In vitro studies of 3-hydroxy-4-pyridinones and their glycosylated derivatives as potential agents for Alzheimer's disease

2010 ◽  
Vol 39 (6) ◽  
pp. 1604-1615 ◽  
Author(s):  
David E. Green ◽  
Meryn L. Bowen ◽  
Lauren E. Scott ◽  
Tim Storr ◽  
Michael Merkel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Vitro Studies

scholarly journals Human Neurospheroid Arrays for In Vitro Studies of Alzheimer’s Disease

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Mehdi Jorfi ◽  
Carla D’Avanzo ◽  
Rudolph E. Tanzi ◽  
Doo Yeon Kim ◽  
Daniel Irimia
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Vitro Studies

scholarly journals Copper-Targeting Approaches in Alzheimer’s Disease: How To Improve the Fallouts Obtained from in Vitro Studies

2019 ◽  
Vol 58 (20) ◽  
pp. 13509-13527 ◽  
Author(s):  
Charlène Esmieu ◽  
Djamila Guettas ◽  
Amandine Conte-Daban ◽  
Laurent Sabater ◽  
Peter Faller ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Vitro Studies

scholarly journals In vitro studies of amyloid β-protein fibril assembly and toxicity provide clues to the aetiology of Flemish variant (Ala692→Gly) Alzheimer's disease

2001 ◽  
Vol 355 (3) ◽  
pp. 869-877 ◽  
Author(s):  
Dominic M. WALSH ◽  
Dean M. HARTLEY ◽  
Margaret M. CONDRON ◽  
Dennis J. SELKOE ◽  
David B. TEPLOW
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amino Acid ◽  
Amino Acid Substitution ◽  
Amyloid Β ◽  
In Vitro Studies ◽  
Amyloid Β Protein ◽  
Wild Type ◽  
Β Protein

In a Flemish kindred, an Ala692 → Gly amino acid substitution in the amyloid β-protein precursor (AβPP) causes a form of early-onset Alzheimer's disease (AD) which displays prominent amyloid angiopathy and unusually large senile plaque cores. The mechanistic basis of this Flemish form of AD is unknown. Previous in vitro studies of amyloid β-protein (Aβ) production in HEK-293 cells transfected with cDNA encoding Flemish AβPP have shown that full-length [Aβ(1–40)] and truncated [Aβ(5–40) and Aβ(11–40)] forms of Aβ are produced. In an effort to determine how these peptides might contribute to the pathogenesis of the Flemish disease, comparative biophysical and neurotoxicity studies were performed on wild-type and Flemish Aβ(1–40), Aβ(5–40) and Aβ(11–40). The results revealed that the Flemish amino acid substitution increased the solubility of each form of peptide, decreased the rate of formation of thioflavin-T-positive assemblies, and increased the SDS-stability of peptide oligomers. Although the kinetics of peptide assembly were altered by the Ala21 → Gly substitution, all three Flemish variants formed fibrils, as did the wild-type peptides. Importantly, toxicity studies using cultured primary rat cortical cells showed that the Flemish assemblies were as potent a neurotoxin as were the wild-type assemblies. Our results are consistent with a pathogenetic process in which conformational changes in Aβ induced by the Ala21 → Gly substitution would facilitate peptide adherence to the vascular endothelium, creating nidi for amyloid growth. Increased peptide solubility and assembly stability would favour formation of larger deposits and inhibit their elimination. In addition, increased concentrations of neurotoxic assemblies would accelerate neuronal injury and death.

scholarly journals REVERSIBLE AND SPECIES-SPECIFIC DEPIGMENTATION EFFECTS OF AZD3293, A BACE INHIBITOR FOR THE TREATMENT OF ALZHEIMER’S DISEASE, ARE RELATED TO BACE2 INHIBITION AND CONFINED TO EPIDERMIS AND HAIR

2016 ◽  
pp. 1-17
Author(s):  
G. Cebers ◽  
T. Lejeune ◽  
B. Attalla ◽  
M. Soderberg ◽  
R.C. Alexander ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Study ◽  
Multiple Dose ◽  
In Vitro Studies ◽  
Beagle Dogs ◽  
Skin Biopsies ◽  
Long Evans ◽  
Dose Levels

