Intracellular Amyloid β: A Modification to the Amyloid Hypothesis in Alzheimer's Disease

Zhang, Yan

doi:10.1002/9783527634323.ch6

Cited by 9 publications

(10 citation statements)

References 116 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A series of review articles has summarized the mechanism of iAβ accumulation and the results of iAβ experiments performed during the last ten years [ 125 , 127 , 128 , 129 , 130 , 131 , 132 ]. iAβ has been widely detected in neuronal cells and primary human neurons, and has a very broad range of interactions with cell organelles and proteins [ 133 , 134 , 135 , 136 , 137 ].…”

Section: Dysregulation Of Protein Homeostasis In Admentioning

confidence: 99%

“…The intraneuronal pool of Aβ has a double origin: slow production of iAβ from APP inside the neurons [ 127 , 128 , 129 , 130 , 131 , 143 , 144 , 145 ] and uptake from the extracellular space. iAβ may induce subcellular compartment structural changes, e.g., stable expression of human iAβ increases the number of Golgi apparatus elements, lysosomes and lipofuscin bodies in the hippocampus in a double APPxPS1 mutant transgenic rat model [ 146 ].…”

Section: Dysregulation Of Protein Homeostasis In Admentioning

confidence: 99%

See 1 more Smart Citation

β-Amyloid and the Pathomechanisms of Alzheimer’s Disease: A Comprehensive View

2017

View full text Add to dashboard Cite

Protein dyshomeostasis is the common mechanism of neurodegenerative diseases such as Alzheimer’s disease (AD). Aging is the key risk factor, as the capacity of the proteostasis network declines during aging. Different cellular stress conditions result in the up-regulation of the neurotrophic, neuroprotective amyloid precursor protein (APP). Enzymatic processing of APP may result in formation of toxic Aβ aggregates (β-amyloids). Protein folding is the basis of life and death. Intracellular Aβ affects the function of subcellular organelles by disturbing the endoplasmic reticulum-mitochondria cross-talk and causing severe Ca2+-dysregulation and lipid dyshomeostasis. The extensive and complex network of proteostasis declines during aging and is not able to maintain the balance between production and disposal of proteins. The effectivity of cellular pathways that safeguard cells against proteotoxic stress (molecular chaperones, aggresomes, the ubiquitin-proteasome system, autophagy) declines with age. Chronic cerebral hypoperfusion causes dysfunction of the blood-brain barrier (BBB), and thus the Aβ-clearance from brain-to-blood decreases. Microglia-mediated clearance of Aβ also declines, Aβ accumulates in the brain and causes neuroinflammation. Recognition of the above mentioned complex pathogenesis pathway resulted in novel drug targets in AD research.

show abstract

Section: Dysregulation Of Protein Homeostasis In Admentioning

confidence: 99%

Section: Dysregulation Of Protein Homeostasis In Admentioning

confidence: 99%

β-Amyloid and the Pathomechanisms of Alzheimer’s Disease: A Comprehensive View

2017

View full text Add to dashboard Cite

show abstract

“…The main clinical symptoms of AD are manifested as progressive cognitive impairment and mental and behavioral abnormality [1]. The characteristic pathological changes in AD include neuronal loss, and the reduction of neurogenesis [2]. It is reported that CREB phosphorylation can promote neurogenesis and compensate damaged neurons, which is of great signi cance for improving cognitive impairment [3].…”

Section: Introductionmentioning

confidence: 99%

The Molecular Mechanism of Scutellaria Barbata Flavonoids in Promoting Neurogenesis and Improving Memory Impairment Mediated by CREB Phosphorylation in Rats

