scholarly journals Neuroprotective effects of the Alzheimer's disease-related gene seladin-1

2008 ◽  
Vol 41 (5) ◽  
pp. 251-261 ◽  
Author(s):  
Alessandro Peri ◽  
Mario Serio
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Regions ◽  
Biological Properties ◽  
Neuroprotective Effects ◽  
Β Amyloid ◽  
The Relationship ◽  
Late Stages ◽  
Disease Related Gene

The endocrine and the nervous system are closely correlated throughout life, starting from the embryo and until the late stages of life. Alzheimer's disease (AD) is the most common neurodegenerative disease associated with ageing. Unfortunately, an effective way to prevent or to cure this disease does not exist, so far. There is evidence that estrogens exert neuroprotective properties, although their efficacy against AD is still a matter of debate. In 2000 a new neuroprotective gene, i.e. seladin-1 (for SELective AD INdicator-1) was identified and found to be down regulated in AD vulnerable brain regions. Seladin-1 inhibits the activation of caspase-3, a key modulator of apoptosis. This protein has also enzymatic activity. In fact, it has been demonstrated that the seladin-1 gene encodes 3-β-hydroxysterol Δ-24-reductase, which catalyzes the synthesis of cholesterol from desmosterol. In recent years, it has been demonstrated that an appropriate amount of membrane cholesterol determines the generation of a barrier against toxic insults and prevents the production of β-amyloid, the histopathological hallmark of AD. This review will summarize the studies that have been focused on the characterization of the biological properties of seladin-1 since its first identification. In particular, the relationship between seladin-1-mediated neuroprotection and estrogens, IGF1 and thyroid hormones, will be described and discussed.

MiR-335-5p Inhibits β-Amyloid (Aβ) Accumulation to Attenuate Cognitive Deficits Through Targeting c-jun-N-terminal Kinase 3 in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 93-101 ◽  
Author(s):  
Dan Wang ◽  
Zhifu Fei ◽  
Song Luo ◽  
Hai Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Western Blot ◽  
Mrna Expression ◽  
Cognitive Deficits ◽  
Protein Levels ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
The Relationship

Objectives: Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease characterized by progressive cognitive impairment and personality changes. Numerous evidences have suggested that microRNAs (miRNAs) are involved in the pathogenesis and development of AD. However, the exact role of miR-335-5p in the progression of AD is still not clearly clarified. Methods: The protein and mRNA levels were measured by western blot and RNA extraction and quantitative real-time PCR (qRT-PCR), respectively. The relationship between miR-335-5p and c-jun-N-terminal kinase 3 (JNK3) was confirmed by dual-luciferase reporter assay. SH-SY5Y cells were transfected with APP mutant gene to establish the in vitro AD cell model. Flow cytometry and western blot were performed to evaluate cell apoptosis. The APP/PS1 transgenic mice were used as an in vivo AD model. Morris water maze test was performed to assess the effect of miR- 335-5p on the cognitive deficits in APP/PS1 transgenic mice. Results: The JNK3 mRNA expression and protein levels of JNK3 and β-Amyloid (Aβ) were significantly up-regulated, and the mRNA expression of miR-335-5p was down-regulated in the brain tissues of AD patients. The expression levels of miR-335-5p and JNK3 were significantly inversely correlated. Further, the dual Luciferase assay verified the relationship between miR-335- 5p and JNK3. Overexpression of miR-335-5p significantly decreased the protein levels of JNK3 and Aβ and inhibited apoptosis in SH-SY5Y/APPswe cells, whereas the inhibition of miR-335-5p obtained the opposite results. Moreover, the overexpression of miR-335-5p remarkably improved the cognitive abilities of APP/PS1 mice. Conclusion: The results revealed that the increased JNK3 expression, negatively regulated by miR-335-5p, may be a potential mechanism that contributes to Aβ accumulation and AD progression, indicating a novel approach for AD treatment.