Background: AZD3293 (also known as LY3314814) is a novel, potent, non-selective BACE1/BACE2 inhibitor currently in Phase 3 clinical development for the treatment of Alzheimer’s disease. Objectives: The purpose of these studies was to characterize the effects, putative mechanism, and reversibility of hypopigmentation following treatment with AZD3293 in pigmented Long-Evans rats, Beagle dogs, human cell cultures, and humans. Design: Nonclinical studies were conducted in Long-Evans pigmented rats, and both young and older Beagle dogs using a variety of oral dose levels of AZD3293 or AZD3839 (BACE inhibition reference compound; used in older dogs only) for dosing durations of 13 to 26 weeks. In vitro studies of normal human epidermal melanocytes and reconstituted human epidermis were also conducted. Skin biopsy data from a multiple-dose Phase 1 clinical study of AZD3293 (NCT01795339) are also reported. Setting: Nonclinical in vivo and in vitro studies were conducted in laboratory settings in the US, Canada, and France; the multiple dose clinical study was conducted in a specialized inpatient setting in the US. Participants: Beagle dogs: 13-week study N=36 young (8-10 mo) animals; 39-week study N=64 young animals; and a second 13-week study N=32 older (30-32 mo) animals. Long-Evans rats: N=68 animals. Multiple-dose clinical study: only data for subjects enrolled in Part 2 of this study are included in this report (N=16). Interventions: AZD3293 was the primary intervention used in these studies. AZD3839, a relatively BACE1-selective reference inhibitor compound was used in one group in the 13 week study in older Beagle dogs and one in vitro assessment. Finally, AZ1340, another relatively BACE1-selective reference inhibitor compound was used only in one in vitro assessment. Measurements: Measurements for the nonclinical studies in dogs and rats included macroscopic observation and assessment of skin biopsies via histopathology, immunochemistry, and electron microscopy. Measurements for the in vitro studies included melanocyte premelanosome protein (PMEL) processing, cytotoxicity, melanin synthesis, Pmel17 labeling, and melanocyte dendricity. Measurements in the clinical study included scoring of melanin content in skin biopsies taken before and after dosing with AZD3293 over 14 days at dose levels up to 150 mg. Results: Depigmentation in rats and dogs was limited to skin, hair, and mucosa with no effects on other pigmented tissues. At a cellular level depigmentation was observed within a week of treatment, whereas the appearance of depigmentation in skin and hair did not become apparent until, at earliest, 4 weeks of treatment. The depigmentation effects were reversible, not associated with degenerative or inflammatory changes, and were dose- and species-dependent in severity. Full recovery of melanization was observed at the microscopic (cellular) level and at least partial recovery was seen in the macroscopic appearance of animals by the end of the 12-week recovery period in both rats and dogs. Interestingly, no changes in melanin production or melanocyte morphology were seen in human primary melanocytes or reconstituted human epidermis in vitro. Finally, there were no changes in melanization level in skin biopsies following 12 days of daily AZD3293 treatment at doses of AZD3293 up to 150 mg/day in human subjects. Conclusions: AZD3293, a novel, potent, non-selective BACE1/BACE2 inhibitor is in development as a potentially disease-modifying treatment for Alzheimer’s disease. Chronic nonclinical studies in Beagle dogs and pigmented rats showed macroscopic and microscopic hypopigmentation effects of AZD3293 that were limited to skin, hair, and mucosa. These effects were shown to be reversible in both species. Analysis of data from nonclinical and in vitro studies suggests that hypopigmentation is caused by BACE2 inhibition resulting in accumulation of a premelanosome protein fragment, which interrupts the normal production of melanin. No macroscopic or microscopic reports of hypopigmentation were observed in a Phase 1 clinical study following 13 doses of AZD3293 over 14 days at dose levels up to 150 mg/day. These data suggest that hypopigmentation is species-specific and humans appear to be least sensitive to the depigmentation effect caused by BACE2 inhibition.

P2-264: Oxysterols, Blood-Brain Barrier (BBB) and Alzheimer's Disease: in vitro studies on endothelial cells and pericytes

2011 ◽  
Vol 7 ◽  
pp. S396-S397
Author(s):  
Julien Saint-Pol ◽  
Elodie Vandenhaute ◽  
Marie-Christine Boucau ◽  
Lucie Dehouck ◽  
Roméo Cecchelli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
In Vitro Studies ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals In vitro tau aggregation inducer molecules influence the effects of MAPT mutations on aggregation dynamics

2021 ◽  
Author(s):  
David J Ingham ◽  
Kelsey M Hillyer ◽  
Madison J McGuire ◽  
Truman Christopher Gamblin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Health Care Cost ◽  
In Vitro Studies ◽  
Chromosome 17 ◽  
Wild Type ◽  
Different Strains ◽  
Tau Aggregation ◽  
Frontotemporal Dementias

Alzheimer's disease (AD) and Alzheimer's disease related dementias (ADRDs) affect 6 million Americans and they are projected to have an estimated health care cost of $355 billion for 2021. A histopathological hallmark of AD and many ADRDs is the aberrant intracellular accumulation of the microtubule associated protein tau. These neurodegenerative disorders that contain tau aggregates are collectively known as tauopathies and recent structural studies have shown that different tauopathies are characterized by different "strains" of tau filaments. In addition, mutations in the gene that encodes for tau protein expression have been associated with a group of tauopathies known as frontotemporal dementias with Parkinsonism linked to chromosome 17 (FTDP-17 or familial frontotemporal dementia). In vitro studies often use small molecules to induce tau aggregation as tau is extremely soluble and does not spontaneously aggregate in typical lab conditions and the use of authentic filaments to conduct in vitro studies is not feasible. This study highlights how different inducer molecules can have fundamental disparities to how disease related mutations effect the aggregation dynamics of tau. Using three different classes of tau aggregation inducer molecules we characterized disease relevant mutations in tau's PGGG motifs at positions P301S, P332S, and P364S. When comparing these mutations to wild type tau, we found that depending on the type of inducer molecule used we saw fundamental differences in total aggregation, aggregation kinetics, immunoreactivity, and filament morphology. These data support the hypothesis that different tau aggregation inducer molecules make different polymorphs and perhaps structurally distinct strains.

Anti-arrhythmic Medication Propafenone a Potential Drug for Alzheimer’s Disease Inhibiting Aggregation of Aβ: In Silico and in Vitro Studies

2016 ◽  
Vol 56 (7) ◽  
pp. 1344-1356 ◽  
Author(s):  
Son Tung Ngo ◽  
Shang-Ting Fang ◽  
Shu-Hsiang Huang ◽  
Chao-Liang Chou ◽  
Pham Dinh Quoc Huy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Silico ◽  
In Vitro Studies ◽  
Potential Drug
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