Frameshift Mutants of β Amyloid Precursor Protein and Ubiquitin-B in Alzheimer's and Down Patients

Leeuwen, Fred W. van; Kleijn, Dominique P.V. de; Hurk, Helma H. van den; Neubauer, Andrea; Sonnemans, M. A. F.; Sluijs, Jacqueline A.; Köycü, Soner; Ramdjielal, R.D.J.; Salehi, Ahmad; Martens, Gerard J.M.; Grosveld, Frank; Burbach, J. Peter H.; Hol, Elly M.

doi:10.1126/science.279.5348.242

Cited by 528 publications

(475 citation statements)

References 28 publications

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“…97), and Aβ-induced neuronal death is mediated by the ATM-dependent DNA damage response pathway 98 . Increasing evidence suggests that ubiquitin-proteasomal degradation of proteins is impaired in AD resulting in the abnormal accumulation of damaged proteins in neurons (UBB+1 mutations) 99 . In this regard it was recently reported that a ubiquitin-conjugating enzyme called E2-25K/ Hip-2 mediates Aβ-induced inihibition of proteasome activity which is required for Aβ-induced apoptosis 100 .…”

Section: Boxmentioning

confidence: 99%

Pathways towards and away from Alzheimer's disease

Mattson

2004

Nature

2,716

2,058

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Slowly, but surely, Alzheimer's disease (AD) patients lose their memory, their cognitive abilities and even their personalities may change dramatically. These changes are due to the progressive dysfunction and death of nerve cells that are responsible for the storage and processing of information. While drugs can temporarily improve memory, at present there are no treatments that can stop or reverse the inexorable neurodegenerative process. But rapid progress towards understanding the cellular and molecular alterations that are responsible for the neuron's demise is increasing optimism that effective preventative and therapeutic strategies are in the offing.Alzheimer's disease (AD) is a neurodegenerative disorder that currently affects nearly 2% of the population in industrialized countries; the risk of AD dramatically increases in individuals beyond the age of 70 and it is predicted that the incidence of AD will triple within the next 50 years (www.alz.org). There can be other causes of memory loss and definitive diagnosis of AD therefore requires postmortem examination of the brain, which must contain sufficient numbers of "plaques" and "tangles" to qualify as AD 1, 2 . Plaques are extracellular deposits of fibrils and amorphous aggregates of amyloid β-peptide (Aβ); diffuse deposits of Aβ are also present in high amounts. Neurofibrillary tangles are intracellular fibrillar aggregates of the microtubule-associated protein tau which exhibit hyperphosphorylation and oxidative modifications. Plaques and tangles are present mainly in brain regions involved in learning and memory and emotional behaviors such as the entorhinal cortex, hippocampus, basal forebrain and amygdala. Brain regions with plaques typically exhibit reduced numbers of synapses, and neurites associated with the plaques are often damaged, suggesting that Aβ damages synapses and neurites. Neurons that employ glutamate or acetylcholine as neurotransmitters appear to be particularly affected, but neurons that produce serotonin and norepinephrine are also damaged. This review focuses on the molecular and cellular abnormalities that occur in the brain in AD, how they result in synaptic dysfunction and cell death, and how they can be counteracted. Central to the disease is altered proteolytic processing of the amyloid precursor protein (APP) resulting in the production and aggregation of neurotoxic forms of Aβ. Neurons that degenerate in AD exhibit increased oxidative damage, impaired energy metabolism and perturbed cellular calcium homeostasis; Aβ appears to be an important instigator of these abnormalities. Genetic and environmental factors can determine one's risk for and an understanding of these risk factors and how they modify the amyloid cascade is leading to the development of interventions for the prevention and treatment of AD that range from changes in diet and lifestyle, to vaccines and drugs.

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Section: Boxmentioning

confidence: 99%

Pathways towards and away from Alzheimer's disease

Mattson

2004

Nature

2,716

2,058

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“…We reported that in short simple repeats in APP transcripts, a dinucleotide deletion could occur, such as DGA in the GAGAG motif in exon 9 or 10 of APP, resulting in the translation of a frame-shifted and truncated APP protein (APP +1 ). This APP +1 , which is, in non-demented controls without any pathology, a secretory protein (Hol et al 2003), accumulates in neurofibrillary tangles and in the neuritic plaques in the hippocampus and temporal cortex of patients suffering from Alzheimer's disease pathology, including those with Down's syndrome (DS) (Hol et al 1998;van Leeuwen et al 1998). The presence of APP +1 in these hallmarks suggests that it could be involved in the process of neurodegeneration contributing to hereditary and non-hereditary forms of Alzheimer's pathology.…”

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confidence: 99%

Frame‐shifted amyloid precursor protein found in Alzheimer's disease and Down's syndrome increases levels of secreted amyloid β40

Dijk

Fischer

Sluijs

et al. 2004

Journal of Neurochemistry

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Frame-shifted amyloid precursor protein (APP +1 ), which has a truncated out-of-frame C-terminus, accumulates in the neuropathological hallmarks of patients with Alzheimer's disease pathology. To study a possible involvement of APP +1 in the pathogenesis of Alzheimer's disease, we expressed APP 695 and APP +1 in the HEK293 cell-line and studied whether the processing of APP 695 was affected. APP +1 is a secretory protein, but high expression of APP 695 and APP +1 results in the formation of intracellular aggregate-like structures containing both proteins and Fe65, an adaptor protein that interacts with APP 695 . APP +1 is shown to interact with APP 695 , suggesting that these structures consist of functional protein complexes. Such an interaction can also be anticipated in post-mortem brains of young Down's syndrome patients without any sign of neuropathology. Here we observed APP +1 immunoreactivity in beaded fibres. Additional support for functional consequences on the processing of APP 695 comes from a 1.4-fold increase in levels of secreted amyloid b 40 in cells co-expressing APP 695 and APP +1 , although APP +1 itself does not contain the amyloid b sequence. Taken together, these data show that co-expression of APP 695 and APP +1 affects the processing of APP 695 in a pro-amyloidogenic way and this could gradually contribute to Alzheimer's disease pathology, as has been implicated in Down's syndrome patients. Keywords: Alzheimer's disease, amyloid b, amyloid precursor protein, Down's syndrome, Fe65, protein interactions.

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“…Thus, different genetic mutations that converge on a particular pathogenic pathway can be extremely informative as to the critical pathogenetic process. 17 A central point to be derived from the study of these neurologic diseases is that at the clinical, pathological, and genetic levels there is considerable heterogeneity. To the degree that genes and gene products can be identified, it will be possible to make increasingly powerful sense of what was previously an heterogeneous amalgamation of different pathogenic processes.…”

Section: IVmentioning

confidence: 99%

Psychiatric research in the 21st century: opportunities and limitations

Heninger

1999

Mol Psychiatry

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The year 2000 prompts numerous prognostications of the events to occur during the next century. Except for the Y2K problem, the year 2000 is little different in substance than 1999 or 2001. However it is useful to use the occasion to consider where we have come from and where we are going. Thinking of the future will help clarify goals, define the problems, identify priorities, and outline pathways for progress.

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Frameshift Mutants of β Amyloid Precursor Protein and Ubiquitin-B in Alzheimer's and Down Patients

Cited by 528 publications

References 28 publications

Pathways towards and away from Alzheimer's disease

Pathways towards and away from Alzheimer's disease

Frame‐shifted amyloid precursor protein found in Alzheimer's disease and Down's syndrome increases levels of secreted amyloid β40

Psychiatric research in the 21st century: opportunities and limitations

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