Dual-function triazole–pyridine derivatives as inhibitors of metal-induced amyloid-β aggregation

Amyloid β-peptide (Aβ) is generated by the consecutive cleavages of β- and γ-secretase. The intramembraneous γ-secretase cleavage critically depends on the activity of presenilins (PS1 and PS2). Although there is evidence that PSs are aspartyl proteases with γ-secretase activity, it remains controversial whether their subcellular localization overlaps with the cellular sites of Aβ production. We now demonstrate that biologically active GFP-tagged PS1 as well as endogenous PS1 are targeted to the plasma membrane (PM) of living cells. On the way to the PM, PS1 binds to nicastrin (Nct), an essential component of the γ-secretase complex. This complex is targeted through the secretory pathway where PS1-bound Nct becomes endoglycosidase H resistant. Moreover, surface-biotinylated Nct can be coimmunoprecipitated with PS1 antibodies, demonstrating that this complex is located to cellular sites with γ-secretase activity. Inactivating PS1 or PS2 function by mutagenesis of one of the critical aspartate residues or by γ-secretase inhibitors results in delayed reinternalization of the β-amyloid precursor protein and its accumulation at the cell surface. Our data suggest that PS is targeted as a biologically active complex with Nct through the secretory pathway to the cell surface and suggest a dual function of PS in γ-secretase processing and in trafficking.

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Amyloid β-peptide and Alzheimer's disease

Essays in Biochemistry ◽

10.1042/bse0560099 ◽

2014 ◽

Vol 56 ◽

pp. 99-110 ◽

Cited By ~ 15

Author(s):

David Allsop ◽

Jennifer Mayes

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Senile Plaques ◽

Strong Support ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Amyloid Cascade Hypothesis ◽

Sequence Of Events ◽

Aβ Amyloid ◽

Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

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Insights into amyloid disease from fly models

Essays in Biochemistry ◽

10.1042/bse0560069 ◽

2014 ◽

Vol 56 ◽

pp. 69-83 ◽

Cited By ~ 1

Author(s):

Ko-Fan Chen ◽

Damian C. Crowther

Keyword(s):

Drosophila Melanogaster ◽

Neurodegenerative Disorders ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Disease Pathogenesis ◽

Amyloid Aggregates ◽

Aβ Amyloid ◽

Polypeptide Chains ◽

Amyloid Diseases

The formation of amyloid aggregates is a feature of most, if not all, polypeptide chains. In vivo modelling of this process has been undertaken in the fruitfly Drosophila melanogaster with remarkable success. Models of both neurological and systemic amyloid diseases have been generated and have informed our understanding of disease pathogenesis in two main ways. First, the toxic amyloid species have been at least partially characterized, for example in the case of the Aβ (amyloid β-peptide) associated with Alzheimer's disease. Secondly, the genetic underpinning of model disease-linked phenotypes has been characterized for a number of neurodegenerative disorders. The current challenge is to integrate our understanding of disease-linked processes in the fly with our growing knowledge of human disease, for the benefit of patients.

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The Inhalation Anesthetic Isoflurane Induces a Vicious Cycle of Apoptosis and Amyloid β-Protein Accumulation

Yearbook of Anesthesiology and Pain Management ◽

10.1016/s1073-5437(08)70801-5 ◽

2008 ◽

Vol 2008 ◽

pp. 35-36

Author(s):

H.T. Lee

Keyword(s):

Amyloid Β ◽

Protein Accumulation ◽

Amyloid Β Protein ◽

Vicious Cycle ◽

Inhalation Anesthetic ◽

Β Protein

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Proteasome Inhibition and Aggresome Formation in Sporadic Inclusion-Body Myositis and in Amyloid-β Precursor Protein-Overexpressing Cultured Human Muscle Fibers

Yearbook of Pathology and Laboratory Medicine ◽

10.1016/s1077-9108(08)70407-9 ◽

2007 ◽

Vol 2007 ◽

pp. 241-243

Author(s):

C.A. Wiley

Keyword(s):

Inclusion Body ◽

Inclusion Body Myositis ◽

Muscle Fibers ◽

Amyloid Β ◽

Proteasome Inhibition ◽

Human Muscle ◽

Precursor Protein ◽

Sporadic Inclusion Body Myositis ◽

Aggresome Formation

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Folate and vitamin B-12 deficiencies additively impaired memory function and disturbed the gut microbiota in amyloid-β infused rats

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000624 ◽

2019 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Sunmin Park ◽

Sunna Kang ◽

Da Sol Kim

Keyword(s):

Insulin Resistance ◽

Gut Microbiota ◽

Insulin Signaling ◽

Gut Microbiome ◽

Metabolic Diseases ◽

Memory Function ◽

Amyloid Β ◽

Impaired Memory ◽

Ca1 Region ◽

Folate And Vitamin B12

Abstract. Folate and vitamin B12(V-B12) deficiencies are associated with metabolic diseases that may impair memory function. We hypothesized that folate and V-B12 may differently alter mild cognitive impairment, glucose metabolism, and inflammation by modulating the gut microbiome in rats with Alzheimer’s disease (AD)-like dementia. The hypothesis was examined in hippocampal amyloid-β infused rats, and its mechanism was explored. Rats that received an amyloid-β(25–35) infusion into the CA1 region of the hippocampus were fed either control(2.5 mg folate plus 25 μg V-B12/kg diet; AD-CON, n = 10), no folate(0 folate plus 25 μg V-B12/kg diet; AD-FA, n = 10), no V-B12(2.5 mg folate plus 0 μg V-B12/kg diet; AD-V-B12, n = 10), or no folate plus no V-B12(0 mg folate plus 0 μg V-B12/kg diet; AD-FAB12, n = 10) in high-fat diets for 8 weeks. AD-FA and AD-VB12 exacerbated bone mineral loss in the lumbar spine and femur whereas AD-FA lowered lean body mass in the hip compared to AD-CON(P < 0.05). Only AD-FAB12 exacerbated memory impairment by 1.3 and 1.4 folds, respectively, as measured by passive avoidance and water maze tests, compared to AD-CON(P < 0.01). Hippocampal insulin signaling and neuroinflammation were attenuated in AD-CON compared to Non-AD-CON. AD-FAB12 impaired the signaling (pAkt→pGSK-3β) and serum TNF-α and IL-1β levels the most among all groups. AD-CON decreased glucose tolerance by increasing insulin resistance compared to Non-AD-CON. AD-VB12 and AD-FAB12 increased insulin resistance by 1.2 and 1.3 folds, respectively, compared to the AD-CON. AD-CON and Non-AD-CON had a separate communities of gut microbiota. The relative counts of Bacteroidia were lower and those of Clostridia were higher in AD-CON than Non-AD-CON. AD-FA, but not V-B12, separated the gut microbiome community compared to AD-CON and AD-VB12(P = 0.009). In conclusion, folate and B-12 deficiencies impaired memory function by impairing hippocampal insulin signaling and gut microbiota in AD rats.

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