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PubMed2004

Platelet APP, ADAM 10 and BACE alterations in the early stages of Alzheimer disease.

Amyloid precursor protein (APP), ADAM 10, and beta-site-APP cleaving enzyme (BACE) alterations were evaluated in platelets of 31 patients with Alzheimer disease (AD) and 15 age-matched controls. A significant modification of these proteins and enzymes involved in the amyloid cascade was detected from the earliest clinically detectable disease stage. This observation suggests that AD is associated with an early metabolic derangement toward amyloidogenic pathways and supports the potential value of APP and secretase measurements for early diagnosis of AD.

ADAM Proteins↗
PubMed2003

Beta-secretase processing of the Alzheimer's amyloid protein precursor (APP).

An integral membrane aspartyl protease, BACE, is responsible for beta-secretase processing of the beta-amyloid precursor protein (APP) to the large secreted sAPPbeta and membrane-bound CTFbeta of 99 residues. CTFbeta is subsequently cleaved within the membrane by gamma-secretase to the amyloid beta protein (Abeta) that is deposited in the Alzheimer's disease (AD) brain. In this manuscript, we argue that BACE is not limiting for Abeta production and report the existence of a high molecular weight complex of BACE that is more active than the monomer. We also present evidence that the BACE complex is enriched in lipid raft fractions prepared from brain membranes. These findings support the hypothesis that cleavage by BACE is limited by trafficking of APP (<10%) to a lipid raft-derived compartment containing the BACE complex. In addition, the localization of the BACE complex to lipid rafts can explain previous findings that cholesterol and glycosylphosphatidylinositol (GPI)-anchored proteins are necessary for beta-secretase processing of APP. We propose that the BACE complex is a better drug target than the monomer for specific inhibition of Abeta biogenesis.

Alzheimer Disease↗
PubMed2006

RNA therapeutics directed to the non coding regions of APP mRNA, in vivo anti-amyloid efficacy of paroxetine, erythromycin, and N-acetyl cysteine.

Lead compounds directed to the 5' leader of the Amyloid Precursor Protein transcript (i.e., paroxetine (SSRI), N-acetyl cysteine (antioxidant), and erythromycin (macrolide antibiotic)) were employed in a pilot study to evaluate their anti-amyloid efficacy in the TgCRND8 transgenic mouse model for Alzheimer's Disease (AD). The relative levels of Abeta peptide were reduced after exposure of mice to paroxetine (N=5), NAC (N=7), and erythromycin (N=7) relative to matched placebo counterparts. Paroxetine limited the levels of APP holoprotein and total Abeta peptide levels (measurements of Abeta were performed at two separate sites by quantitative western blotting and ELISA assay). The paroxetine data provided proof-of-concept for our strategy for further screening the APP 5'UTR target to identify novel drugs that exhibit anti-amyloid efficacy in vivo. Erythromycin and azithromycin were macrolide antibiotics that markedly changed the cleavage of the APP C-Terminal Fragment (CTF) in SH-SY5Y cells. Erythromycin provided orally to TgCRND8 mice consistently (100%) reduced brain Abeta(1-42) levels. These data demonstrated a highly statistically significant anti-amyloid trend for paroxetine, NAC and erythromycin. The potential for conducting further studies with these compounds using larger cohorts of TgCRND8 mice is discussed, particularly since erythromycin has recently been exposed to mice for a further 6 months (N=6). It will be possible to employ the chemical structures of paroxetine and erythromycin as starting points for drug design and development for AD therapeutics.

5' Untranslated Regions↗
PubMed2026

A Multimethod Evaluation to Assess Feasibility, Acceptability, and Preliminary Efficacy of HPVVaxFacts, a Tailored Mobile Web App, for Parents With Unvaccinated Children: Pilot 2-Arm Randomized Controlled Trial.

