Effect of Advanced Glycation End Products on the Progression of Alzheimer’s Disease

Chou, Ping-Song; Wu, Meng‐Ni; Yang, Chen-Cheng; Shen, Cheng-Ting; Yang, Yuan‐Han

doi:10.3233/jad-190639

Cited by 36 publications

(29 citation statements)

References 31 publications

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“…Recent studies demonstrate that the development of AGE parallels the development of the cognitive deficit [11]. The AGE pentosidine is an indicator of Alzheimer's disease [79].…”

Section: Discussionmentioning

confidence: 99%

“…At autopsy, oxidative stress in the brain is as widespread as plaques and tangles [9]. Increases in Advanced Glycation End products (AGE), toxic protein modifications that are indicative of altered glucose metabolism, and their receptor, RAGE, occur in the brain [10] and periphery [11] of AD patients, in both plaques and tangles [12].…”

Section: Introductionmentioning

confidence: 99%

“…AGE are a biomarker implicated in aging and the development, or worsening of many degenerative diseases, such as diabetes, atherosclerosis, chronic renal disease, and AD. High concentrations of AGE appear predictive of long-term decline in cognition-related daily living performance in patients with AD as measured by Clinical Dementia Rating (CDR) [11] or Mini Mental Status Exam (MMSE) [34].…”

Section: Introductionmentioning

confidence: 99%

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Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial

Gibson

Luchsinger

Cirio

et al. 2020

JAD

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Background: In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer’s disease (AD) including impaired cognition, amyloid-β plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation. Objective: To collect preliminary data on feasibility, safety, and efficacy in individuals with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD in a placebo-controlled trial of benfotiamine. Methods: A twelve-month treatment with benfotiamine tested whether clinical decline would be delayed in the benfotiamine group compared to the placebo group. The primary clinical outcome was the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were the clinical dementia rating (CDR) score and fluorodeoxyglucose (FDG) uptake, measured with brain positron emission tomography (PET). Blood AGE were examined as an exploratory outcome. Results: Participants were treated with benfotiamine (34) or placebo (36). Benfotiamine treatment was safe. The increase in ADAS-Cog was 43% lower in the benfotiamine group than in the placebo group, indicating less cognitive decline, and this effect was nearly statistically significant (p = 0.125). Worsening in CDR was 77% lower (p = 0.034) in the benfotiamine group compared to the placebo group, and this effect was stronger in the APOE ɛ4 non-carriers. Benfotiamine significantly reduced increases in AGE (p = 0.044), and this effect was stronger in the APOE ɛ4 non-carriers. Exploratory analysis derivation of an FDG PET pattern score showed a treatment effect at one year (p = 0.002). Conclusion: Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD.

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“…Recent studies demonstrate that the development of AGE parallels the development of the cognitive deficit [11]. The AGE pentosidine is an indicator of Alzheimer's disease [79].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial

Gibson

Luchsinger

Cirio

et al. 2020

JAD

View full text Add to dashboard Cite

show abstract

“…Expression of receptors for advanced glycation end products (RAGE) is upregulated by abundant advanced glycation end products (AGEs) during diabetes-associated complications. The AGE–RAGE axis is involved in the onset of diseases such as Alzheimer’s disease, cancer, and osteoporosis [ 4 , 5 , 6 ]. According to recent studies, AGEs affect the glomerular filtration rate, resulting in chronic renal failure [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Methylglyoxal-Derived Advanced Glycation End Product (AGE4)-Induced Apoptosis Leads to Mitochondrial Dysfunction and Endoplasmic Reticulum Stress through the RAGE/JNK Pathway in Kidney Cells

Jeong

Lee

2021

IJMS

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Advanced glycation end products (AGEs) are formed via nonenzymatic reactions between reducing sugars and proteins. Recent studies have shown that methylglyoxal, a potent precursor for AGEs, causes a variety of biological dysfunctions, including diabetes, inflammation, renal failure, and cancer. However, little is known about the function of methylglyoxal-derived AGEs (AGE4) in kidney cells. Therefore, we verified the expression of endoplasmic reticulum (ER) stress-related genes and apoptosis markers to determine the effects of AGE4 on human proximal epithelial cells (HK-2). Moreover, our results showed that AGE4 induced the expression of apoptosis markers, such as Bax, p53, and kidney injury molecule-1, but downregulated Bcl-2 and cyclin D1 levels. AGE4 also promoted the expression of NF-κB, serving as a transcription factor, and the phosphorylation of c-Jun NH2-terminal kinase (JNK), which induced cell apoptosis and ER stress mediated by the JNK inhibitor. Furthermore, AGE4 induced mitochondrial dysfunction by inducing the permeabilization of the mitochondrial membrane and ATP synthesis. Through in vitro and in vivo experiments, this study provides a new perspective on renal dysfunction with regard to the AGE4-induced RAGE /JNK signaling pathway, which leads to renal cell apoptosis via the imbalance of mitochondrial function and ER stress in kidney damage.

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“…On the other hand, diabetes mellitus and AD are linked with the pathogenesis of advanced glycated end (AGE) products [ 11 ]. Glycated apolipoproteins are associated with a higher incidence of diabetes and Alzheimer’s disease [ 12 ], even though the mechanism has not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Structural and Functional Impairments of Reconstituted High-Density Lipoprotein by Incorporation of Recombinant β-Amyloid42

Cho

2021

Molecules

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Beta (β)-amyloid (Aβ) is a causative protein of Alzheimer’s disease (AD). In the pathogenesis of AD, the apolipoprotein (apo) A-I and high-density lipoprotein (HDL) metabolism is essential for the clearance of Aβ. In this study, recombinant Aβ42 was expressed and purified via the pET-30a expression vector and E.coli production system to elucidate the physiological effects of Aβ on HDL metabolism. The recombinant human Aβ protein (51 aa) was purified to at least 95% purity and characterized in either the lipid-free and lipid-bound states with apoA-I. Aβ was incorporated into the reconstituted HDL (rHDL) (molar ratio 95:5:1, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC):cholesterol:apoA-I) with various apoA-I:Aβ ratios from 1:0 to 1:0.5, 1:1 and 1:2. With an increasing molar ratio of Aβ, the α-helicity of apoA-I was decreased from 62% to 36% with a red shift of the Trp wavelength maximum fluorescence from 337 to 340 nm in apoA-I. The glycation reaction of apoA-I was accelerated further by the addition of Aβ. The treatment of fructose and Aβ caused more multimerization of apoA-I in the lipid-free state and in HDL. The phospholipid-binding ability of apoA-I was impaired severely by the addition of Aβ in a dose-dependent manner. The phagocytosis of LDL into macrophages was accelerated more by the presence of Aβ with the production of more oxidized species. Aβ severely impaired tissue regeneration, and a microinjection of Aβ enhanced embryotoxicity. In conclusion, the beneficial functions of apoA-I and HDL were severely impaired by the addition of Aβ via its detrimental effect on secondary structure. The impairment of HDL functionality occurred more synergistically by means of the co-addition of fructose and Aβ.

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Effect of Advanced Glycation End Products on the Progression of Alzheimer’s Disease

Cited by 36 publications

References 31 publications

Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial

Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial

Methylglyoxal-Derived Advanced Glycation End Product (AGE4)-Induced Apoptosis Leads to Mitochondrial Dysfunction and Endoplasmic Reticulum Stress through the RAGE/JNK Pathway in Kidney Cells

Structural and Functional Impairments of Reconstituted High-Density Lipoprotein by Incorporation of Recombinant β-Amyloid42

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