The role of mitochondrial defects and oxidative stress in Alzheimer’s disease

Islam, Badar Ul; Jabir, Nasimudeen R.; Tabrez, Shams

doi:10.1080/1061186x.2019.1584808

Cited by 34 publications

(23 citation statements)

References 170 publications

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“…Therefore, neuronal loss and memory deficits were frequently seen in Aβ treated cell models and Aβ overexpression animal models [7]. The full-length of APP was found in the brain and mitochondria of AD transgenic mouse [23] and phospho- APP is subsequently cleaved by the β-secretase and γ-secretase, thus results in the generation of the soluble APPβ fragment (sAPPβ) and Aβ. We showed that the expression levels of Aβ1-40 and Aβ1-42 were significantly increased in the hippocampi and platelets of APP/PS1 mice comparing to C57 wild-type mice at the same age.…”

Section: Discussionmentioning

confidence: 99%

Studies on APP metabolism related to age-associated mitochondrial dysfunction in APP/PS1 transgenic mice

Chen

et al. 2019

Aging

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The aging brain with mitochondrial dysfunction and a reduced adenosine 5’-triphosphate (ATP) has been implicated in the onset and progression of β-Amyloid (Aβ)-induced neuronal toxicity in AD. To unravel the function of ATP and the underlying mechanisms on AD development, APP/PS1 double transgenic mice and wild-type (WT) C57 mice at 6 and 10 months of age were studied. We demonstrated a decreased ATP release in the hippocampus and platelet of APP/PS1 mice, comparing to C57 mice at a relatively early age. Levels of Aβ were raised in both hippocampus and platelet of APP/PS1 mice, accompanied by a decrease of α-secretase activity and an increase of β-secretase activity. Moreover, our results presented an age-dependent rise in mitochondrial vulnerability to oxidation in APP/PS1 mice. In addition, we found decreased pSer473-Akt levels, increased GSK3β activity by inhibiting phosphorylation at Ser9 in aged APP/PS1 mice and these dysfunctions probably due to down-regulation of Bcl-2 and up-regulation of cleaved caspase-3. Therefore, we demonstrate that PI3K/Akt/GSK3β signaling pathway could be involved in Aβ-associated mitochondrial dysfunction of APP/PS1 mice and APP abnormal metabolism in platelet might provide potential biomarkers for early diagnosis of AD.

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Section: Discussionmentioning

confidence: 99%

Studies on APP metabolism related to age-associated mitochondrial dysfunction in APP/PS1 transgenic mice

Chen

et al. 2019

Aging

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“…Alzheimer's disease (AD) is the most common form of dementia in older adults accounting for 60-80% of all cases of dementia [1]. It has been reported that AD affects 2% of the population in industrialized countries [2], more than 10% of the population over the age of 65, and 50% of the population over the age of 85 [3].…”

Section: Introductionmentioning

confidence: 99%

Exploring pathways to Hospital Care for Patients with Alzheimer’s disease and related dementias in rural South Western Uganda

Kakongi

Rukundo

Gelaye

et al. 2020

BMC Health Serv Res

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Background: In order to analyze use of health services and identify sources of delays in accessing the right care for patients with Alzheimer's disease and related dementias (AD/ADRD), understanding of care seeking pathways is needed. The objectives of this study were: (i) to explore pathways to hospital care for patients with AD/ADRD and (ii) to describe challenges experienced by the patients and their families while seeking health care. Methods: Using purposive sampling, 30-in-depth, semi-structured interviews were conducted among caregivers of older adults diagnosed with dementia from rural Southwestern, Uganda. Data was analyzed using ATLAS. Ti software. Results: There was variability in pathways to care from individual to individual. There was one broader theme captured: points of care choice with four broader categories: hospitals, clinics, places of religious worship and traditional healers' shrines, each with its facilitating factors, outcomes and challenges encountered. Most of the respondents reported use of hospitals at first and second visit to the health care point but places of religious worship became more common from third to sixth health care encounter. Major improvements (58.1%) were observed on hospital use but little or no help with prayers, clinics and traditional healers. The challenges experienced with formal points of care focused on lack and cost of prescribed drugs, weakening effect of the drugs, lack of skills to manage the condition, and lack of improvement in quality of life. These challenges together with knowledge gap about the disease and belief in spiritual healing facilitated the shift from formal to informal health care pathways, more particularly the places of religious worship.

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“…Protein aggregation is suggested to be connected with environmental factors, amongst which, imbalance in metal ion homeostasis is one of the significant factor ( Huang et al, 2019 , Mezzaroba et al, 2019 , Xu et al, 2016 ). There are many scientific documents that advocate the presence of metal ions in the amyloid plaques of Alzheimer's disease, Lewy's bodies of Parkinson's disease, and in other amyloidosis markers ( Islam et al, 2019 , Jabir et al, 2018 , Khan et al, 2012 ). Moreover, fibrillation is the process where a polypeptide travels from its native conformation to fibrillar aggregates, which are predominantly cross-beta sheets rich and can easily escape to the cellular degradation process ( Mitra, 2019 , Khan et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Al (III) metal augment thermal aggregation and fibrillation in protein: Role of metal toxicity in neurological diseases

Khan

Tabrez

Rehman

et al. 2020

Saudi Journal of Biological Sciences

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Protein fibrillation is a leading cause of innumerable neurodegenerative diseases. The exact underlying mechanism associated with the formation of fibrils is yet to be known. Recently, the role of metal ions resulting into fibrillation of proteins has gained attention of the scientific community. In this piece of work, we have investigated the effect of the aluminum (Al) metal ion on the kinetics of aggregation of bovine serum albumin (BSA) protein under physiological conditions by employing several biophysical and microscopic techniques. Quenching of tryptophan fluorescence was observed along with 9 nm blue shift, demonstrating BSA becomes more hydrophobic during unfolding pathway of thermal denaturation. Moreover, ANS (8-Anilino-1-naphthalene sulfonic acid) binding shows quenching in fluorescence intensity with increasing time of incubation at 65 °C, suggesting unfolding leading to the disruption of hydrophobic patches in BSA. Besides, Thioflavin T intensity indicated a significant acceleration in BSA fibrillation at a ratio of 1:1 and 1:2 of BSA and Al (III) metal ion respectively. In addition, circular dichroism (CD) spectroscopy study revealed the transition of BSA from α-helical conformation to the β-sheet rich structure. Molecular docking analysis demonstrated significant binding affinity (−1.2 kcal/mol) of Al (III) with BSA involving Phe501, Phe506, Val575, Thr578, Gln579, Leu531 residues. Transmission electron microscopy (TEM) reaffirm augmentation of thermal-induced BSA fibril formation in the presence of Al (III) metal ions. This study highlights the metal chelating potency as the possible therapeutic target for neurological diseases.

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The role of mitochondrial defects and oxidative stress in Alzheimer’s disease

Cited by 34 publications

References 170 publications

Studies on APP metabolism related to age-associated mitochondrial dysfunction in APP/PS1 transgenic mice

Studies on APP metabolism related to age-associated mitochondrial dysfunction in APP/PS1 transgenic mice

Exploring pathways to Hospital Care for Patients with Alzheimer’s disease and related dementias in rural South Western Uganda

Al (III) metal augment thermal aggregation and fibrillation in protein: Role of metal toxicity in neurological diseases

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