BACKGROUND: Mobile health (mHealth) interventions may improve provider-parent communication on human papillomavirus (HPV) vaccination to reduce concerns, and increase intention and uptake. HPVVaxFacts (233 Analytics) is a novel, mobile web app delivering tailored education based on the Health Belief Model and Theory of Reasoned Action, addressing parental concerns preclinic visit. OBJECTIVE: This study aimed to assess the feasibility, acceptability, and preliminary efficacy of HPVVaxFacts among parents of adolescents aged 9-17 years. METHODS: We conducted a pilot, randomized controlled trial in 2 urban Tennessee clinics from June to September 2023 comparing 2 groups: tailored education via HPVVaxFacts mobile web app (intervention, n=27), and nutrition education (attention control, n=30). Eligible parents had or were caregivers to a child aged 9 to 17 years unvaccinated against HPV, had a mobile phone, had an upcoming clinic visit, and spoke English. The recruitment strategy was patient intake software-Phreesia (Phreesia, Inc) and eClinicalWorks (eClinicalWorks). Although unblinded, parents could deduce their study arm assignment. Providers were blinded. Feasibility, acceptability, and preliminary efficacy (HPV vaccine knowledge, concerns, intentions, and vaccination rates) were assessed using multimethod evaluation. Parents were assessed at baseline and immediately post intervention via surveys. Vaccination rates were assessed at 12 months post intervention via electronic health records. Nineteen parent interviews were conducted up to 9 months post intervention. A clinic staff consultation (n=6) was 1 month post intervention. RESULTS: Of 57 enrolled parents, most were female (52/57, 91%), non-Hispanic White (44/57, 77%), had &#x2264;US $80,000 household income (32/57, 56%), and had some college or less (27/57, 47%). In total, 81% (29/36) of parents viewed HPVVaxFacts. Post intervention, HPV vaccine initiation was higher in the intervention group compared to the attention control group (48% vs 17%; difference 0.24; 95% CI 0.03-0.46; P=.01). Parents in the HPVVaxFacts arm demonstrated a greater reduction in knowledge (ie, knowledge increase; mean change: -0.6 vs 0.1) and concern scores (mean change: -3.4 vs -1.4) than those in the nutrition education arm. However, between-arm differences were not statistically significant (P=.13 and P=.14, respectively). The majority found the study protocol and HPVVaxFacts acceptable. Benefits of HPVVaxFacts include confirming their decision to vaccinate, supporting parent-child discussion on the vaccine, and answering questions preclinic visit or offering questions for the provider. Study protocol delivery and mobile web app instructions were suggested areas for improvement. Barriers for HPVVaxFacts use include content in English only and digital format. CONCLUSIONS: Our study suggests HPVVaxFacts was feasible and acceptable among parents to provide previsit, tailored information on HPV vaccination. Outcomes offer a positive trajectory but need more exploration. Next steps include a well-powered efficacy trial to determine the impact of HPVVaxFacts on initiation vaccine rates and parental hesitancy factors, as well as to explore an interaction, effect modification, and mediation among different variables.

Humans↗
PubMed1998

Somatic mutation analysis of the APP and Presenilin 1 and 2 genes in Alzheimer's disease brains.

The molecular basis for sporadic Alzheimer disease (AD) remains largely unknown. We hypothesized that in some cases of sporadic AD, a somatic mutation in an embryonic cell committed to neuronal development within the amyloid precursor protein (APP), the presenilin 1 (PS-1) or the presenilin 2 (PS-2) genes (genes known to be involved in familial AD) may result in AD phenotype. Using PCR, denaturing gradient gel electrophoresis (DGGE), restriction enzyme digest and direct DNA sequencing, we analyzed these genes in 99 brain tissues from patients with histopathologically proven AD. One brain sample showed a mutation within the PS-1 gene, His163 Arg, later shown to be a germline mutation. No other migration abnormalities were demonstrated in any sample in exon 16 or 17 of the APP gene or the coding exons of the PS-1 gene. Restriction digest pattern was normal with regard to the predominant PS-2 gene mutation (N141I). A known mutation in the APP gene, as well as novel mutations within the PS-1 gene were easily detected by DGGE (Reznick Wolf et al. manuscript submitted). We conclude that the genes that are involved in familial AD do not display somatic mutations in the brains of sporadic AD patients, and that other molecular mechanisms are probably involved in the pathogenesis of sporadic AD.

Alzheimer Disease↗
PubMed1996

Identification of acute-phase proteins (APP) in circulating immune complexes (CIC) in esophageal cancer patients' sera.

The occurrence of increased circulating immune complexes (CIC) in sera of patients with esophageal cancer and their usefulness for diagnosis and prognosis have not been demonstrated. Circulating acute-phase proteins (APP) related to esophageal cancer have been described but without any association with CIC. This is a study to measure CIC, C-reactive protein (CRP), and alpha 1-acidic glycoprotein (AAG) in pretreatment esophageal cancer sera and to analyze the presence of both APP associated with these CIC. Increased CIC levels were found in 57% of sera from esophageal cancer patients; elevated CRP was detected in 87% and AAG in 47%. Western blot analysis showed the presence of CRP and AAG in CIC-derived fractions. We conclude that: (1) CIC, CRP, and AAG are elevated in esophageal cancer sera; (2) they may be considered possible useful clinical parameters in pretreatment esophageal cancer patients; (3) these APPs appear in CIC precipitates and may possibly be involved in their composition.

