform sub-task and the probe trial but not in the visible platform test. These results indicate a selective spatial deficit and disinhibitory tendencies in a mouse model with amyloid pathology.

Amyloid beta-Protein Precursor↗

PubMed2006

Palmitic acid-treated astrocytes induce BACE1 upregulation and accumulation of C-terminal fragment of APP in primary cortical neurons.

High-fat diet is a significant risk factor for the development of Alzheimer's disease (AD). In addition, the AD brain is characterized by elevated levels of fatty acids as compared to that of healthy controls. Despite this, it is unclear how elevated levels of fatty acids are related to the pathogenesis of AD. The present study examines the role of saturated fatty acid, palmitic acid (PA), in causing BACE1 upregulation and consequent amyloidogenic processing of beta-amyloid precursor protein (APP), one of the main characteristic signatures of AD pathology. Here, primary rat cortical neurons and astrocytes were treated with pathological concentration of PA. There was no change in the BACE1 levels in the rat cortical neurons treated directly with PA as compared to controls. The conditioned medium from PA-treated astrocytes, however, caused BACE1 upregulation in the cortical neurons. Moreover, there was a consequent increase in the cleavage of APP leading to the accumulation of the C-terminal fragment of APP (C99) in the cortical neurons. Co-treatment of neurons with 1,3-dimethyl urea (DMU), an antioxidant, decreased PA-induced upregulation in the levels of BACE1 and C99. The present results establish an important role of saturated fatty acids in AD-associated amyloidogenesis through astroglia-mediated oxidative stress.

Alzheimer Disease↗

PubMed2004

Impaired conditioned taste aversion learning in APP transgenic mice.

Cognition in transgenic mouse models of Alzheimer's disease (AD) has been predominantly characterized in explicit spatial orientation tasks. However, dementia in AD encompasses also implicit memory systems. In the present study a line of transgenic mice (TgCRND8) encoding a double mutated allele of the human amyloid precursor protein (APP) genes was evaluated in an implicit associative learning task of conditioned taste aversion (CTA). CTA is a form of Pavlovian classical conditioning, in which a mouse learns to avoid a novel taste of saccharine (conditioned stimulus) paired with an experimentally induced (systemic injection of lithium chloride) nausea (unconditioned stimulus). In contrast to conditioned non-Tg mice, TgCRND8 APP mice developed weaker aversion against saccharine and quickly increased its consumption in repeated tests. These results indicate that TgCRND8 mice show a significant impairment not only in explicit spatial memory, as has been previously shown [Nature 408 (2000) 979], but also in implicit memory. Control experiments confirmed that TgCRND8 and non-Tg mice had comparable taste sensitivities in response to appetitive as well as aversive tastes. The study suggests that the CTA paradigm can be a sensitive tool to evaluate deficits in implicit associative learning in APP transgenic mouse models of AD.

Alzheimer Disease↗

PubMed2006

Bosentan preserves endothelial function in mice overexpressing APP.

This study was designed to test the hypothesis that Alzheimer's disease (AD) is associated with endothelial dysfunction and that chronic endothelin-1 antagonism preserves endothelial function in mice overexpressing the AD amyloid precursor protein (APP). Three groups of mice were studied: C57BL/6 (normal control, n = 6), transgenic mice overexpressing APP (Tg2576, n = 5), and Tg2576 mice fed Bosentan (100 mg/(kg day)(-1)), a combined endothelin A and B receptor antagonist, for 4 months (Tg2576+Bosentan, n = 5). Mice were sacrificed at the age of 7 months. In vitro, the endothelium-dependent aortic vasorelaxation was significantly attenuated in Tg2576 mice as compared to C57BL/6 and Tg2576+Bosentan mice. In contrast, Tg2576+Bosentan and C57BL/6 mice showed similar endothelium-dependent aortic vasorelaxation. Similarly, endothelium-dependent carotid vasorelaxation was significantly attenuated in Tg2576 mice compared to C57BL/6 and Tg2576+Bosentan mice. There was no difference between the three groups in the response to nitroprusside. The current study demonstrates the presence of endothelial dysfunction in both carotid and aortic arteries in mice overexpressing APP and suggests a pathophysiological role for the endogenous endothelin system in AD.

Alzheimer Disease↗

PubMed2006

Impaired spatial memory in APP-overexpressing mice on a homocysteinemia-inducing diet.

Consumption of a diet that significantly elevates homocysteine (homocysteinemia) induces cell death in the CA3 hippocampal subfield in amyloid precursor protein (APP) over-expressing transgenic mice but not in wild-type controls. We assessed behavioral and other neuropathological effects of a homocysteinemia-inducing diet in aged APP-overexpressing mice. Starting at 16-18 months of age, mice were fed either a treatment diet lacking folate, choline, and methionine, and supplemented with homocysteine, or a control diet containing normal amounts of folate, choline and methionine but no homocysteine. After 5 months on the experimental diets, performance on a delayed non-matching-to-position working-memory task was unimpaired. In contrast, spatial reference memory in the water maze was impaired in transgenic mice on the treatment diet. Transgenic mice had higher homocysteine levels than wild-type mice even when fed the control diet, suggesting an effect of genotype on homocysteine metabolism. Methyl-donor deficiency did not alter amyloid deposition in the transgenic mice. These results suggest that disrupted homocysteine metabolism may induce Abeta-associated memory impairments and neurodegeneration in APP overexpressing mice.

Amyloid beta-Protein Precursor↗

PubMed2000

Regulation of APP cleavage by alpha-, beta- and gamma-secretases.

