Mitochondrial dysfunction, oxidative stress, neuroinflammation, and metabolic alterations in the progression of Alzheimer’s disease: A meta-analysis of in vivo magnetic resonance spectroscopy studies

Song, Tao; Song, Xiaopeng; Zhu, Chenyawen; Patrick, Regan; Skurla, Miranda; Santangelo, Isabella; Green, Morgan; Harper, David G.; Ren, Boyu; Forester, Brent P.; Öngür, Döst; Du, Fei

doi:10.1016/j.arr.2021.101503

Cited by 123 publications

(80 citation statements)

References 171 publications

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“…The pathological mechanism of AD is too complex to explain it merely with Aβ and tau accumulation. Scientists have found that many pathological processes, for instance, neural inflammation ( Leng and Edison, 2021 ), oxidative stress ( Song et al, 2021 ) and metal dysregulation ( Wang et al, 2020 ; Aaseth et al, 2021 ), involved in Aβ deposition and tau hyperphosphorylation, driving the insidious progression before AD diagnosis. Currently, the involvement of iron in the early pathology of AD has been well accepted since the discovery of the link between dysregulation of brain iron homeostasis and AD pathogenesis in 1953 ( Goodman, 1953 ).…”

Section: Impact Of Iron Overload On Alzheimer’s Disease Pathologymentioning

confidence: 99%

“…Growing evidence have proved that Aβ triggers the chain events downstream in the pathological course of AD, including tau pathology. However, other processes such as neural inflammation ( Leng and Edison, 2021 ), oxidative stress ( Song et al, 2021 ), apoptosis ( Sharma et al, 2021 ), autophagy ( Zhang et al, 2021 ) and metal dysregulation ( Wang et al, 2020 ; Aaseth et al, 2021 ) are also found in AD pathology. Some of these processes are even involved in the deposition of Aβ.…”

Section: Introductionmentioning

confidence: 99%

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Iron Dyshomeostasis and Ferroptosis: A New Alzheimer’s Disease Hypothesis?

Wang

Shen

et al. 2022

Front. Aging Neurosci.

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Iron plays a crucial role in many physiological processes of the human body, but iron is continuously deposited in the brain as we age. Early studies found iron overload is directly proportional to cognitive decline in Alzheimer’s disease (AD). Amyloid precursor protein (APP) and tau protein, both of which are related to the AD pathogenesis, are associated with brain iron metabolism. A variety of iron metabolism-related proteins have been found to be abnormally expressed in the brains of AD patients and mouse models, resulting in iron deposition and promoting AD progression. Amyloid β (Aβ) and hyperphosphorylated tau, two pathological hallmarks of AD, can also promote iron deposition in the brain, forming a vicious cycle of AD development-iron deposition. Iron deposition and the subsequent ferroptosis has been found to be a potential mechanism underlying neuronal loss in many neurodegenerative diseases. Iron chelators, antioxidants and hepcidin were found useful for treating AD, which represents an important direction for AD treatment research and drug development in the future. The review explored the deep connection between iron dysregulation and AD pathogenesis, discussed the potential of new hypothesis related to iron dyshomeostasis and ferroptosis, and summarized the therapeutics capable of targeting iron, with the expectation to draw more attention of iron dysregulation and corresponding drug development.

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Section: Impact Of Iron Overload On Alzheimer’s Disease Pathologymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Iron Dyshomeostasis and Ferroptosis: A New Alzheimer’s Disease Hypothesis?

Wang

Shen

et al. 2022

Front. Aging Neurosci.

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“…Little attention has been given to taurine concentrations measured by MRS in the brain of AD patients relative to those in healthy individuals ([ 164 , 165 ] and references therein). That is because most MRS studies were conducted at low magnetic fields.…”

Section: Brain Taurine In Diabetesmentioning

confidence: 99%

Taurine Supplementation as a Neuroprotective Strategy upon Brain Dysfunction in Metabolic Syndrome and Diabetes

2022

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Obesity, type 2 diabetes, and their associated comorbidities impact brain metabolism and function and constitute risk factors for cognitive impairment. Alterations to taurine homeostasis can impact a number of biological processes, such as osmolarity control, calcium homeostasis, and inhibitory neurotransmission, and have been reported in both metabolic and neurodegenerative disorders. Models of neurodegenerative disorders show reduced brain taurine concentrations. On the other hand, models of insulin-dependent diabetes, insulin resistance, and diet-induced obesity display taurine accumulation in the hippocampus. Given the possible cytoprotective actions of taurine, such cerebral accumulation of taurine might constitute a compensatory mechanism that attempts to prevent neurodegeneration. The present article provides an overview of brain taurine homeostasis and reviews the mechanisms by which taurine can afford neuroprotection in individuals with obesity and diabetes. We conclude that further research is needed for understanding taurine homeostasis in metabolic disorders with an impact on brain function.

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“…administration. There is increasing evidence that oxidative stress and neuroinflammation are contributing factors toward pathogenesis and progression of AD [ 2 , 36 , 37 ]. Effective mitigation of oxidative and inflammatory phenomenon could be beneficial in preventing severity and cognitive consequences of AD pathology.…”

Section: Resultsmentioning

confidence: 99%

Dipeptide of ψ-GSH Inhibits Oxidative Stress and Neuroinflammation in an Alzheimer’s Disease Mouse Model

et al. 2022

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Supplementation of glutathione (GSH) levels through varying formulations or precursors has thus far appeared to be a tenable strategy to ameliorate disease-associated oxidative stress. Metabolic liability of GSH and its precursors, i.e., hydrolysis by the ubiquitous γ-glutamyl transpeptidase (γ-GT), has limited successful clinical translation due to poor bioavailability. We addressed this problem through the design of γ-GT-resistant GSH analogue, ψ-GSH, which successfully substituted in GSH-dependent enzymatic systems and also offered promise as a therapeutic for Alzheimer’s disease (AD). With the aim to improve its bioavailability, we studied the utility of a ψ-GSH precursor, dipeptide 2, as a potential AD therapeutic. Compound 2 retains the γ-GT stable ureide linkage and the thiol group for antioxidant property. By engaging glutathione synthetase, compound 2 was able to generate ψ-GSH in vivo. It was found to be a modest cofactor of glutathione peroxidase and prevented cytotoxicity of Aβ1–42-aggregates in vitro. Studies of compound 2 in an acute AD model generated by intracerebroventricular injection of Aβ1–42 showed cognitive benefits, which were augmented by its combination with glycine along with mitigation of oxidative stress and inflammatory pathology. Collectively, these results support further optimization and evaluation of ψ-GSH dipeptide as a potential therapeutic in transgenic AD models.

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Mitochondrial dysfunction, oxidative stress, neuroinflammation, and metabolic alterations in the progression of Alzheimer’s disease: A meta-analysis of in vivo magnetic resonance spectroscopy studies

Cited by 123 publications

References 171 publications

Iron Dyshomeostasis and Ferroptosis: A New Alzheimer’s Disease Hypothesis?

Iron Dyshomeostasis and Ferroptosis: A New Alzheimer’s Disease Hypothesis?

Taurine Supplementation as a Neuroprotective Strategy upon Brain Dysfunction in Metabolic Syndrome and Diabetes

Dipeptide of ψ-GSH Inhibits Oxidative Stress and Neuroinflammation in an Alzheimer’s Disease Mouse Model

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