Abstract:Alzheimer’s disease (AD) is an irreversible, age-related progressive neurological disorder, and the most common type of dementia in aged people. Neuropathological lesions of AD are neurofibrillary tangles (NFTs), and senile plaques comprise the accumulated amyloid-beta (Aβ), loaded with metal ions including Cu, Fe, or Zn. Some reports have identified metal dyshomeostasis as a neurotoxic factor of AD, among which Cu ions seem to be a central cationic metal in the formation of plaque and soluble oligomers, and h… Show more
“…38 Interestingly, Parkinson's and Alzheimer's diseases have been associated with both high and low copper levels in the brain. 39,40 Corroborating our studies, increased histone acetylation was associated with reduced HDAC levels in mouse brains as well as midbrain tissues of patients with Parkinson's disease. 41 Previous studies have shown a role for class IIa HDACs in gene expression regulation of cardiac hypertrophy and contractile dysfunction.…”
Histone deacetylases 4 and 5 are involved in the epigenetic regulation of key Wilson disease (WD) metabolic pathways and are targets sensitive to dietary modulations. Understanding epigenetic mechanisms in WD contributes to better comprehension of WD phenotypic variability and other common liver conditions.
“…38 Interestingly, Parkinson's and Alzheimer's diseases have been associated with both high and low copper levels in the brain. 39,40 Corroborating our studies, increased histone acetylation was associated with reduced HDAC levels in mouse brains as well as midbrain tissues of patients with Parkinson's disease. 41 Previous studies have shown a role for class IIa HDACs in gene expression regulation of cardiac hypertrophy and contractile dysfunction.…”
Histone deacetylases 4 and 5 are involved in the epigenetic regulation of key Wilson disease (WD) metabolic pathways and are targets sensitive to dietary modulations. Understanding epigenetic mechanisms in WD contributes to better comprehension of WD phenotypic variability and other common liver conditions.
“…Some studies reported the potential role of Aβ monomers as antioxidants, depending on the metal ion concentration in vitro [ 49 , 50 ]. In contrast, other studies showed that oligomeric Aβ, the dominant form in patients with AD, promotes ROS production in cooperation with metal ions in vitro and in vivo [ 51 , 52 , 53 , 54 ]. In addition, inhibition of the γ-secretase activity was reported to reduce the levels of ROS and oxidize proteins, and to enhance resistance to oxidative stress [ 55 ].…”
Section: Dysregulation Of Redox Homeostasis In Neurodegenerative Diseasesmentioning
Autophagy, a main degradation pathway for maintaining cellular homeostasis, and redox homeostasis have recently been considered to play protective roles in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Increased levels of reactive oxygen species (ROS) in neurons can induce mitochondrial damage and protein aggregation, thereby resulting in neurodegeneration. Oxidative stress is one of the major activation signals for the induction of autophagy. Upon activation, autophagy can remove ROS, damaged mitochondria, and aggregated proteins from the cells. Thus, autophagy can be an effective strategy to maintain redox homeostasis in the brain. However, the interaction between redox homeostasis and autophagy is not clearly elucidated. In this review, we discuss recent studies on the relationship between redox homeostasis and autophagy associated with neurodegenerative diseases and propose that autophagy induction through pharmacological intervention or genetic activation might be a promising strategy to treat these disorders.
“…Major pathological hallmarks of AD are senile plaques (SPs), composed of self-polymerized amyloid-β peptide (Aβ), and neurofibrillary tangles (NFTs) of hyperphosphorylated tau proteins (Selkoe, 1991;Hardy and Higgins, 1992). In accordance with the metal hypothesis of AD, Aβ deposition, and tau hyperphosphorylation are aggravated by metal ions, thus promoting the development of AD (Liu et al, 2011;Zhang et al, 2019;Ejaz et al, 2020;Singh et al, 2020;Spotorno et al, 2020). The "metal hypothesis" describes the unbalanced theory of the level and location of metal ions in the pathogenesis of AD (Yang et al, 2019;Patel and Aschner, 2021).…”
Alzheimer’s disease (AD) is a type of neurodegenerative disease that is associated with the accumulation of amyloid plaques. Increasing non-amyloidogenic processing and/or manipulating amyloid precursor protein signaling could reduce AD amyloid pathology and cognitive impairment. D-penicillamine (D-Pen) is a water-soluble metal chelator and can reduce the aggregation of amyloid-β (Aβ) with metals in vitro. However, the potential mechanism of D-Pen for treating neurodegenerative disorders remains unexplored. In here, a novel type of chitosan-based hydrogel to carry D-Pen was designed and the D-Pen-CS/β-glycerophosphate hydrogel were characterized by scanning electron microscopy and HPLC. Behavior tests investigated the learning and memory levels of APP/PS1 mice treated through the D-Pen hydrogel nasal delivery. In vivo and in vitro findings showed that nasal delivery of D-Pen-CS/β-GP hydrogel had properly chelated metal ions that reduced Aβ deposition. Furthermore, D-Pen mainly regulated A disintegrin and metalloprotease 10 (ADAM10) expression via melatonin receptor 1 (MTNR1α) and the downstream PKA/ERK/CREB pathway. The present data demonstrated D-Pen significantly improved the cognitive ability of APP/PS1 mice and reduced Aβ generation through activating ADAM10 and accelerating non-amyloidogenic processing. Hence, these findings indicate the potential of D-Pen as a promising agent for treating AD.
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