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At least 595 records · Page 33Linked to original sources
PubMed2004

Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage.

BACKGROUND: Anti-Abeta immunotherapy in transgenic mice reduces both diffuse and compact amyloid deposits, improves memory function and clears early-stage phospho-tau aggregates. As most Alzheimer disease cases occur well past midlife, the current study examined adoptive transfer of anti-Abeta antibodies to 19- and 23-month old APP-transgenic mice. METHODS: We investigated the effects of weekly anti-Abeta antibody treatment on radial-arm water-maze performance, parenchymal and vascular amyloid loads, and the presence of microhemorrhage in the brain. 19-month-old mice were treated for 1, 2 or 3 months while 23-month-old mice were treated for 5 months. Only the 23-month-old mice were subject to radial-arm water-maze testing. RESULTS: After 3 months of weekly injections, this passive immunization protocol completely reversed learning and memory deficits in these mice, a benefit that was undiminished after 5 months of treatment. Dramatic reductions of diffuse Abeta immunostaining and parenchymal Congophilic amyloid deposits were observed after five months, indicating that even well-established amyloid deposits are susceptible to immunotherapy. However, cerebral amyloid angiopathy increased substantially with immunotherapy, and some deposits were associated with microhemorrhage. Reanalysis of results collected from an earlier time-course study demonstrated that these increases in vascular deposits were dependent on the duration of immunotherapy. CONCLUSIONS: The cognitive benefits of passive immunotherapy persist in spite of the presence of vascular amyloid and small hemorrhages. These data suggest that clinical trials evaluating such treatments will require precautions to minimize potential adverse events associated with microhemorrhage.

Journal Article↗
PubMed2005

An African American family with early-onset Alzheimer disease and an APP (T714I) mutation.

The occurrence of an APP T174I mutation is described in a large American family of African descent with Alzheimer disease. The clinical characteristics were an unusually early onset of disease (early 30s), similar to a previously reported age at onset of this mutation in an Austrian family. Distinct from that family, seizures and myoclonus were prominent features of the disease in this kindred.

Adult↗
PubMed1995

CDEBP, a site-specific DNA-binding protein of the 'APP-like' family, is required during the early development of the mouse.

A murine protein, termed CDEBP, was previously shown to bind the double-stranded DNA motif GTCACATG, identical to the yeast centromeric element CDEI. The cDNA sequence showed three domains with extensive similarities to the amyloid beta precursor protein (APP). The protein is homologous over its entire length to the human protein designated APPH. In situ immunofluorescence assays using antibodies raised against distinct parts of CDEBP detected discrete sites of accumulation inside the interphase nucleus, and the bulk of the protein was not associated with mitotic chromosomes. One of the complexes with double-stranded CDEI oligonucleotides detected by gel shift assay was not present when the protein had been selectively removed from nuclear extracts by immunoprecipitation. We reported previously that microinjection into one-cell mouse embryos of DNA fragments including the CDEI sequence results in an early arrest of development with abnormal nuclei containing variable amounts of DNA. The same characteristic figures were observed when embryos were treated with antisense oligonucleotides complementary to parts of the CDEBP coding region. Complexes between the CDEBP protein and CDEI sites in the mouse genome thus appear to play a critical role in the replication/segregation of the embryonic genome.

3T3 Cells↗
PubMed1985

The relative frequency and topographical distribution of somatostatin-, GRP-, APP-, glucagon-, 5-HT-, and neurotensin-immunoreactive cells in the proventriculus of seven species of birds.

The relative frequency and topographical distribution of proventricular endocrine cells were examined immunohistochemically in seven species of birds: common finch, pigeon, quail, chicken, duck, gull and kite. Gastrin releasing peptide (GRP), somatostatin-, avian pancreatic polypeptide (APP)-, glucagon-, 5-hydroxytryptamine (5-HT)- and neurotensin-immunoreactive cells were observed in this study. GRP- and somatostatin-immunoreactive cells were found in all species examined. All six kinds of immunoreactive cells were found with varying frequency in the pigeon, quail and gull, but not all immunoreactives were found in the other species examined. Species differences with regard to the relative frequency and topographical distribution of proventricular endocrine cells were observed.

Animals↗
PubMed1995

Molecular mapping of 21 features associated with partial monosomy 21: involvement of the APP-SOD1 region.

We compared the phenotypes, karyotypes, and molecular data for six cases of partial monosomy 21. Regions of chromosome 21, the deletion of which corresponds to particular features of monosomy 21, were thereby defined. Five such regions were identified for 21 features. Ten of the features could be assigned to the region flanked by genes APP and SOD1: six facial features, transverse palmar crease, arthrogryposis-like symptoms, hypertonia, and contribution to mental retardation. This region, covering the interface of bands 21q21-21q22.1, is 4.7-6.4 Mb long and contains the gene encoding the glutamate receptor subunit GluR5 (GRIK1).