Acute-Phase Proteins↗
PubMed1987

Effects of hypophysectomy on plasma levels of pancreatic polypeptide (APP) and insulin in adult chickens.

Adenohypophysectomy (hypox) was carried out in adult chickens in an attempt to assess what role, if any, the anterior pituitary gland plays in maintaining basal levels of plasma insulin (IRI) and avian pancreatic polypeptide (APP) both before and immediately after a fast-refeed regimen. Each bird was tube-fed 61 gms twice daily, body weights were taken daily, and blood samples drawn daily just before the second feeding. All birds were fasted for 24 hr on days 4-5, another blood sample taken, and then refed the usual gruel. Blood samples were taken at 5,15,30,90 and 180 min after refeeding. Hypox caused an immediate and sustained decrease in plasma IRI and a significant but transient increase in plasma APP which lasted 3-4 days before returning to normal; plasma glucose was marginally decreased. Refeeding resulted in a trend of less response (increase) in all three parameters studied in the hypox group. It is suggested that in chickens, hypox may lead to a release phenomenon from a normal inhibitory role which the anterior pituitary gland plays on APP release.

Animals↗
PubMed1998

Simultaneous quantification of APP and tau mRNA by RT-PCR.

We describe here a method for simultaneous relative quantitation of APP and tau expressions in rat muscle using polymerase chain reaction combined with reverse transcription. The target mRNAs were coamplified with an internal control, glyceraldehyde-3-phosphate dehydrogenase (G3PD). The amplified products were measured with a laser image analyzer, and the values were plotted against the cycle number. In the exponential phase of amplification, the linearity and reproducibility of RT-PCR demonstrate identical efficiencies of cDNA synthesis and PCR amplification for APP, tau and G3PD. These results suggest that in the exponential phase of amplification, a relative quantitation of target mRNAs could be accomplished by normalization with internal control. Preliminary experiments indicate that the expressions of both APP and tau in rat muscle were first increased and then decreased by chronic intoxication with chloroquine.

Alzheimer Disease↗
PubMed2006

Minocycline affects microglia activation, Abeta deposition, and behavior in APP-tg mice.

Activated microglia and reactive astrocytes invade and surround cerebral beta amyloid (Abeta) plaques in Alzheimer's disease (AD), but the role of microglia in plaque development is still unclear. In this study, minocycline was administered for 3 months, prior to and early in Abeta plaque formation in amyloid precursor protein transgenic mice (APP-tg). When minocycline was given to younger mice, there was a small but significant increase in Abeta deposition in the hippocampus, concurrent with improved cognitive performance relative to vehicle treated mice. If APP-tg mice received minocycline after Abeta deposition had begun, microglial activation was suppressed but this did not affect Abeta deposition or improve cognitive performance. In vitro studies demonstrated that minocycline suppressed microglial production of IL-1beta, IL-6, TNF, and NGF. Thus, minocycline has different effects on Abeta plaque deposition and microglia activation depending on the age of administration. Our data suggest that this may be due to the effects of minocycline on microglial function. Therefore, anti-inflammatory therapies to suppress microglial activation or function may reduce cytokine production but enhance Abeta plaque formation early in AD.

Age Factors↗
PubMed2005

Stimulation of G-proteins in human control and Alzheimer's disease brain by FAD mutants of APP(714-723): implication of oxidative mechanisms.

We report the effects of amyloid precursor protein (APP) fragment 714-723 (APP(714-723); peptide P1) and its V717F and V717G mutants (peptides P2 and P3, respectively) on G-protein activity ([35S]GTPgammaS binding) in membranes from postmortem human control and Alzheimer's disease (AD) brains. The peptides P1, P2, and P3 revealed a significant stimulatory effect on [35S]GTPgammaS binding in control temporal cortex. The most potent stimulator, P3, at 10 microM concentration enhanced [35S]GTPgammaS binding by 500%. The effect was threefold stronger than that for wild-type P1 and twofold stronger than that for P2. In sporadic AD, the stimulatory effect of P1, P2, and P3 on G-proteins was reduced significantly whereas in Swedish familial AD (SFAD), only P1 elicited marked stimulation (at 10 microM by 50%). In control sensory postcentral cortex, the stimulation of G-proteins by P3 was 1.5-fold lower than that in control temporal cortex, whereas in AD and SFAD the effect showed no remarkable regional difference. Treatment of membranes with H2O2 produced 1.5-fold higher stimulation in [35S]GTPgammaS binding to temporal cortex than that in binding to sensory postcentral cortex. In AD and SFAD, the stimulation by H2O2 revealed no significant regional difference. Glutathione, desferrioxamine (DFO), and 17beta-estradiol markedly decreased the strong stimulatory effect by P3 on [35S]GTPgammaS binding to control temporal cortex, with the protective effect by DFO being most potent. The G(alphaO)-protein levels were not changed in AD or SFAD brain membranes as compared to levels in control membranes. We suggest that strong G-protein stimulation by P3 in the human brain implies the specific (per)oxidation mechanism that might be affected by regional content of peroxidizing substrates and antioxidants.