A Biomarker Combining Imaging and Neuropsychological Assessment for Tracking Early Alzheimer's Disease in Clinical Trials

2018 ◽  
Vol 15 (5) ◽  
pp. 429-442 ◽  
Author(s):  
Nishant Verma ◽  
S. Natasha Beretvas ◽  
Belen Pascual ◽  
Joseph C. Masdeu ◽  
Mia K. Markey ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Latent Variable ◽  
Brain Regions ◽  
Disease Assessment ◽  
Latent Variable Analysis ◽  
The Relationship ◽  
Selection Of

Background: Combining optimized cognitive (Alzheimer's Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimer's disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimer's disease. Method: Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimer's clinical trials that combines cognitive and atrophy markers. Results: Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8±4.9% specificity at 80% sensitivity) that will evolve to Alzheimer's disease for clinical trials. Conclusion: The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimer’s disease.

scholarly journals Reported Hearing Loss in Alzheimer’s Disease Is Associated With Loss of Brainstem and Cerebellar Volume

2021 ◽  
Vol 15 ◽  
Author(s):  
Daniel A. Llano ◽  
Susanna S. Kwok ◽  
Viswanath Devanarayan ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hearing Loss ◽  
Normal Subjects ◽  
Neural Substrates ◽  
Epidemiological Studies ◽  
Brain Regions ◽  
Pathological State ◽  
Brain Volumes ◽  
The Relationship

Multiple epidemiological studies have revealed an association between presbycusis and Alzheimer’s Disease (AD). Unfortunately, the neurobiological underpinnings of this relationship are not clear. It is possible that the two disorders share a common, as yet unidentified, risk factor, or that hearing loss may independently accelerate AD pathology. Here, we examined the relationship between reported hearing loss and brain volumes in normal, mild cognitive impairment (MCI) and AD subjects using a publicly available database. We found that among subjects with AD, individuals that reported hearing loss had smaller brainstem and cerebellar volumes in both hemispheres than individuals without hearing loss. In addition, we found that these brain volumes diminish in size more rapidly among normal subjects with reported hearing loss and that there was a significant interaction between cognitive diagnosis and the relationship between reported hearing loss and these brain volumes. These data suggest that hearing loss is linked to brainstem and cerebellar pathology, but only in the context of the pathological state of AD. We hypothesize that the presence of AD-related pathology in both the brainstem and cerebellum creates vulnerabilities in these brain regions to auditory deafferentation-related atrophy. These data have implications for our understanding of the potential neural substrates for interactions between hearing loss and AD.

scholarly journals Proteomic signatures of brain regions affected by tau pathology in early and late stages of Alzheimer's disease

2019 ◽  
Vol 130 ◽  
pp. 104509 ◽  
Author(s):  
Clarissa Ferolla Mendonça ◽  
Magdalena Kuras ◽  
Fábio César Sousa Nogueira ◽  
Indira Plá ◽  
Tibor Hortobágyi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Regions ◽  
Tau Pathology ◽  
Late Stages

scholarly journals Natural Scaffolds with Multi-Target Activity for the Potential Treatment of Alzheimer’s Disease

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2182 ◽  
Author(s):  
Luca Piemontese ◽  
Gabriele Vitucci ◽  
Marco Catto ◽  
Antonio Laghezza ◽  
Filippo Perna ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Structural Characteristics ◽  
Biological Properties ◽  
Cognitive Capacity ◽  
Aβ Aggregation ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Ad Therapy ◽  
Target Activity

