Early Intervention in Alzheimer’s Disease: How Early is Early Enough?

Fan, Dong-Yu; Wang, Yanjiang

doi:10.1007/s12264-019-00429-x

“…To evaluate the toxicity of capsaicin, the cells were seeded in 96-well plates (5 × 10 4 cells/ml) and incubated without (control) or with various concentrations of capsaicin (5,10,25,50,75, 100, 125, 150 μM) for 24 h. The cell culture medium was changed immediately before the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay to avoid an interaction between MTT and capsaicin. Then 10 μl MTT (5 mg/ml, Sigma-Aldrich, USA) solution was added for 4 h. The supernatant was then removed, and 100 μl DMSO was added to dissolve the dye crystals.…”

Section: Mtt Assaymentioning

confidence: 99%

“…There is no effective therapy to cure AD or even to halt the course of the disease. With the failure of a series of clinical trials, the strategy of AD treatment has recently shifted to disease prevention, with clinical testing carried out in at-risk populations [1][2][3][4][5] . In fact, our analysis suggests that one-third of AD cases worldwide are attributable to several common modifiable risk factors [6][7][8] , most of which can be controlled by healthy dietary and lifestyle, making dietary and lifestyle intervention research hotspots 9,10 .…”

Section: Introductionmentioning

confidence: 99%

Capsaicin consumption reduces brain amyloid-beta generation and attenuates Alzheimer’s disease-type pathology and cognitive deficits in APP/PS1 mice

Wang

¹

,

Sun

²

,

Xiang

³

et al. 2020

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Alzheimer's disease (AD) is the most common cause of age-related dementia and is currently incurable. The failures of current clinical trials and the establishment of modifiable risk factors have shifted the AD intervention from treatment to prevention in the at-risk population. Previous studies suggest that there is a geographic overlap between AD incidence and spicy food consumption. We previously reported that capsaicin-rich diet consumption was associated with better cognition and lower serum Amyloid-beta (Aβ) levels in people aged 40 years and over. In the present study, we found that intake of capsaicin, the pungent ingredient in chili peppers, reduced brain Aβ burden and rescued cognitive decline in APP/PS1 mice. Our in vivo and in vitro studies revealed that capsaicin shifted Amyloid precursor protein (APP) processing towards α-cleavage and precluded Aβ generation by promoting the maturation of a disintegrin and metalloproteinase 10 (ADAM10). We also found that capsaicin alleviated other AD-type pathologies, such as tau hyperphosphorylation, neuroinflammation and neurodegeneration. The present study suggests that capsaicin is a potential therapeutic candidate for AD and warrants clinical trials on chili peppers or capsaicin as dietary supplementation for the prevention and treatment of AD.

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“…4748 The experimental results obtained with AIE-CNPy-AD is of great significance because APP/PS1 transgenic mice are found to exhibit memory deficits from 5 months old on which is early clinical presentations, confirming that AIE-CNPy-AD can diagnose AD of APP/PS1 transgenic mice during the period of early biological manifestations, prior to the appearance of clinical presentations. 43,47,49 Furthermore, as shown in Figure S15, ThS could neither give discriminatory signals between the APP/PS1 transgenic mice and wild-type mice nor provide distinct signals among mice of different ages, manifesting that our probe outperforms the clinically used gold-standard probe and could be used as an upgraded alternative to the commercially available ones.…”

Section: In-vivo Tracking Of Aβ Plaques In App/ps1 Mice At a Super-eamentioning

confidence: 94%

Rationally Designing Simple Rod-Like Amphiphilic NIR-Emissive AIE Probes for Precise In-Vivo Detection of Aβ Fibrils/Plaques at A Super-Early Stage

Wang¹,

Dong²,

Zhang³

et al. 2021

Preprint

0

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With increase of social aging, Alzheimer's disease (AD) has been one of the serious diseases threatening human health. The occurrence of Aβ fibrils or plaques is recognized as the hallmark of AD. Currently, optical imaging has stood out to be a promising technique for the imaging of Aβ fibrils/plaques and the diagnosis of AD. However, restricted by their poor blood-brain barrier (BBB) penetrability, short-wavelength excitation and emission, and aggregation-caused quenching (ACQ) effect, the clinically used gold-standard optical probes such as <a>thioflavin</a> T (ThT) and thioflavin S (ThS), are not effective enough in the early diagnosis of AD in vivo. Herein, we put forward an “all-in-one” design principle and demonstrate its feasibility in developing high-performance fluorescent probes which are specific to Aβ fibrils/plaques and promising for super-early in-vivo diagnosis of AD. As a proof of concept, a simple rod-like amphiphilic NIR fluorescent AIEgen, i.e., AIE-CNPy-AD, is developed by taking the specificity, BBB penetration ability, deep-tissue penetration capacity, high signal-to-noise ratio (SNR) into consideration. AIE-CNPy-AD is constituted by connecting the electron-donating and accepting moieties through single bonds and tagging with a propanesulfonate tail, giving rise to the NIR fluorescence, aggregation-induced emission (AIE) effect, amphiphilicity, and rod-like structure, which in turn result in high binding-affinity and excellent specificity to Aβ fibrils/plaques, satisfactory ability to penetrate BBB and deep tissues, ultrahigh SNR and sensitivity, and high-fidelity imaging capability. In-vitro, ex-vivo, and in-vivo <a>identifying of Aβ fibrils/plaques</a> in different strains of mice indicate that AIE-CNPy-AD holds the universality to the detection of Aβ fibrils/plaques. It is noteworthy that AIE-CNPy-AD is even able to trace the small and sparsely distributed Aβ fibrils/plaques in very young AD model mice such as 4-month-old APP/PS1 mice which are reported to be the youngest mice to have Aβ deposits in brains, suggesting its great potential in diagnosis and intervention of AD at a super-early stage.

