In Vitro and In Vivo Comparison of Curcumin-Encapsulated Chitosan-Coated Poly(lactic-co-glycolic acid) Nanoparticles and Curcumin/Hydroxypropyl-β-Cyclodextrin Inclusion Complexes Administered Intranasally as Therapeutic Strategies for Alzheimer’s Disease

Abstract The term “propagon” is used to define proteins that may transmit misfolding in vitro, in tissues or in organisms. Among propagons, misfolded tau is thought to be involved in the pathogenic mechanisms of various “tauopathies” that include Alzheimer's disease, progressive supranuclear palsy, and argyrophilic grain disease. Here, we review the available data in the literature and point out how the prion-like tau propagation has been extended from Alzheimer's disease to tauopathies. First, in Alzheimer’s disease, the progression of tau aggregation follows stereotypical anatomical stages which may be considered as spreading. The mechanisms of the propagation are now subject to intensive and controversial research. It has been shown that tau may be secreted in the interstitial fluid in an active manner as reflected by high and constant concentration of extracellular tau during Alzheimer’s pathology. Animal and cell models have been devised to mimic tau seeding and propagation, and despite their limitations, they have further supported to the prion-like propagation hypothesis. Finally, such new ways of thinking have led to different therapeutic strategies in anti-tau immunotherapy among tauopathies and have stimulated new clinical trials. However, it appears that the prion-like propagation hypothesis mainly relies on data obtained in Alzheimer’s disease. From this review, it appears that further studies are needed (1) to characterize extracellular tau species, (2) to find the right pathological tau species to target, (3) to follow in vivo tau pathology by brain imaging and biomarkers and (4) to interpret current clinical trial results aimed at reducing the progression of these pathologies. Such inputs will be essential to have a comprehensive view of these promising therapeutic strategies in tauopathies.

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Natural Anti-inflammatory compounds as Drug candidates in Alzheimer’s disease

Current Medicinal Chemistry ◽

10.2174/0929867327666200730213215 ◽

2020 ◽

Vol 27 ◽

Author(s):

Reyaz Hassan Mir ◽

Abdul Jalil Shah ◽

Roohi Mohi-ud-din ◽

Faheem Hyder Potoo ◽

Mohd. Akbar Dar ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Natural Products ◽

Protective Action ◽

New Drugs ◽

Huperzine A ◽

Brain Disorder ◽

Anti Inflammatory

: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder characterized by memory impairment, dementia, oxidative stress in elderly people. Currently, only a few drugs are available in the market with various adverse effects. So to develop new drugs with protective action against the disease, research is turning to the identification of plant products as a remedy. Natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Phytochemicals including Curcumin, Resveratrol, Quercetin, Huperzine-A, Rosmarinic acid, genistein, obovatol, and Oxyresvertarol were reported molecules for the treatment of AD. Several alkaloids such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo. In conclusion, natural products from plants represent interesting candidates for the treatment of AD. This review highlights the potential of specific compounds from natural products along with their synthetic derivatives to counteract AD in the CNS.

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Rutin and Its Cyclodextrin Inclusion Complexes: Physico-chemical Evaluation and in vitro Activity on B164A5 Murine Melanoma Cell Line

Current Pharmaceutical Biotechnology ◽

10.2174/1389201019666180209165523 ◽

2018 ◽

Vol 18 (13) ◽

pp. 1067-1077 ◽

Cited By ~ 4

Author(s):

Danciu Corina ◽

Bojin Florina ◽

Pinzaru Iulia ◽

Dehelean Cristina ◽

Ambrus Rita ◽

...

Keyword(s):

Cell Line ◽

Inclusion Complexes ◽

Melanoma Cell Line ◽

In Vitro Activity ◽

Cyclodextrin Inclusion Complexes ◽

Chemical Evaluation ◽

Cyclodextrin Inclusion ◽

Physico Chemical ◽

Murine Melanoma Cell Line

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In vivo Evaluation and Alzheimer’s Disease Treatment Outcome of siRNA Loaded Dual Targeting Drug Delivery System

Current Pharmaceutical Biotechnology ◽

10.2174/1389201020666190204141046 ◽

2019 ◽

Vol 20 (1) ◽

pp. 56-62 ◽

Cited By ~ 1

Author(s):

Chi Zhang ◽

Zhichun Gu ◽

Long Shen ◽

Xianyan Liu ◽

Houwen Lin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Treatment Outcome ◽