Aged↗
PubMed2005

Noninvasive in vivo MRI detection of neuritic plaques associated with iron in APP[V717I] transgenic mice, a model for Alzheimer's disease.

Transgenic mice overexpressing the London mutant of human amyloid precursor protein (APP[V717I]) in neurons develop amyloid plaques in the brain, thus demonstrating the most prominent neuropathological hallmark of Alzheimer's disease. In vivo 3D T2*-weighted MRI on these mice (24 months of age) revealed hypointense brain inclusions that affected the thalamus almost exclusively. Upon correlating these MRI observations with a panel of different histologic staining techniques, it appeared that only plaques that were positive for both thioflavin-S and iron were visible on the MR images. Numerous thioflavin-S-positive plaques in the cortex that did not display iron staining remained invisible to MRI. The in vivo detection of amyloid plaques in this mouse model, using the intrinsic MRI contrast arising from the iron associated with the plaques, creates an unexpected opportunity for the noninvasive investigation of the longitudinal development of the plaques in the same animal. Thus, this work provides further research opportunities for analyzing younger APP[V717I] mouse models with the knowledge of the final outcome at 24 months of age.

Alzheimer Disease↗
PubMed2001

A novel approach for studying endogenous abeta processing using cultured primary neurons isolated from APP transgenic mice.

The central component of senile amyloid plaques in Alzheimer's disease (AD) is the beta-amyloid peptide (Abeta), derived from proteolytic processing of the amyloid precursor protein (APP). In this study, we developed an in vitro model to measure and identify soluble Abeta from primary cortical neurons. Neurons were isolated from mice transgenic for human APP695 containing the K670N, M671L double mutation. We characterized soluble Abeta using Western blot and ELISA assays. We found that the Abeta levels in conditioned media from these neurons were readily detectable and almost five times higher than in CSF. The majority of Abeta in the media was Abeta1-40; however, Abeta1-42 was also detectable. When the neurons were exposed to Phorbol 12-myristate 13-acetate (PMA), alpha1-antichymotrypsin, or alpha1-antitrypsin, the alterations of soluble Abeta levels were consistent with other models reported. Most importantly, the soluble Abeta in our model was remarkably stable, and aliquots were unchanged after prolonged incubations or repeated freeze/thaw cycles. The Abeta appeared to be monomeric by Western blot analysis. Soluble Abeta coimmunoprecipitated with endogenous mouse apolipoprotein E from the primary cultures. Taken together, our data demonstrated that using a Western blot assay to detect soluble Abeta from transgenic mouse overexpressing APP695 is sensitive, specific, and reliable and provides an accessible model for examining the neuronal metabolism of APP and Abeta.

Amyloid beta-Peptides↗
PubMed1998

Stable association of presenilin derivatives and absence of presenilin interactions with APP.

Mutations in two related genes, presenilin 1 and 2 presenilin 2 (PS1 and PS2), cosegregate with Alzheimer's disease. PS1 and PS2 are highly homologous polytopic membrane proteins that are subject to endoproteolytic cleavage in vivo. The resulting N- and C-terminal derivatives are the preponderant PS-related species that accumulate in cultured cells and tissue. In earlier studies, we demonstrated that PS1 N- and C-terminal derivatives accumulate to 1:1 stoichiometry and that the absolute levels of fragments are established by a tightly regulated and saturable mechanism. These findings led to the suggestion that the levels of PS1 derivatives might be determined by their association with limiting cellular components. In this study, we use in situ chemical cross-linking and coimmunoprecipitation analyses to document that the N- and C-terminal derivatives of either PS1 or PS2 can be coisolated. Moreover, and in contrast to published reports which documented that PS1 and PS2 form stable heteromeric assemblies with the beta-amyloid precursor protein (APP), we have failed to provide evidence for physiological complexes between PS1 and PS2 holoproteins or their derivatives with APP.

Alzheimer Disease↗
PubMed2000

Neuroanatomical abnormalities in behaviorally characterized APP(V717F) transgenic mice.