Adolescent↗
PubMed2026

USleep: efficacy of app-based audio interventions to improve sleep disturbance in working adults, a multi-arm randomized controlled trial.

STUDY OBJECTIVES: To evaluate the efficacy of three categories of standalone, audio-based sleep interventions (Bedtime Stories, Sleep Sounds, Sleep Skills) delivered via mental health application (MHapp) in improving sleep among working adults with sleep disturbance. METHODS: A multi-arm, parallel randomized controlled trial was conducted. Adults with self-reported sleep disturbances were recruited online and randomly allocated to Bedtime Stories, Sleep Sounds, Sleep Skills, or digital control. Participants completed self-report questionnaires on sleep disturbance and other related outcomes at baseline (t0) and after the 4-week intervention (t1). The primary analysis followed an intention-to-treat approach using mixed-effects models. RESULTS: A total of 495 working adults (mean age = 32.7 years; 55.8% female) were randomized. For sleep disturbance (primary outcome), the between-group Hedges' g effect sizes were very small and not statistically significant (Bedtimes stories vs. control: g = 0.12, 95% CI -0.13 to 0.37, Sleep Sounds vs. control: g = 0.14, 95% CI -0.11 to 0.39, Sleep Skills 0.07, 95% CI -0.07 to 0.29), with slightly greater reductions in sleep disturbance for the intervention groups than control. The same pattern was observed for sleep-related impairment, mental health, well-being, and pre-sleep arousal. CONCLUSION: Audio-based sleep interventions delivered via a MHapp did not demonstrate superior efficacy over a digital control condition in reducing self-reported sleep disturbance among working adults. Although safe and well-tolerated, their use as standalone treatments for sleep disturbance is not supported by these findings. Future research should explore effectiveness in real-world settings, including user content choice across categories, and use objective sleep measures. CLINICAL TRIAL REGISTRATION: Registered at https://www.isrctn.com/ under "Evaluating the efficacy of audio-based digital tools to improve sleep on the Unmind workplace well-being platform"; https://www.isrctn.com/ISRCTN13426045; registration number: 13426045.

Humans↗
PubMed2003

Chronic glial activation, neurodegeneration, and APP immunoreactive deposits following acute administration of double-stranded RNA.

Several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, are associated with immunocompetent microglia, leading to the suggestion that chronic glial-mediated inflammation contributes to the neurodegeneration seen in these diseases. Little direct evidence supports this hypothesis, and no suitable rodent models exist that do not involve the use of blunt trauma or ischaemia, events that are infrequently encountered in the human disease state. In the present study, we report that administration of double-stranded RNA, a classical inducer of interferon-gamma (IFN-gamma), causes rapid and persistent activation of microglia and astrocytes, as well as induction of interleukin-1beta (IL-beta) and nitric oxide synthase. In close temporal succession to glial activation, there is neurodegeneration, with neuron loss involving apoptosis in selected brain regions including the septal nucleus, hippocampus, cortex and thalamus, along with hippocampal atrophy. This neuronal loss is accompanied by punctate deposits of material that are immunoreactive for amyloid precursor protein, beta-amyloid peptide (Abeta), and apolipoprotein E. The findings may have clinical relevance, since the administration of the nonsteroidal antiinflammatory agent (NSAID) ibuprofen markedly reduces the neurodegeneration observed in the absence of significant glial inhibition. These findings may be relevant to the pathogenesis of Alzheimer's disease in particular, and to other neurodegenerative diseases involving inflammation.

Amyloid beta-Peptides↗
PubMed2002

Gamma-secretase-like cleavages of Notch and beta APP are mutually exclusive in human cells.

Presenilins 1 and 2 are two transmembrane proteins that seem necessary for controlling the proteolytic cleavages of two substrates, betaAPP and Notch, giving rise to Abeta (amyloid beta-peptide) and NICD (Notch Intracellular Domain), respectively. It is a matter for discussion whether presenilins act directly as the cleaving enzyme (referred to as gamma-secretase) or indirectly as a regulator of the substrates/enzymes trafficking to the permissive cell compartment where gamma-secretase cleavage could occur. Here we examined whether betaAPP and Notch undergo mutually exclusive proteolytic events in HEK293 cells or whether they behave as substrates able to compete for a single protease. We show that the overexpression of mDeltaE-Notch-1 does not influence the endogenous recovery of secreted and intracellular Abeta nor those derived from betaAPP-overexpressing HEK293 cells. We establish, conversely, that increasing amounts of betaAPP do not modify the steady-state generation of NICD nor affect the kinetic of production. These data indicate that the proteolytic cleavages leading to the productions of Abeta and NICD are mutually exclusive events in HEK293 cells, and suggest that distinct proteolytic activities contribute to betaAPP and Notch processing.