Neuroprotective Effect ◽

Sirna Delivery ◽

Repeated Administration ◽

Spatial Learning And Memory ◽

In Vivo Evaluation

Background: To deliver drugs to treat Alzheimer’s Disease (AD), nanoparticles should firstly penetrate through blood brain barrier, and then target neurons. Methods: Recently, we developed an Apo A-I and NL4 dual modified nanoparticle (ANNP) to deliver beta-amyloid converting enzyme 1 (BACE1) siRNA. Although promising in vitro results were obtained, the in vivo performance was not clear. Therefore, in this study, we further evaluated the in vivo neuroprotective effect and toxicity of the ANNP/siRNA. The ANNP/siRNA was 80.6 nm with good stability when incubated with serum. In vivo, the treatment with ANNP/siRNA significantly improves the spatial learning and memory of APP/PS1 double transgenic mice, as determined by mean escape latency, times of crossing the platform area during the 60 s swimming and the percentage of the distance in the target quadrant. Results and Conclusion: After the treatment, BACE1 RNA level of ANNP/siRNA group was greatly reduced, which contributed a good AD treatment outcome. Finally, after repeated administration, the ANNP/siRNA did not lead to significant change as observed by HE staining of main organs, suggesting the good biocompatibility of ANNP/siRNA. These results demonstrated that the ANNP was a good candidate for AD targeting siRNA delivery.

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Electromagnetic field in Alzheimer’s disease: a literature review of recent preclinical and clinical studies

Current Alzheimer Research ◽

10.2174/1567205017666201130085853 ◽

2020 ◽

Vol 17 ◽

Author(s):

Reem Habib Mohamad Ali Ahmad ◽

Marc Fakhoury ◽

Nada Lawand

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

In Vivo Studies ◽

Key Factors ◽

Potential Benefits ◽

Preclinical And Clinical Studies ◽

The Brain

: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive loss of neurons leading to cognitive and memory decay. The main signs of AD include the irregular extracellular accumulation of amyloidbeta (Aβ) protein in the brain and the hyper-phosphorylation of tau protein inside neurons. Changes in Aβ expression or aggregation are considered key factors in the pathophysiology of sporadic and early-onset AD and correlate with the cognitive decline seen in patients with AD. Despite decades of research, current approaches in the treatment of AD are only symptomatic in nature and are not effective in slowing or reversing the course of the disease. Encouragingly, recent evidence revealed that exposure to electromagnetic fields (EMF) can delay the development of AD and improve memory. This review paper discusses findings from in vitro and in vivo studies that investigate the link between EMF and AD at the cellular and behavioural level, and highlights the potential benefits of EMF as an innovative approach for the treatment of AD.

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Targeting PPARalpha in Alzheimer's Disease

Current Alzheimer Research ◽

10.2174/1567205014666170505094549 ◽

2018 ◽

Vol 15 (4) ◽

pp. 345-354 ◽

Cited By ~ 13

Author(s):

Barbara D'Orio ◽

Anna Fracassi ◽

Maria Paola Cerù ◽

Sandra Moreno

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Redox Homeostasis ◽

Antioxidant Response ◽

Peroxisome Proliferator ◽

Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

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Targeting Tau Hyperphosphorylation via Kinase Inhibition: Strategy to Address Alzheimer's Disease

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200106125910 ◽

2020 ◽

Vol 20 (12) ◽

pp. 1059-1073 ◽

Cited By ~ 3

Author(s):

Ahmad Abu Turab Naqvi ◽

Gulam Mustafa Hasan ◽

Md. Imtaiyaz Hassan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Tau Protein ◽

Glycogen Synthase ◽

Paired Helical Filaments ◽

Tau Hyperphosphorylation ◽

Microtubule Stabilization ◽

Extracellular Signal

Microtubule-associated protein tau is involved in the tubulin binding leading to microtubule stabilization in neuronal cells which is essential for stabilization of neuron cytoskeleton. The regulation of tau activity is accommodated by several kinases which phosphorylate tau protein on specific sites. In pathological conditions, abnormal activity of tau kinases such as glycogen synthase kinase-3 β (GSK3β), cyclin-dependent kinase 5 (CDK5), c-Jun N-terminal kinases (JNKs), extracellular signal-regulated kinase 1 and 2 (ERK1/2) and microtubule affinity regulating kinase (MARK) lead to tau hyperphosphorylation. Hyperphosphorylation of tau protein leads to aggregation of tau into paired helical filaments like structures which are major constituents of neurofibrillary tangles, a hallmark of Alzheimer’s disease. In this review, we discuss various tau protein kinases and their association with tau hyperphosphorylation. We also discuss various strategies and the advancements made in the area of Alzheimer's disease drug development by designing effective and specific inhibitors for such kinases using traditional in vitro/in vivo methods and state of the art in silico techniques.

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Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease

Cell Death and Differentiation ◽

10.1038/s41418-020-00685-9 ◽

2021 ◽

Author(s):

Wen-Dai Bao ◽

Pei Pang ◽

Xiao-Ting Zhou ◽

Fan Hu ◽

Wan Xiong ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Memory Impairment ◽

Iron Homeostasis ◽

Critical Role ◽

Gene Set Enrichment Analysis ◽

Molecular Characteristics ◽

Intracellular Iron

AbstractIron homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer’s mouse model and Alzheimer’s patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpnfl/fl mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpnfl/fl/NEXcre and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.

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