An Efficient Molecular Luminophore based on Tetraphenylethylene (TPE) Enabling intracellular Detection and Therapeutic Benefits of Hydrogen Sulfide in Alzheimer’s Disease

2021 ◽  
pp. 131118
Author(s):  
Adukkadan N. Ramya ◽  
Manu M. Joseph ◽  
Varsha Karunakaran ◽  
Chekrain Valappil Shihas Ahammed ◽  
Animesh Samanta ◽  
...  
PPAR Research ◽  
2018 ◽  
Vol 2018 ◽  
pp. 1-20 ◽  
Author(s):  
Manoj Govindarajulu ◽  
Priyanka D. Pinky ◽  
Jenna Bloemer ◽  
Nila Ghanei ◽  
Vishnu Suppiramaniam ◽  
...  

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPARγ more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPARγ agonists influence various pathologies in AD with emphasis on development of novel selective PPARγ modulators.


2021 ◽  
Vol 11 (11) ◽  
pp. 1423
Author(s):  
Zackary Bowers ◽  
Panchanan Maiti ◽  
Ali Bourcier ◽  
Jarod Morse ◽  
Kenneth Jenrow ◽  
...  

Combined treatments using polyphenols and omega fatty acids provide several therapeutic benefits for a variety of age-related disorders, including Alzheimer’s disease (AD). Previously, we found a commercial product, Total Body Rhythm (TBR), consisting of tart cherry extract, a potent polyphenol, and omega fatty acids, significantly reduced memory, and neuropathological deficits in the 192 IgG-saporin mouse model of AD. The present study assessed the efficacy of TBR for treating behavioral and neuropathological deficits in the 5xFAD model of AD. Both 6- and 12-month-old 5xFAD mice and age-matched wild-type controls received TBR (60 mg/kg) or the equivalent dose of vehicle (0.5% methylcellulose) via oral administration, every other day for two months. All mice were tested in the open field (OF), novel object recognition (NOR), and the Morris water maze (MWM) tasks. In addition, neuronal morphology, neurodegeneration, Aβ plaque load, and glial activation were assessed. TBR treatment reduced memory deficits in the MWM and NOR tests and lessened anxiety levels in the OF task, mostly in the 6-month-old male mice. TBR also protected against neuron loss, reduced activation of astrocytes and microglia, primarily in 6-month-old mice, and attenuated Aβ deposition. These results suggest that the combination of tart cherry extract and omega fatty acids in TBR can reduce AD-like deficits in 5xFAD mice.


2014 ◽  
Vol 21 (10) ◽  
pp. 1665-1669 ◽  
Author(s):  
Hai-Jun Wei ◽  
Xiang Li ◽  
Xiao-Qing Tang

2020 ◽  
Vol 27 ◽  
Author(s):  
Mohamed El Massry ◽  
Lynn M. Alaeddine ◽  
Leen Ali ◽  
Celine Saad ◽  
Assaad A. Eid

: Metabolic stress, transduced as an altered cellular redox and energy status, presents as the main culprit in many diseases including diabetes. However, its role in the pathology of neurological disorders is still not fully elucidated. Metformin, a biguanide compound, is an FDA approved antidiabetic drug generally used for the treatment of type 2 diabetes. The recently described wide spectrum of action executed by this drug suggests a potential therapeutic benefit in a panoply of disorders. Current studies imply that metformin could play a neuroprotective role by reversing hallmarks of brain injury (metabolic dysfunction, neuronal dystrophy and cellular loss), in addition to cognitive and behavioral alterations that accompany the onset of certain brain diseases such as Alzheimer’s disease (AD) and depression. However, the mechanisms by which metformin exerts its protective effect in neurodegenerative disorders is not yet fully elucidated. The aim of this review is to reexamine the mechanisms through which metformin performs its function while concentrating on its effect on reestablishing homeostasis in a metabolically disturbed milieu. We will also highlight the importance of metabolic stress, not only as a component of many neurological disorders, but also as a primary driving force for neural insult. Of interest, we will explore the involvement of metabolic stress in the pathobiology of AD and depression. The derangement in major metabolic pathways including AMPK, insulin and glucose transporters will be dissected and the potential therapeutic benefits of metformin administration on the reversal of brain injury in such metabolism dependent diseases will be exposed.