Proteolytic cleavage of the amyloid protein from the amyloid protein precursor (APP) by APP secretases is a key event in Alzheimer's disease (AD) pathogenesis. alpha-Secretases cleave APP within the amyloid sequences, whereas beta- and gamma-secretases cleave on the N- and C-terminal ends respectively. The transmembrane aspartyl protease BACE has been identified as beta-secretase and several proteases (ADAM-10, TACE, PC7) may be alpha-secretases. A number of studies have suggested that presenilins could be gamma-secretases, although this remains to be demonstrated conclusively. Inhibition of beta- and gamma-secretase, or stimulation of alpha-secretase, is a rational strategy for therapeutic intervention in AD.

Amino Acid Sequence↗

PubMed2003

A new wrestler in the battle between alpha- and beta-secretases for cleavage of APP.

Modulation of the proteases that process the amyloid precursor protein (APP) is a major therapeutic strategy for the treatment and prevention of Alzheimer's disease (AD). The discovery of a novel endogenous modulator of alpha-secretase-mediated, in preference to beta-secretase-mediated, cleavage of APP implicates sumoylation in the etiology of AD, and offers a new therapeutic target for intervention in APP processing.

Alzheimer Disease↗

PubMed1999

Progressive and gender-dependent cognitive impairment in the APP(SW) transgenic mouse model for Alzheimer's disease.

To determine if early cognitive sensorimotor deficits exist in APP(SW) transgenic mice overexpressing human amyloid precursor protein (APP). Tg+ and Tg- animals at both 3 and 9 months of age (3M and 9M, respectively) were evaluated in a comprehensive battery of measures. The performance of all Tg+ mice at both ages was no different from all Tg- controls in Y-maze alternations, water maze acquisition, passive avoidance, and active avoidance testing. By contrast, results from other tasks revealed substantive cognitive deficits in Tg+ mice that were usually gender-dependent and sometimes progressive in nature. Between 3M and 9M, a progressive impairment was observed in circular platform performance by Tg+ males, as was a progressive deficit in visible platform testing for all Tg+ animals. Other transgenic effects included both impaired water maze retention and circular platform performance in 3M Tg+ females; this later effect was responsible for an overall (males + females) Tg+ deficit in circular platform performance at 3M. Sensorimotor testing revealed several Tg+ effects, most notably an increased activity of Tg+ males in both open field and Y-maze at 3M. Significant correlations between a number of behavioral measures were observed, although factor analysis suggests that each task measured components of sensorimotor/cognitive function not measured by other tasks. Finally, Tg+ mice had lower survivability than Tg- animals through 9M (85 vs. 96%). In summary, these results demonstrate the presence of gender-related and progressive cognitive deficits in APP(SW) transgenic mice at a relatively early age (i.e., prior to overt, beta-amyloid deposition in the brain), suggesting a pathophysiologic role for elevated levels of 'soluble' beta-amyloid in such impairments.

Alzheimer Disease↗

PubMed1997

Expression and characterization of human beta-secretase candidates metalloendopeptidase MP78 and cathepsin D in beta APP-overexpressing cells.

Human beta-secretase candidates, MP78 (h-MP78, EC 3.4.24.15) and cathepsin D (Cat D, EC 3.4.23.5), were evaluated for their ability to enhance amyloid-beta-protein (A beta) secretion when overexpressed in beta APP-containing cells. HEK-293 cells stably co-expressing h-MP78 or Cat D and h-beta APP695 were metabolically labeled with [35S]methionine and A beta secretion was quantified in the conditioned media by immunoprecipitation and ELISA without showing any significant increase in A beta production. Because Cat D is known to have a higher affinity for APP-substrate containing the Swedish familial Alzheimer's disease double mutation (SFAD, K595N and M596L substitutions in beta APP695) than for the wild type substrate [Dreyer et al., Eur. J. Biochem., 224 (1994) 265-271], the effect of Cat D overexpression was tested in a HEK293/beta APPSFAD stable cell line. ELISA analysis of the conditioned media from these cells did also not reveal any increase in A beta generation. In addition, recombinant h-MP78 purified from E. coli cleaved an APP-derived substrate spanning the beta-secretase site (ISEVKMD1AEFRHDS) at multiple sites, but the beta-site cleavage was only a minor one; cleavage occurred predominantly at K-M and E-F bonds. Human liver Cat D also cleaved the same substrate at multiple sites, yet the major cleavage at pH 4.0 occurred at the amyloidogenic D1 site. These findings indicate that h-MP78 does not have the cleavage specificity required for a beta-secretase protease and although Cat D fulfilled the amyloidogenic cleavage specificity, the results of the co-expression experiments make both enzymes less likely candidates as relevant beta-secretases.

Amino Acid Sequence↗

PubMed1981

Avian pancreatic polypeptide (APP) immunoreactive neurons in the spinal cord and spinal trigeminal nucleus.

Using indirect immunofluorescence technique, avian pancreatic polypeptide (APP) immunoreactive cell bodies and fibres have been observed in the superficial laminae of the dorsal horn of the spinal cord and of the spinal trigeminal nucleus. Fibres were also seen in the ventral horns, in low numbers at the cervical and thoracic levels and in high numbers at the lower lumbar and upper sacral levels. Neither total cord transection, nor dorsal rhizotomy, nor capsaicin treatment seemed to affect the APP systems described above. The present findings suggest that an APP-like peptide may be involved in processing of sensory information at the level of the first relay station.

Animals↗