Biogenesis and metabolism of Alzheimer’s disease Aβ amyloid peptides

Evin, Geneviève; Weidemann, Andreas

doi:10.1016/s0196-9781(02)00063-3

Cited by 161 publications

(153 citation statements)

References 178 publications

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“…Although it is generally accepted that elevated levels of Ab42 trigger the manifestation of disease symptoms, both peptides are found in amyloid plaques, which consist of aggregated amyloid and are one of the neuropathological hallmarks of Alzheimer's disease. However, Ab42 is considered the more toxic form of b-amyloid, due to its hydrophobic nature and self-aggregation properties (Evin and Weidemann 2002). Recent research suggests that oligomerized, soluble Ab42 is toxic to the cells and may also contribute to the manifestation of the disease (Walsh et al 2002;Cleary et al 2005).…”

mentioning

confidence: 99%

Identification of Novel Genes That Modify Phenotypes Induced by Alzheimer's β-Amyloid Overexpression in Drosophila

Cao

Song²,

Gangi

et al. 2008

Genetics

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Sustained increases in life expectancy have underscored the importance of managing diseases with a high incidence in late life, such as various neurodegenerative conditions. Alzheimer's disease (AD) is the most common among these, and consequently significant research effort is spent on studying it. Although a lot is known about the pathology of AD and the role of b-amyloid (Ab) peptides, the complete network of interactions regulating Ab metabolism and toxicity still eludes us. To address this, we have conducted genetic interaction screens using transgenic Drosophila expressing Ab and we have identified mutations that affect Ab metabolism and toxicity. These analyses highlight the involvement of various biochemical processes such as secretion, cholesterol homeostasis, and regulation of chromatin structure and function, among others, in mediating toxic Ab effects. Several of the mutations that we identified have not been linked to Ab toxicity before and thus constitute novel potential targets for AD intervention. We additionally tested these mutations for interactions with tau and expanded-polyglutamine overexpression and found a few candidate mutations that may mediate common mechanisms of neurodegeneration. Our data offer insight into the toxicity of Ab and open new areas for further study into AD pathogenesis

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mentioning

confidence: 99%

Identification of Novel Genes That Modify Phenotypes Induced by Alzheimer's β-Amyloid Overexpression in Drosophila

Cao

Song²,

Gangi

et al. 2008

Genetics

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“…Mutations in the genes for presenilin 1 and 2 modulate c-secretase cleavage of APP, also leading to an increase in the production of this more amyloidogenic form of Ab (Borchelt et al 1996;Scheuner et al 1996). Hence, modulation of APP processing and the production of Ab play an important role in AD pathogenesis (Evin and Weidemann 2002;Hardy and Selkoe 2002;Edbauer et al 2003).…”

mentioning

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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“…These amyloid bodies contain fibrillogenic protein (amyloid fibrils that are smooth, straight and about 10 nm in diameter) and nonfibril components (ApoE and serum Aβ component). The SPs, also called neuritic plaques or amyloid plaques, are extracellular accumulation of Aβ protein [21] .…”

Section: Biochemistry Of Spsmentioning

confidence: 99%

“…A domain that is involved in neuritic outgrowth delineates to a short sequence present after the insertion of exon 7 product [21] . The vital roles of APP isoform are given below [31] .…”

Section: Formation Of Aβ-peptidesmentioning

confidence: 99%

Pathogenesis of Alzheimer's Disease: Role of Amyloid-beta and Hyperphosphorylated Tau Protein

Sajjad¹,

Arif²,

Shah³

et al. 2018

pharmaceutical-sciences

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Sajjad, et al.: Pathogenesis of Alzheimer's DiseaseThe pathological emblems of Alzheimer's disease are the accumulation of amyloid-β plaques and neurofibrillary tangles. The alluvium of toxic amyloid-β-protein in the form of aggregates is central to the pathogenesis of Alzheimer's disease. The aggregate formation is due to the structural refitting of α-helical sheet of normal, soluble amyloid-β-protein to the β-sheets, which lead to oligomeric, fibrillar, insoluble and disease causing amyloid-β 42. Mounting data suggests that another factor, the tau protein ripens into highly phosphorylated form by several kinases after Aβ-stimulation leads to tangle formation resulting in neuronal bereavement in hippocampus and entorhinal regions as the disease progresses further. An overview has been presented in this review of the role of tau as an important partner of amyloid-β in the pathogenesis of Alzheimer's disease, both of which could be used as biomarkers for diagnosis and risk assessment with other molecular chaperones, which are associated with Alzheimer's disease. As a part of common pathophysiological mechanism the understanding of amyloid-β and tau toxicities might be helpful for finding molecular targets for the prevention or even cure of Alzheimer's disease.

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Biogenesis and metabolism of Alzheimer’s disease Aβ amyloid peptides

Cited by 161 publications

References 178 publications

Identification of Novel Genes That Modify Phenotypes Induced by Alzheimer's β-Amyloid Overexpression in Drosophila

Identification of Novel Genes That Modify Phenotypes Induced by Alzheimer's β-Amyloid Overexpression in Drosophila

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

Pathogenesis of Alzheimer's Disease: Role of Amyloid-beta and Hyperphosphorylated Tau Protein

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