A few symptomatic drugs are currently available for Alzheimer’s Disease (AD) therapy, but these molecules are only able to temporary improve the cognitive capacity of the patients if administered in the first stages of the pathology. Recently, important advances have been achieved about the knowledge of this complex condition, which is now considered a multi-factorial disease. Researchers are, thus, more oriented toward the preparation of molecules being able to contemporaneously act on different pathological features. To date, the inhibition of acetylcholinesterase (AChE) and of β-amyloid (Aβ) aggregation as well as the antioxidant activity and the removal and/or redistribution of metal ions at the level of the nervous system are the most common investigated targets for the treatment of AD. Since many natural compounds show multiple biological properties, a series of secondary metabolites of plants or fungi with suitable structural characteristics have been selected and assayed in order to evaluate their potential role in the preparation of multi-target agents. Out of six compounds evaluated, 1 showed the best activity as an antioxidant (EC50 = 2.6 ± 0.2 μmol/µmol of DPPH) while compound 2 proved to be effective in the inhibition of AChE (IC50 = 6.86 ± 0.67 μM) and Aβ1–40 aggregation (IC50 = 74 ± 1 μM). Furthermore, compound 6 inhibited BChE (IC50 = 1.75 ± 0.59 μM) with a good selectivity toward AChE (IC50 = 86.0 ± 15.0 μM). Moreover, preliminary tests on metal chelation suggested a possible interaction between compounds 1, 3 and 4 and copper (II). Molecules with the best multi-target profiles will be used as starting hit compounds to appropriately address future studies of Structure-Activity Relationships (SARs).

Discovery and characterization of novel indole and 7-azaindole derivatives as inhibitors of β-amyloid-42 aggregation for the treatment of Alzheimer’s disease

2017 ◽  
Vol 27 (6) ◽  
pp. 1405-1411 ◽  
Author(s):  
Nampally Sreenivasachary ◽  
Heiko Kroth ◽  
Pascal Benderitter ◽  
Anne Hamel ◽  
Yvan Varisco ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Β Amyloid

scholarly journals Following spatial Aβ aggregation dynamics in evolving Alzheimer’s disease pathology by imaging stable isotope labeling kinetics

2021 ◽  
Vol 7 (25) ◽  
pp. eabg4855
Author(s):  
Wojciech Michno ◽  
Katie M. Stringer ◽  
Thomas Enzlein ◽  
Melissa K. Passarelli ◽  
Stephane Escrig ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mass Spectrometry Imaging ◽  
Isotope Labeling ◽  
Brain Regions ◽  
Plaque Development ◽  
Aβ Aggregation ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Detailed Picture

β-Amyloid (Aβ) plaque formation is the major pathological hallmark of Alzheimer’s disease (AD) and constitutes a potentially critical, early inducer driving AD pathogenesis as it precedes other pathological events and cognitive symptoms by decades. It is therefore critical to understand how Aβ pathology is initiated and where and when distinct Aβ species aggregate. Here, we used metabolic isotope labeling in APPNL-G-F knock-in mice together with mass spectrometry imaging to monitor the earliest seeds of Aβ deposition through ongoing plaque development. This allowed visualizing Aβ aggregation dynamics within single plaques across different brain regions. We show that formation of structurally distinct plaques is associated with differential Aβ peptide deposition. Specifically, Aβ1-42 is forming an initial core structure followed by radial outgrowth and late secretion and deposition of Aβ1-38. These data describe a detailed picture of the earliest events of precipitating amyloid pathology at scales not previously possible.

scholarly journals Tau seeding activity anticipates phospho-tau pathology in Alzheimer’s disease

2018 ◽  
Author(s):  
Sarah K. Kaufman ◽  
Kelly Del Tredici ◽  
Talitha L. Thomas ◽  
Heiko Braak ◽  
Marc I. Diamond
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Visual Cortex ◽  
Brain Regions ◽  
Tau Pathology ◽  
Age Related ◽  
Important Addition ◽  
Disease Stages ◽  
Relationship Of ◽  
The Relationship

