Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model

Karuppagounder, Saravanan S.; Xu, Hui; Shi, Qingli; Chen, Lian H.; Pedrini, Steve; Pechman, David; Baker, Harriet; Beal, M. Flint; Gandy, Sam; Gibson, Gary E.

doi:10.1016/j.neurobiolaging.2007.12.013

Cited by 122 publications

(99 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although these mutations account for only a small subset of PD patients, sporadic cases of PD also generally show alterations in mitochondrial function, usually decreased complex I activity (25,52). This possibly occurs through aging-related loss of mitochondrial fitness or exposure to complex I toxins, such as rotenone (25), all of which increase ROS-mediated damage and accumulation of protein aggregates (13,14,(63)(64)(65).…”

Section: Discussionmentioning

confidence: 99%

Loss of Mitochondrial Function Impairs Lysosomes

Demers-Lamarche

Guillebaud

Tlili

et al. 2016

Journal of Biological Chemistry

198

193

View full text Add to dashboard Cite

Alterations in mitochondrial function, as observed in neurodegenerative diseases, lead to disrupted energy metabolism and production of damaging reactive oxygen species. Here, we demonstrate that mitochondrial dysfunction also disrupts the structure and function of lysosomes, the main degradation and recycling organelle. Specifically, inhibition of mitochondrial function, following deletion of the mitochondrial protein AIF, OPA1, or PINK1, as well as chemical inhibition of the electron transport chain, impaired lysosomal activity and caused the appearance of large lysosomal vacuoles. Importantly, our results show that lysosomal impairment is dependent on reactive oxygen species. Given that alterations in both mitochondrial function and lysosomal activity are key features of neurodegenerative diseases, this work provides important insights into the etiology of neurodegenerative diseases.A prominent feature of neurodegenerative diseases, including Parkinson disease (PD) 3 and Alzheimer disease, is the accumulation of undigested protein aggregates (1, 2). Although the underlying mechanisms are complex, several cellular alterations can cause aggregate accumulation, including impaired quality control pathways and the generation of reactive oxygen species (ROS) as a consequence of mitochondrial damage (1, 3).In healthy cells, protein aggregates and damaged cellular components are delivered to lysosomes to be degraded through a process termed autophagy (1, 2, 4, 5). As such, autophagy plays an important neuroprotective role. Nevertheless, the defects in degradation pathways observed in neurodegenerative diseases extend well beyond alterations in autophagy. Specifically, disruption of lysosomal function has been linked to neuronal loss in several neurodegenerative diseases. For example, mutations in the lysosomal ATPase ATP13A2 cause PD, whereas lysosomal dysfunction in Gaucher disease leads to Parkinsonism and the appearance of Lewy bodies (6, 7). In addition, the ␣-synuclein-containing Lewy bodies found in PD are positive for lysosomal markers, suggesting that they represent lysosomes that failed to degrade their content (8). In fact, lysosomal alterations are a common feature of PD (8 -11). Nevertheless, the pathological consequences of a loss of lysosomal function extend well beyond PD, because a wide variety of mutations that impair lysosomes and cause the accumulation of intracellular material (lysosomal storage diseases) show features of neurodegeneration (12).A second key metabolic pathway required for neuronal survival is mitochondrial activity. In fact, mitochondrial dysfunction is a common feature of neurodegenerative diseases. For example, decreased activity of complex I of the electron transport chain (ETC) is present in a number of PD cases (13, 14), whereas amyloid ␤, Tau tangles, and Htt aggregates all cause mitochondrial dysfunction (15-17). In addition, several genes mutated in PD (including PINK1, Parkin, and DJ-1) affect mitochondrial function and turnover (18 -21), whereas deregulation of mitochon...

show abstract

Section: Discussionmentioning

confidence: 99%

Loss of Mitochondrial Function Impairs Lysosomes

Demers-Lamarche

Guillebaud

Tlili

et al. 2016

Journal of Biological Chemistry

198

193

View full text Add to dashboard Cite

show abstract

“…Our previous study showed that TDP reduction is a significant biomarker for AD diagnosis [10]. The reduction of brain glucose metabolism and its possible pathogenic indicator, TDP reduction, implicate multiple pathogenic pathways in AD, including oxidative stress [11], neuroinflammation [12], and enhanced activity of glycogen synthase kinase-3 [13] and b-secretase [14]. Therefore, we hypothesized that disruption of thiamine metabolism directly contributes to AD pathogenesis by perturbing glucose utilization and by activating multiple pathophysiological cascades in the brain [15].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Long-Term Cognitive Improvement After Benfotiamine Administration in Patients with Alzheimer’s Disease

et al. 2016

View full text Add to dashboard Cite

To date, we still lack disease-modifying therapies for Alzheimer's disease (AD). Here, we report that long-term administration of benfotiamine improved the cognitive ability of patients with AD. Five patients with mild to moderate AD received oral benfotiamine (300 mg daily) over 18 months. All patients were examined by positron emission tomography with Pittsburgh compound B (PiB-PET) and exhibited positive imaging with bamyloid deposition, and three received PiB-PET imaging at follow-up. The five patients exhibited cognitive improvement as assayed by the Mini-Mental Status Examination (MMSE) with an average increase of 3.2 points at month 18 of benfotiamine administration. The three patients who received follow-up PiB-PET had a 36.7% increase in the average standardized uptake value ratio in the brain compared with that in the first scan. Importantly, the MMSE scores of these three had an average increase of 3 points during the same period. Benfotiamine significantly improved the cognitive abilities of mild to moderate AD patients independently of brain amyloid accumulation. Our study provides new insight to the development of diseasemodifying therapy.

show abstract

“…Despite of these evidences, it remains unclear whether the mitochondrial dysfunction responsible of increased ROS production in AD could be a previous step to the Aβ plaques accumulation. In this regard, some studies describe ROS production as an early event before the plaques appearance that could induce the Aβ accumulation (Caspersen et al, 2005;Manczak et al, 2006;Yao et al, 2007;Karuppagounder et al, 2009). …”

Section: In Alzheimer´s Diseasementioning

confidence: 99%

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Morán

Moreno-Lastres

Marín-Buera

et al. 2012

Free Radical Biology and Medicine

140

View full text Add to dashboard Cite

For decades mitochondria have been considered static round shaped organelles in charge of energy production. On the contrary, they are highly dynamic cellular components that undergo continuous cycles of fusion and fission influenced, for instance, by oxidative stress, cellular energy requirements, or the cell cycle state. New important functions beyond energy production have been attributed to mitochondria, such as the regulation of cell survival due to their role in the modulation of apoptosis, autophagy and aging. Primary mitochondrial diseases due to mutations in genes involved in these new mitochondrial functions, and the implication of mitochondrial dysfunction in multifactorial human pathologies like cancer, Alzheimer's and Parkinson's diseases, or diabetes has been demonstrated. Therefore, mitochondria are set at a central point of the equilibrium between health and disease, and a better understanding of mitochondrial functions will open new fields to explore the role of these mitochondrial pathways in human pathologies. The present review will dissect the relationships between the activity and assembly defects of the mitochondrial respiratory chain, oxidative damage, and alterations in mitochondrial dynamics, with special focus at their implications in neurodegeneration.

show abstract

Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model

Cited by 122 publications

References 54 publications

Loss of Mitochondrial Function Impairs Lysosomes

Loss of Mitochondrial Function Impairs Lysosomes

Long-Term Cognitive Improvement After Benfotiamine Administration in Patients with Alzheimer’s Disease

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Contact Info

Product

Resources

About