Liu

Cheng

et al. 2023

Preprint

View full text Add to dashboard Cite

Background The present study was aimed to investigate the effect and molecular mechanism of Scutellaria barbata flavonoids (SBFs) in promoting neurogenesis and improving memory impairment mediated by CREB phosphorylation in rats. Methods Alzheimer’s disease (AD) model was established by intracerebroventricular injection of amyloid beta-peptide 25–35 (Aβ25−35) in combination with aluminum trichloride (AlCl3) and recombinant human transforming growth factor-β1 (RHTGF-β1) (composited Aβ) in rats. The Morris water maze was used to screen the successful AD model of rats. The screened successful AD model rats were randomly divided into three groups including a model group and two drug groups of 140 mg/kg SBFs and 0.5 mg/kg Rolipram (Positive control drug). After administration for 38 days, the Morris water maze test was used to measure the learning and memory ability of the rats. HE staining was used to observe the morphology of neurons in the hippocampus and cerebral cortex regionsof the rats' brains. Immunohistochemistry was used to detect the expression of NeuN in the hippocampal gyrus of rats. The mRNA expression of TrkB, RSK,CREB, and BDNF and the protein expression of NeuN, TrkB, RSK, P-CREB-Ser133, and BDNF in the hippocampus and cerebral cortex of the rats were assayed by quantitative real-time PCR (qPCR) and Western blotting methods. Results Intracerebroventricular injection of composited Aβ induced memory impairment, impaired neurons, decreased the protein expression of NeuN in the hippocampal gyrus, increased the mRNA expression levels of TrkB, RSK and BDNF, decreased the mRNA expression level of CREB and the protein expression levels of NeuN, TrkB, RSK, P-CREB-Ser133 and BDNF in the hippocampus and cerebral cortex of rats. However, SBFs attenuated memory impairment which was induced by composited Aβ in rats and ameliorated neuropathological changes in the brain, increased the expression of NeuN protein in the hippocampal gyrus, and regulated mRNA and protein expressions in composited Aβ treated rats. Rolipram ameliorated learning and memory disorder induced by composited Aβ, increased the protein expression of P-CREB-Ser133, increased the expression of NeuN protein in the hippocampal gyrus, promoted neurogenesis, and improved the neuropathological changes in the brain. The effect of SBFs was also similar to Rolipram. Conclusion The effect of SBFs was consistent with the positive control drug Rolipram. SBFs could promote neurogenesis and improve learning and memory impairment in AD rats, and its mechanism was mediated by CREB phosphorylation.

show abstract

“…14 In addition, chemicals with Aβ inhibition property might have potential to treat AD. 15 Importantly, in order to combat multiple pathological features of AD, a multitarget-directed ligands (MTDLs) strategy has been developed. 16 ASS234, a donepezilbased MTDL, could produce multiple anti-AD effects, including the inhibition of Aβ aggregation and the suppression of AChE activity.…”

Section: ■ Introductionmentioning

confidence: 99%

Dimeric Tacrine(10)-hupyridone as a Multitarget-Directed Ligand To Treat Alzheimer’s Disease

Xuan

Yan

et al. 2021

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a neurodegenerative disorder with multiple pathological features. Therefore, a multitarget-directed ligands (MTDLs) strategy has been developed to treat AD. We have previously designed and synthesized dimeric tacrine(10)-hupyridone (A10E), a novel tacrine derivative with acetylcholinesterase (AChE) inhibition and brain-derived neurotrophic factor (BDNF) activation activity, by linking tacrine and a fragment of huperzine A. However, it was largely unknown whether A10E could act on other AD targets and produce cognitive-enhancing ability in AD animal models. In this study, A10E could prevent cognitive impairments in APP/PS1 transgenic mice and β-amyloid (Aβ) oligomers-treated mice, with higher potency than tacrine and huperzine A. Moreover, A10E could effectively inhibit Aβ production and deposition, alleviate neuroinflammation, enhance BDNF expression, and elevate cholinergic neurotransmission in vivo. At nanomolar concentrations, A10E could inhibit Aβ oligomers-induced neurotoxicity via the activation of tyrosine kinase receptor B (TrkB)/Akt pathway in SH-SY5Y cells. Furthermore, Aβ oligomerization and fibrillization could be directly disrupted by A10E. Importantly, A10E at high concentrations did not produce obvious hepatotoxicity. Our results indicated that A10E could produce anti-AD neuroprotective effects via the inhibition of Aβ aggregation, the activation of the BDNF/TrkB pathway, the alleviation of neuroinflammation, and the decrease of AChE activity. As MTDLs could produce additional benefits, such as overcoming the deficits of drug combination and enhancing the compliance of AD patients, our results also suggested that A10E might be developed as a promising MTDL lead for the treatment of AD.

show abstract

Intracellular Amyloid β: A Modification to the Amyloid Hypothesis in Alzheimer's Disease

Cited by 9 publications

References 116 publications

β-Amyloid and the Pathomechanisms of Alzheimer’s Disease: A Comprehensive View

β-Amyloid and the Pathomechanisms of Alzheimer’s Disease: A Comprehensive View

The Molecular Mechanism of Scutellaria Barbata Flavonoids in Promoting Neurogenesis and Improving Memory Impairment Mediated by CREB Phosphorylation in Rats

Dimeric Tacrine(10)-hupyridone as a Multitarget-Directed Ligand To Treat Alzheimer’s Disease

Contact Info

Product

Resources

About