On the origin of Alzheimer's disease. Trials and tribulations of the amyloid hypothesis

Castello, Michael A.; Soriano, Salvador

doi:10.1016/j.arr.2013.10.001

Cited by 81 publications

(58 citation statements)

References 31 publications

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“…Despite more than 20 years as the de facto basis for AD research, the amyloid cascade hypothesis has failed to provide a clear mechanism of AD pathogenesis or halt disease progress in a myriad of drug trials [5,6,357]. In contrast, the Taubased hypothesis has provided a more reasonable molecular explanation.…”

Section: Discussionmentioning

confidence: 95%

“…NFTs are composed of the misfolded hyperphosphorylated microtubule-associated protein Tau (MAPT or Tau), whereas APs are extracellular deposits of misfolded and aggregated amyloid-beta peptides (Aβ). Because both NFTs and APs are persistently found in areas with severe neuronal death, these proteins were considered to be the main cause of neuronal loss and the emergence of dementia, which is a crucial symptom of AD; however, numerous drug trials based on these proteins have failed to provide a useful AD therapy [5,6]. A postmortem study demonstrated that the misfolded protein accumulation is a shared pattern in many neurodegenerative diseases, including AD [7,8].…”

Section: Introductionmentioning

confidence: 98%

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The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer’s Disease

Sulistio

Heese

2015

Mol Neurobiol

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One of the shared hallmarks of neurodegenerative diseases is the accumulation of misfolded proteins. Therefore, it is suspected that normal proteostasis is crucial for neuronal survival in the brain and that the malfunction of this mechanism may be the underlying cause of neurodegenerative diseases. The accumulation of amyloid plaques (APs) composed of amyloid-beta peptide (Aβ) aggregates and neurofibrillary tangles (NFTs) composed of misfolded Tau proteins are the defining pathological markers of Alzheimer's disease (AD). The accumulation of these proteins indicates a faulty protein quality control in the AD brain. An impaired ubiquitin-proteasome system (UPS) could lead to negative consequences for protein regulation, including loss of function. Another pivotal mechanism for the prevention of misfolded protein accumulation is the utilization of molecular chaperones. Molecular chaperones, such as heat shock proteins (HSPs) and FK506-binding proteins (FKBPs), are highly involved in protein regulation to ensure proper folding and normal function. In this review, we elaborate on the molecular basis of AD pathophysiology using recent data, with a particular focus on the role of the UPS and molecular chaperones as the defensive mechanism against misfolded proteins that have prion-like properties. In addition, we propose a rational therapy approach based on this mechanism.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 98%

The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer’s Disease

Sulistio

Heese

2015

Mol Neurobiol

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“…Such substances include the neurodegenerative marker amyloid-ß (Aß) which is a substrate for P-gp (15,16). Cerebral accumulation of Aβ-plaques is a hallmark, and probably also the major cause, of Alzheimer's disease (AD) (17). In humans, both a shorter duration and a reduced quality of sleep result in increased accumulation of Aβ in the brain (18).…”

Section: Introductionmentioning

confidence: 99%

P-glycoprotein Function in the Rodent Brain Displays a Daily Rhythm, a Quantitative In Vivo PET Study

Savolainen

Meerlo

Elsinga

et al. 2016

AAPS J

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Abstract.The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from harmful compounds. P-glycoprotein (P-gp) is one of the major efflux transporters at the BBB. In the present study, we assessed whether (1) P-gp function in the brain is constant or fluctuates across the day and (2) if it is affected by sleep deprivation. Four groups of rats were PET scanned with a radiolabeled P-gp substrate [18 F]MC225, each at a different moment of the 12-h light-dark cycle to study diurnal variations: early sleep phase (ZT3), late sleep phase (ZT9), early active phase (ZT15), and late active phase (ZT21). In two additional groups, controls were allowed to sleep normally while experimental animals were sleep-deprived for 10 h in a slowly rotating drum during the sleep phase. Kinetic modeling with a one-tissue compartment model fit resulted for all brain regions in 1.2-1.8-fold higher distribution volumes (V T ) at ZT15 than at other time points. V T -values at ZT3, ZT9, and ZT21 were not significantly different from each other. Regional tracer distribution volumes in controls and sleep-deprived animals were also not significantly different. Our results indicate that P-gp function in rats displays a daily rhythm with reduced function at the beginning of the active phase. This rhythm is not dependent on sleep since acute sleep deprivation had no effect. Knowing the diurnal variation of P-gp function could be important for the design of PET studies and for choosing the correct administration time for P-gpdependent drugs.

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“…As a most common dementia, Alzheimer's disease (AD) is characterized by neuropathological hallmarks of extracellular senile plaques, intracellular neurofibrillary tangles, progressive loss of neurons, synaptic dysfunction, and disequilibrium of multiple neurotransmitter systems [1][2][3] . Although the central hypothesis for the pathogenesis of AD is the amyloid hypothesis, the exact mechanism underlying AD pathogenesis remains unclear [4] .…”

Section: Introductionmentioning

confidence: 99%

Curcumin inhibits appoptosin-induced apoptosis via upregulating heme oxygenase-1 expression in SH-SY5Y cells

Zheng

Zhang

et al. 2015

Acta Pharmacol Sin

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Aim: Appoptosin (SLC25A38) is a pro-apoptotic protein, which is upregulated in Alzheimer's disease (AD) brains and plays an important role in promoting the pathological progress of AD. The aim of this study was to investigate the effects of curcumin from the rhizome of Curcuma longa on appoptosin-induced apoptosis in SH-SY5Y cells. Methods: SH-SY5Y cells were pretreated with curcumin, then transfected with appoptosin or vector. The apoptotic cells were detected with Annexin V staining analysis by flow cytometry. The expression of cleaved caspase-3, appoptosin, heme oxygenase-1 (HO-1) was examined using Western blotting. Intracellular level of ROS was measured with DCFH-DA staining by flow cytometry analysis. Mitochondrial membrane potential (ΔΨm) was detected with JC-1 staining under a fluorescence microscope and quantified by fluorescence ratio detection. Results: Overexpression of appoptosin in SH-SY5Y cells markedly increased cell apoptosis accompanied by reduced HO-1 expression, increased intracellular heme level, ROS overproduction and ΔΨm impairment. Treatment of SH-SY5Y cells with curcumin (2.5-20 μmol/L) for 24 h did not significantly affect their viability. However, pretreatment with curcumin (2.5-20 μmol/L) dose-dependently attenuated all above-mentioned pathological changes in appoptosin-transfected SH-SY5Y cells. Conclusion: Curcumin inhibits appoptosin-induced apoptosis in SH-SY5Y cells by upregulating the expression of HO-1, reducing the production of intracellular heme and ROS, and preventing the ΔΨm loss.

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On the origin of Alzheimer's disease. Trials and tribulations of the amyloid hypothesis

Cited by 81 publications

References 31 publications

The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer’s Disease

The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer’s Disease

P-glycoprotein Function in the Rodent Brain Displays a Daily Rhythm, a Quantitative In Vivo PET Study

Curcumin inhibits appoptosin-induced apoptosis via upregulating heme oxygenase-1 expression in SH-SY5Y cells

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