AbstractAlzheimer’s disease (AD) is characterized by accumulation of tau neurofibrillary tangles (NFTs) and, according to the prion model, transcellular propagation of pathological “seeds” may underlie its progression. Staging of NFT pathology with phospho-tau antibody is useful to classify AD and primary age-related tauopathy (PART) cases. The locus coeruleus (LC) shows the earliest phospho-tau signal, whereas other studies suggest that pathology begins in the transentorhinal/entorhinal cortices (TRE/EC). The relationship of tau seeding activity, phospho-tau pathology, and progression of neurodegeneration remains obscure. Consequently, we employed an established cellular biosensor assay to quantify tau seeding activity in fixed human tissue, in parallel with AT8 phospho-tau staining of immediately adjacent sections. We studied four brain regions from each of n=247 individuals across a range of disease stages. We detected the earliest and most robust seeding activity in the TRE/EC. The LC did not uniformly exhibit seeding activity until later NFT stages. We also detected seeding activity in the first temporal gyrus and visual cortex at stages before NFTs and/or AT8-immunopositivity were detectable. AD and putative PART cases exhibited similar patterns of seeding activity that anticipated histopathology across all NFT stages. Our findings are consistent with the prion model and suggest that pathological seeding activity begins in the TRE/EC rather than in the LC, and may offer an important addition to classical histopathology.

scholarly journals Therapeutic Potential Of Multifunctional Derivatives Of Cholinesterase Inhibitors

2020 ◽  
Vol 19 ◽  
Author(s):  
Maja Przybyłowska ◽  
Krystyna Dzierzbicka ◽  
Szymon Kowalski ◽  
Klaudia Chmielewska ◽  
Iwona Inkielewicz-Stepniak
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Amyloid Plaque ◽  
Β Amyloid ◽  
Derivatives Of ◽  
And Oxidative Stress ◽  
Pro Inflammatory Cytokines

: The aim of this work is review of tacrine analogues from the last three years, which were not included in the latest review work, donepezil and galantamine hybrids from 2015 and rivastigmine derivatives from 2014. In this account we summarize the efforts toward the development and characterization of non-toxic inhibitors of cholinesterases based on mentioned drugs with various interesting additional properties such as antioxidant, decreasing β-amyloid plaque aggregation, nitric oxide production, pro-inflammatory cytokines release, monoamine oxidase-B activity, cytotoxicity and oxidative stress in vitro and in animal model that classify these hybrids as potential multifunctional therapeutic agents for Alzheimer’s disease. Moreover, herein, we have described the cholinergic hypothesis, mechanisms of neurodegeneration and current pharmacotherapy of Alzheimer’s disease which is based on the restoration of cholinergic function through blocking enzymes that break down acetylcholine.

scholarly journals Functional Foods: An Approach to Modulate Molecular Mechanisms of Alzheimer’s Disease

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2347
Author(s):  
Anna Atlante ◽  
Giuseppina Amadoro ◽  
Antonella Bobba ◽  
Valentina Latina
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Food Product ◽  
Neuroprotective Effects ◽  
The Road ◽  
Beneficial Effects ◽  
Β Amyloid ◽  
The Brain

A new epoch is emerging with intense research on nutraceuticals, i.e., “food or food product that provides medical or health benefits including the prevention and treatment of diseases”, such as Alzheimer’s disease. Nutraceuticals act at different biochemical and metabolic levels and much evidence shows their neuroprotective effects; in particular, they are able to provide protection against mitochondrial damage, oxidative stress, toxicity of β-amyloid and Tau and cell death. They have been shown to influence the composition of the intestinal microbiota significantly contributing to the discovery that differential microorganisms composition is associated with the formation and aggregation of cerebral toxic proteins. Further, the routes of interaction between epigenetic mechanisms and the microbiota–gut–brain axis have been elucidated, thus establishing a modulatory role of diet-induced epigenetic changes of gut microbiota in shaping the brain. This review examines recent scientific literature addressing the beneficial effects of some natural products for which mechanistic evidence to prevent or slowdown AD are available. Even if the road is still long, the results are already exceptional.

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