2020 ◽  
Vol 35 (7) ◽  
pp. 312-317
Author(s):  
Amanda Mueller ◽  
Danielle R. Fixen

Studies have reported changes in the endocannabinoid system in the brain of patients with Alzheimer's disease (AD), playing a role in the pathophysiology of AD. Cannabinoids have been shown to have neuroprotective properties, reduce neuroinflammation, and enhance neurogenesis. Evidence suggests that the utilization of marijuana products containing both tetrahydrocannabinol (THC) and cannabidiol (CBD) or CBD alone have been effective and safe for use in older people with agitation associated with dementia. A review in 2017 summarized positive findings for therapeutic benefits of cannabinoids in agitation of AD and dementia, but there was no definitive conclusion because of varying cannabinoid products. Cannabinoids were shown to be well tolerated, with few short-term side effects. This differs from first-line medications utilized for dementia behaviors, which can have unwanted side effects. Further research regarding the safety, efficacy, and variability of these products in older people is needed.


Author(s):  
M.N. Sabbagh

On March 21, 2019, the aducanumab development team conducting the EMERGE and ENGAGE studies announced that the trials had met a pre-specified futility endpoint (1). The consequences of that announcement were far reaching, as many companies that had invested heavily in targeting amyloid were left to consider if targeting amyloid still remained a viable strategy for developing effective Alzheimer’s disease (AD) therapeutics. Following that announcement, the remaining BACE inhibitor trials announced safety concerns or efficacy concerns effectively ending elenbecestat, umibecestat, lanabecestat, atabecestat, and verubecestat as possible treatments for AD (2). Given that gamma secretase inhibitors and modulators had failed in the past, altering or halting production of amyloid appears to no longer offer viable therapeutic benefits moving forward. To further complicate this already troubling situation, the TMS/cognitive stimulation treatment combination (3) has not received FDA approval.


2021 ◽  
pp. 1-12
Author(s):  
Matthew John Mold ◽  
Adam O’Farrell ◽  
Benjamin Morris ◽  
Christopher Exley

Background: Familial Alzheimer’s disease (fAD) is driven by genetic predispositions affecting the expression and metabolism of the amyloid-β protein precursor. Aluminum is a non-essential yet biologically-reactive metal implicated in the etiology of AD. Recent research has identified aluminum intricately and unequivocally associated with amyloid-β in senile plaques and, more tentatively, co-deposited with neuropil-like threads in the brains of a Colombian cohort of donors with fAD. Objective: Herein, we have assessed the co-localization of aluminum to immunolabelled phosphorylated tau to probe the potential preferential binding of aluminum to senile plaques or neurofibrillary tangles in the same Colombian kindred. Methods: Herein, we have performed phosphorylated tau-specific immunolabelling followed by aluminum-specific fluorescence microscopy of the identical brain tissue sections via a sequential labelling method. Results: Aluminum was co-localized with immunoreactive phosphorylated tau in the brains of donors with fAD. While aluminum was predominantly co-located to neurofibrillary tangles in the temporal cortex, aluminum was more frequently co-deposited with cortical senile plaques. Conclusion: These data suggest that the co-deposition of aluminum with amyloid-β precedes that with neurofibrillary tangles. Extracellularly deposited amyloid-β may also be more immediately available to bind aluminum versus intracellular aggregates of tau. Therapeutic approaches to reduce tau have demonstrated the amelioration of its synergistic interactions with amyloid-β, ultimately reducing tau pathology and reducing neuronal loss. These data support the intricate associations of aluminum in the neuropathology of fAD, of which its subsequent reduction may further therapeutic benefits observed in ongoing clinical trials in vivo.


Author(s):  
Basma E. Aboulhoda ◽  
Laila A. Rashed ◽  
Hoda Ahmed ◽  
Eman M. M. Obaya ◽  
Walaa Ibrahim ◽  
...  

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