Histological analyses were performed on the brains of APP(V717F) transgenic (Tg)mice previously studied in a battery of behavioral tests. We describe here the regional and age-dependent deposition of amyloid in both heterozygous and homozygous Tg mice. We also report that Tg mice show significant and age-dependent changes in synaptic density measured by synaptophysin immunoreactivity. Surprisingly, a rather marked hippocampal atrophy is observed as early as 3 months of age in Tg mice (20-40%). Statistical analyses revealed that the deficits in object recognition memory are related to the number of amyloid deposits in specific brain regions, whereas deficits in spatial reference and working memory are related to the changes in synaptic density and hippocampal atrophy. Our study suggests that the behavioral deficits observed in Tg mice are only in part related to amyloid deposition, but are also related to neuroanatomical alterations secondary to overexpression of the APP(V717F) transgene and independent of amyloid deposition.

Age Factors↗
PubMed2002

Long-term potentiation is increased in the CA1 area of the hippocampus of APP(swe/ind) CRND8 mice.

The present study reports changes in synaptic function and plasticity [long-term potentiation (LTP)] in a recently developed mouse model of Alzheimer's disease (CRND8 line) harboring a double amyloid precursor protein mutation (APP(swe/ind)). In 9-week-old preplaque transgenic (Tg) mice brain slices, basal synaptic function in the hippocampal CA1 area was unchanged. Only one of three different LTP induction protocols revealed early influence of genotype on synaptic plasticity. By 20 weeks of age, there were numerous plaques in the hippocampus from Tg mice associated with more robust evidence for genotype-related effects in synaptic function. Field potential maximum slope was consistently decreased and LTP was increased, irrespective of the stimulation protocol used. In addition, there was clear evidence of increased synaptic excitability in Tg mice. Furthermore, the maximum amplitude of evoked IPSCs was decreased whereas the maximum amplitude of evoked EPSCs was increased in 20-week-old Tg mice. Collectively, these results suggest a number of APP genotype-related changes in the fine-tuning of the CA1 area circuitry, some of which are likely to contribute to the pathology-dependent effects on LTP observed in CRND8 mice.

Aging↗
PubMed1997

Estrogens influence growth, maturation, and amyloid beta-peptide production in neuroblastoma cells and in a beta-APP transfected kidney 293 cell line.

During development in vivo and in vitro, estrogens: a) increase brain excitability, particularly in limbic structures; b) are responsible for the maturation and cyclicity of limbic-hypothalamic interrelations; c) enhance myelinogenesis; and d) may act with NGF to stimulate neurite formation. In senescence, estrogen administration would improve memory in postmenopausal women. The absence or low levels of estrogens after menopause would increase prevalence of Alzheimer's dementia (AD) more in women than men, irrespective of age or ethnicity. In the present study, addition of 17-beta estradiol to cultured human neuroblastoma cells affected growth slightly, but stimulated cell maturation as shown by increased tyrosine hydroxylase activity. The extracellular deposition in brain tissue and around blood vessels of the amyloid beta-peptide (A beta), a 4.3 kD fragment of the larger integral membrane protein, beta-amyloid precursor protein (beta-APP), is considered an important characteristic of AD. We investigated whether 17-beta estradiol may influence the formation of the A beta (thus the abnormal accumulation of amyloid proteins) in neuroblastoma cells and in a beta-APP transfected human kidney 293 cell line. Two doses of 17 beta-estradiol were added to the cultures of both cell lines. Cells were grown until confluence, metabolically labeled with 35S-methionine, immunoprecipitated with the rabbit antiserum R1282, gel electrophoresed and autoradiographed in order to compare levels of A beta under the different estradiol concentrations. While in neuroblastoma cells, levels of A beta were only slightly reduced after estradiol and a dose-effect relationship with the hormone could not be demonstrated, in the 293 cells, A beta band intensity decreased as concentration of estradiol increased. These data support the role of estrogen in normal and abnormal brain metabolism and suggest potential hormonal interventions which may reduce or prevent the formation of amyloid deposits occur in AD.

Alzheimer Disease↗
PubMed1992

A novel mutation in the beta-protein coding region of the amyloid beta-protein precursor (APP) gene.

A novel mutation, a C to T transition at base pair 2124 in exon 17 of the amyloid beta-protein precursor (APP) gene, has been identified by direct sequencing of amplified DNA from two Alzheimer's disease (AD) patients. A simple oligonucleotide-hybridization procedure was developed to allow population studies of this DNA variation. The mutation, which is silent at the protein level, was present in 2 out of 12 investigated AD patients, in 1 out of 60 non-AD patients and in 1 out of 30 healthy individuals. The mutation can be used as a new marker for linkage studies involving the APP gene, although more comprehensive population studies are required to determine the status of the mutation as a possible risk factor for the development of AD.

Alzheimer Disease↗