Amyloid Precursor Protein Secretases↗
PubMed2002

Time course of the development of Alzheimer-like pathology in the doubly transgenic PS1+APP mouse.

Doubly transgenic mice expressing both a mutated amyloid precursor protein and a mutated presenilin-1 protein accumulate A(beta) deposits as they age. The early A(beta) deposits were found to be primarily composed of fibrillar A(beta) and resembled compact amyloid plaques. As the mice aged, nonfibrillar A(beta) deposits increased in number and spread to regions not typically associated with amyloid plaques in Alzheimer's disease. The fibrillar, amyloid-containing deposits remained restricted to cortical and hippocampal structures and did not increase substantially beyond the 12-month time point. Even at early time points, the fibrillar deposits were associated with dystrophic neurites and activated astrocytes expressing elevated levels of glial fibrillary acidic protein. Microglia similarly demonstrated increased staining for complement receptor-3 in the vicinity of A(beta) deposits at early time points. However, when MHC-II staining was used to assess the degree of microglial activation, full activation was not detected until mice were 12 months or older. Overall, the regional pattern of A(beta) staining resembles that found in Alzheimer disease; however, a progression from diffuse A(beta) to more compact amyloid deposits is not observed in the mouse model. It is noted that the activation of microglia at 12 months is coincident with the apparent stabilization of fibrillar A(beta) deposits, raising the possibility that activated microglia might clear fibrillar A(beta) deposits at a rate similar to their rate of formation, thereby establishing a relatively steady-state level of amyloid-containing deposits.

Aging↗
PubMed2002

A presenilin 1 mutation associated with familial frontotemporal dementia inhibits gamma-secretase cleavage of APP and notch.

A novel presenilin 1 mutation, insR352, associated with a frontal temporal dementia phenotype has been identified (E. A. Rogaeva et al., 2001, Neurology 57, 621-625). This mutation does not increase Abeta42 levels, but instead acts as dominant negative presenilin, decreasing amyloid beta protein (Abeta) production by inhibiting gamma-secretase cleavage of the Abeta precursor. The distinct clinical phenotype associated with this mutation suggests that chronic partial inhibition of gamma-secretase activity may result in neurodegeneration.

Amyloid Precursor Protein Secretases↗
PubMed2005

Cholesterol and Alzheimer's disease: statins, cholesterol depletion in APP processing and Abeta generation.

Molecular and more specifically subcellular analyses of the neurodegenerative mechanisms involved in Alzheimer's disease (AD) had been considered most of the time an interplay of proteins and genes. However, some of the observations could not be explained this way. Recently, a number of research groups found the missing link ... lipids! Among the variety of lipids that had been investigated, most investigations had been focused on cholesterol and some derivatives. A recent statistic found that for every primary research article on AD and cholesterol/statins, approximately two reviews were published. This clearly reflects as much the interest in this topic, as it gives evidence that this field is still in its juvenile phase and most aspects have yet to be covered or clarified. To date there is evidently no final answer to whether this approach will eventually provide a therapeutic solution to treat or prevent AD. At the end of the day such answers can only be obtained from clinical studies and to date only two studies with a suitable design have published their results, one of them with preliminary results only. This review focuses on what we know about the cellular mechanisms involved in the AD-lipid connection and what kinds of problematic issues; theoretical and practical, are at hand.

Alzheimer Disease↗
PubMed2002

Conversion from preclinical to dinical stage of Alzheimer's disease as shown by decline of cognitive function in carriers of the Swedish APP-mutation.

The characterisation of the borderline syndrome between normal cognitive function and Alzheimer's disease (AD), often mentioned as Mild Cognitive Impairment (MCI) has been a goal for recent research. However, a variety of definitions of MCI-like syndromes and the uncertainty about the final diagnosis have hampered progress. To overcome these problems, the present study will describe cognitive function in two healthy mutation carriers and two matched non-carriers of the Swedish double mutation family, during the time period when carriers convert to a symptomatic stage, i.e., true preclinical AD, and finally into the stage when a clinical diagnosis of AD is first possible. The findings question the generality of common MCI concepts and the commonly held beliefs about cognitive features in late preclinical stage of AD.

Alzheimer Disease↗
PubMedDate not supplied

Trace elements in biological systems: nuclear techniques app.

Nuclear techniques are very useful in the simultaneous determination of many trace elements in biological samples; the sensitivity depends on the method and on the elements in study and in many cases is better than 0;1 ppm. Proton-induced X-ray fluorescence and alpha-particle elastic diffusion techniques are described; the methods of sample preparation, the sensitivity obtained and some experimental results are included.

Alpha Particles↗