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“…4748 The experimental results obtained with AIE-CNPy-AD is of great significance because APP/PS1 transgenic mice are found to exhibit memory deficits from 5 months old on which is early clinical presentations, confirming that AIE-CNPy-AD can diagnose AD of APP/PS1 transgenic mice during the period of early biological manifestations, prior to the appearance of clinical presentations. 43,47,49 Furthermore, as shown in Figure S15 Figure 6A, 6F, and Figure S16, the Aβ plaques were imaged with high resolution and high contrast. Moreover, it can be clearly observed that the Aβ plaques in brain slices of 6-month-old APP/PS1 transgenic mice were larger and richer in number than those of 4-month-old APP/PS1 transgenic mic, while no significant Aβ plaques were found in the brain slices of 2-month-old, 3-month-old APP/PS1 transgenic mice ( Figure S16), and all the age-matched WT mice ( Figure S17).…”

Section: In-vivo Tracking Of Aβ Plaques In App/ps1 Mice At a Super-eamentioning

confidence: 96%

Rationally Designing Simple Rod-Like Amphiphilic NIR-Emissive AIE Probes for Precise In-Vivo Detection of Aβ Fibrils/Plaques at A Super-Early Stage

Wang¹,

Mei²,

Zhang³

et al. 2021

Preprint

0

View full text Add to dashboard Cite

With increase of social aging, Alzheimer's disease (AD) has been one of the serious diseases threatening human health. The occurrence of Aβ fibrils or plaques is recognized as the hallmark of AD. Currently, optical imaging has stood out to be a promising technique for the imaging of Aβ fibrils/plaques and the diagnosis of AD. However, restricted by their poor blood-brain barrier (BBB) penetrability, short-wavelength excitation and emission, and aggregation-caused quenching (ACQ) effect, the clinically used gold-standard optical probes such as <a>thioflavin</a> T (ThT) and thioflavin S (ThS), are not effective enough in the early diagnosis of AD in vivo. Herein, we put forward an “all-in-one” design principle and demonstrate its feasibility in developing high-performance fluorescent probes which are specific to Aβ fibrils/plaques and promising for super-early in-vivo diagnosis of AD. As a proof of concept, a simple rod-like amphiphilic NIR fluorescent AIEgen, i.e., AIE-CNPy-AD, is developed by taking the specificity, BBB penetration ability, deep-tissue penetration capacity, high signal-to-noise ratio (SNR) into consideration. AIE-CNPy-AD is constituted by connecting the electron-donating and accepting moieties through single bonds and tagging with a propanesulfonate tail, giving rise to the NIR fluorescence, aggregation-induced emission (AIE) effect, amphiphilicity, and rod-like structure, which in turn result in high binding-affinity and excellent specificity to Aβ fibrils/plaques, satisfactory ability to penetrate BBB and deep tissues, ultrahigh SNR and sensitivity, and high-fidelity imaging capability. In-vitro, ex-vivo, and in-vivo <a>identifying of Aβ fibrils/plaques</a> in different strains of mice indicate that AIE-CNPy-AD holds the universality to the detection of Aβ fibrils/plaques. It is noteworthy that AIE-CNPy-AD is even able to trace the small and sparsely distributed Aβ fibrils/plaques in very young AD model mice such as 4-month-old APP/PS1 mice which are reported to be the youngest mice to have Aβ deposits in brains, suggesting its great potential in diagnosis and intervention of AD at a super-early stage.

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Early Intervention in Alzheimer’s Disease: How Early is Early Enough?

Cited by 37 publications

References 13 publications

Capsaicin consumption reduces brain amyloid-beta generation and attenuates Alzheimer’s disease-type pathology and cognitive deficits in APP/PS1 mice

Capsaicin consumption reduces brain amyloid-beta generation and attenuates Alzheimer’s disease-type pathology and cognitive deficits in APP/PS1 mice

Rationally Designing Simple Rod-Like Amphiphilic NIR-Emissive AIE Probes for Precise In-Vivo Detection of Aβ Fibrils/Plaques at A Super-Early Stage

Rationally Designing Simple Rod-Like Amphiphilic NIR-Emissive AIE Probes for Precise In-Vivo Detection of Aβ Fibrils/Plaques at A Super-Early Stage

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